1543CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

1.0

0.8

0.6

0.4

0.2

0.0

0246 8 10

Time, years

Proportion remaining AIDS-free

<500

500 to 3000

3001 to 10,000

>30,000

10,001 to 30,000

FIGURE 202-22 Relationship between levels of virus and rates of disease progression. Kaplan-Meier curves

showing proportion of 1604 patients remaining AIDS-free over 10 years, stratified by baseline HIV-1 RNA categories

(copies per milliliter). (From Multicenter AIDS Cohort Study; JW Mellors, A Muñoz, JV Giorgi, JB Margolick, CJ

Tassoni, P Gupta, LA Kingsley, JA Todd, AJ Saah, R Detels, JP Phair, CR Rinaldo Jr.)

progressively in viremic HIV-infected individuals in the absence of ART.

The decline in CD4+ T cells may be gradual or abrupt, the latter usually

reflecting a significant spike in the level of plasma viremia. Most patients

are relatively asymptomatic while this progressive decline is taking place

(see below) and are often described as being in a state of clinical latency.

However, this term is misleading; it does not mean disease latency, since

progression, although slow in many cases and often without symptoms,

is generally relentless as evidenced by readily detectable plasma viremia,

during this period. Furthermore, clinical latency should not be confused with microbiologic latency since varying levels of virus replication

inevitably occur during this period of clinical latency. Even in those rare

patients, such as elite controllers, who have <50 copies of HIV RNA per

milliliter in the absence of therapy, there is virtually always some degree

of low-level ongoing virus replication.

■ ADVANCED HIV DISEASE

In untreated patients or in patients in whom therapy has not adequately controlled virus replication, after a variable period, usually

measured in years, the CD4+ T-cell count falls below a critical level

(<200/μL) and the patient becomes highly susceptible to opportunistic

disease (Fig. 202-17). For this reason, the CDC case definition of stage

3 (AIDS) includes all HIV-infected individuals >5 years of age with

CD4+ T-cell counts below this level (Table 202-2). Patients may experience constitutional signs and symptoms or may develop an opportunistic disease abruptly without any prior symptoms. The depletion of

CD4+ T cells continues to be progressive and unrelenting in this phase.

It is not uncommon for CD4+ T-cell counts in the untreated patient to

drop to as low as 10/μL or even to zero. In countries where ART as well

as prophylaxis and treatment for opportunistic infections are readily

accessible, survival is increased dramatically even in those patients

with advanced HIV disease. In contrast, untreated patients who progress to this severest form of immunodeficiency usually succumb to

opportunistic infections or neoplasms (see below).

■ LONG-TERM SURVIVORS, LONG-TERM

NONPROGRESSORS, AND ELITE CONTROLLERS

It is important to distinguish between the terms long-term survivor and

long-term nonprogressor. Long-term nonprogressors are by definition

long-term survivors; however, the reverse is not always true. Predictions from one study that antedated the availability of effective ART

estimated that ~13% of homosexual/bisexual men who were infected

at an early age may remain free of clinical AIDS for >20 years. Many

of these individuals may have gradually progressed in their degree of

immune deficiency; however, they certainly survived for a considerable

period. With the advent of effective ART, the survival of HIV-infected

individuals has dramatically increased. Early in the AIDS pandemic,

prior to the availability of antiretroviral therapy,

if a patient presented with a life-threatening

opportunistic infection, the median survival

was 26 weeks from the time of presentation.

Currently, an HIV-infected 20-year-old individual who is appropriately treated with ART

can expect to live at least 50 years according

to mathematical model projections. In the

face of ART, long-term survival is now commonplace. Definitions of long-term nonprogressors have varied considerably over the

years, and so such individuals constitute a

heterogeneous group. Long-term nonprogressors were first described in the 1990s.

Originally, individuals were considered to

be long-term nonprogressors if they had

been infected with HIV for a long period

(≥10 years), their CD4+ T-cell counts were

in the normal range, their plasma viremia

remained relatively low (undetectable to

several thousand copies of HIV RNA/ml

plasma), and they remained clinically stable

over years without receiving ART. Approximately 5–15% of HIV-infected individuals fell into this broader nonprogressor category. However, this group was rather heterogeneous and

over time a significant proportion of these individuals progressed and

ultimately required antiretroviral therapy. From this broader group, a

much smaller subgroup of “elite” controllers was identified, and they

constituted a fraction of 1% of HIV-infected individuals. These elite

controllers, by definition, have extremely low levels of plasma viremia

that is often undetectable by standard assays and normal CD4+ T-cell

counts. It is noteworthy that their HIV-specific immune response,

especially HIV-specific CD8+ CTLs that can clear infected CD4+ T

cells, is robust and clearly superior to those of HIV-infected progressors. In this group of elite controllers certain HLA class I haplotypes are

overrepresented, particularly HLA-B57-01 and HLA-B27-05. Outside

of the subgroup of elite controllers, a number of other genetic factors

have been shown to be involved to a greater or lesser degree in the control of virus replication and thus in the rate of HIV disease progression

(see “Genetic Factors in HIV-1 and AIDS Pathogenesis,” below).

■ LYMPHOID ORGANS AND HIV PATHOGENESIS

Regardless of the portal of entry of HIV, lymphoid tissues are the major

anatomic sites for the establishment and propagation of HIV infection.

Despite the use of measurements of plasma viremia to determine the

level of disease activity, virus replication occurs mainly in lymphoid

tissue and not in blood; indeed, the level of plasma viremia directly

reflects virus production in lymphoid tissue.

Some patients experience progressive generalized lymphadenopathy early in the course of the infection; others experience varying

degrees of transient lymphadenopathy. Lymphadenopathy reflects the

cellular activation and immune response to the virus in the lymphoid

tissue, which is generally characterized by follicular or germinal center

hyperplasia. Lymphoid tissue involvement is a common denominator

of virtually all patients with HIV infection, even those without easily

detectable lymphadenopathy.

Examinations of lymph tissue and peripheral blood in patients and

monkeys during various stages of HIV and SIV infection, respectively,

have led to substantial insight into the pathogenesis of HIV disease.

In most of the original human studies, peripheral lymph nodes were

the predominant sources for analyses into changes in lymphoid tissues

associated with HIV and SIV infection, whereas more recent studies

have expanded to include the GALT, where the earliest burst of virus

replication occurs associated with marked depletion of CD4+ T cells.

A variety of techniques, including sensitive molecular approaches

to measure the level of HIV DNA or RNA and imaging approaches

to visualize virus and cells in location or suspension, have been

employed to describe events associated with HIV disease. During acute

HIV infection resulting from mucosal transmission, virus replication

1544 PART 5 Infectious Diseases

FIGURE 202-23 HIV in the lymph node of an HIV-infected individual. An individual

cell infected with HIV shown expressing HIV RNA by in situ hybridization using a

radiolabeled molecular probe. Original ×500. (Reproduced with permission from G

Pantaleo et al: HIV infection is active and progressive in lymphoid tissue during the

clinically latent stage of disease. Nature 362:355, 1993.)

Primary

infection

Establishment of

infection in GALT

Destruction of

Immune System

Accelerated virus

replication

Immune activation

mediated by

cytokines and HIV

envelope-mediated

aberrant cell signaling

Massive viremia

Wide dissemination

to lymphoid organs

HIV-specific

immune response

Trapping of virus and

establishment of chronic,

persistent infection

Rapid CD4+ T-cell turnover

Partial immunologic

control of virus replication

FIGURE 202-24 Events that transpire from primary HIV infection through the establishment of chronic persistent

infection to the ultimate destruction of the immune system. See text for details. CTLs, cytolytic T lymphocytes; GALT,

gut-associated lymphoid tissue.

progressively amplifies from scattered lymphoid cells in the lamina propria of the gut to draining lymph nodes, leading to high levels of plasma

viremia. The GALT plays a major role in the amplification of virus

replication, and virus is disseminated from replication in the GALT to

peripheral lymphoid tissues. A profound degree of cellular activation

occurs within lymphoid tissues (see below) and is reflected in follicular

or germinal center hyperplasia. At this time copious amounts of extracellular virions (both infectious and defective) are trapped on the processes of the follicular dendritic cells (FDCs) that form the stromal cell

network in the light zones of lymph node germinal centers. Virions that

have bound complement components on their surfaces attach to the

surface of FDCs via interactions with complement receptors and likely

via Fc receptors that bind to antibodies that are attached to the virions.

The use of in situ hybridization techniques, including those that allow

detection of viral RNA in the context of tissue architecture, has revealed

that HIV is primarily expressed in CD4+ T cells of the paracortical area

and, to a lesser extent, in specialized CD4+ T cells (see below) in light

zones of germinal centers (Fig. 202-23). The persistence of trapped

virus on the surface of FDC likely reflects both a long-lived viral reservoir and virus that is replaced by continual expression in nearby CD4+

T cells. The trapped virus, either as whole

virion or shed envelope, also serves as a

continual activator of CD4+ T cells, thus

driving further virus replication.

During the early stages of HIV disease,

the architecture of lymphoid tissues is

generally preserved and may even be

hyperplastic owing to an increased presence of B cells and specialized CD4+

T cells called follicular helper CD4+ T

cells (TFH) in prominent germinal centers. Extracellular virions can be seen by

electron microscopy attached to FDC

processes. The trapping of antigen is

a physiologically normal function for

the FDCs, which present antigen to B

cells and secrete factors such as CXCL13

that retain B and TFH cells in the light

zones of germinal centers. These FDC

functions, along with stimulatory factors

produced by TFH cells, contribute to the

generation of B-cell memory. However,

in the case of HIV, persistent cellular

activation, resulting in a shift to secretion

of proinflammatory cytokines such as

interleukin (IL) 1β, tumor necrosis factor

(TNF) α, IFN-γ, and IL-6, can induce viral replication (see below) and

diminish the effectiveness of the immune response against the virus.

In addition, the CD4+ TFH cells that are recruited into the germinal

center to provide help to B cells in the generation of an HIV-specific

immune response are highly susceptible to infection and may be an

important component of the HIV reservoir. Thus, in HIV infection, a

normal physiologic function of the immune system, i.e., the generation

of an HIV-specific immune response that contributes to the clearance

of virus, can also have deleterious consequences.

As HIV disease progresses, the architecture of lymphoid tissues

begins to show disruption. Confocal microscopy reveals destruction

of the fibroblastic reticular cell (FRC) and FDC networks in the T-cell

zone and B-cell follicles/germinal centers, respectively. The mechanisms

of destruction are not completely understood, but they are thought to

be associated with collagen deposition causing fibrosis and a shift in

the expression of certain cytokines, namely decreases in IL-7 and lymphotoxin-α, which are critical to the maintenance of lymphoid tissues

and their lymphocyte constituents, and increased levels of transforming

growth factor (TGF)-β. As the disease progresses to an advanced stage,

there is complete disruption of the architecture of the lymphoid tissues,

accompanied by dissolution of the FRC and FDC networks. At this

point, the lymph nodes are “burnt out.” This destruction of lymphoid

tissue compounds the immunodeficiency of HIV disease and contributes both to the inability to control HIV replication and to the inability

to mount adequate immune responses against opportunistic pathogens

and vaccination. The events from primary infection to the ultimate

destruction of the immune system are illustrated in Fig. 202-24. In nonhuman primate studies and some human studies that have examined

GALT following SIV or HIV infection, the basal level of cellular activation combined with virus-mediated activation leads to the rapid infection and elimination of an estimated 50–90% of CD4+ T cells in the gut.

■ THE ROLE OF IMMUNE ACTIVATION AND

INFLAMMATION IN HIV PATHOGENESIS

Activation of the immune system and variable degrees of inflammation

are essential components of any appropriate immune response to a foreign antigen. However, immune activation and inflammation, which are

aberrant in certain individuals with HIV, play a critical role in the pathogenesis of HIV disease as well as other chronic conditions associated with

HIV infection. Immune activation and inflammation in individuals with

HIV contribute substantially to (1) the replication of HIV, (2) the induction of immune dysfunction, and (3) the increased incidence of chronic

conditions such as premature cardiovascular disease (Table 202-4).

1545CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

INDUCTION OF HIV REPLICATION BY ABERRANT IMMUNE ACTIVATION

The immune system is normally in a state of homeostasis, awaiting

perturbation by foreign antigenic stimuli. Once the immune response

deals with and clears the antigen, the system returns to relative quiescence (Chap. 349). This is generally not the case in HIV infection

where, in the untreated patient, virus replication is invariably persistent

with very few exceptions and as a result immune activation is persistent. HIV replicates most efficiently in activated CD4+ T cells; in HIV

infection, chronic activation provides the cell substrates necessary

for persistent virus replication throughout the course of HIV disease,

particularly in the untreated patient. Even in certain patients receiving

ART whose levels of plasma viremia are suppressed to <50 copies per

milliliter, there are low but detectable degrees of virus replication that

drives low-level persistent immune activation. In addition, immune

activation may result from RNA transcription of the integrated DNA of

defective proviruses. From a virologic standpoint, although quiescent

CD4+ T cells can be infected with HIV, albeit inefficiently, reverse

transcription, integration, and virus spread are much more efficient in

activated cells. Furthermore, cellular activation induces expression of

virus in cells latently infected with HIV. In essence, immune activation

and inflammation provide the engine that drives HIV replication. In

addition to endogenous factors such as cytokines, a number of exogenous factors such as other microbes that are associated with heightened

cellular activation can enhance HIV replication and thus may play a

role in HIV pathogenesis.

Co-infection with a range of viruses, such as HSV types 1 and 2,

cytomegalovirus (CMV), human herpesvirus (HHV) 6, Epstein-Barr

virus (EBV), HBV, HCV, adenovirus, and HTLV-1 have been shown

to upregulate HIV expression. In addition, infestation with nematodes

has been shown to be associated with a heightened state of immune

activation that facilitates HIV replication; in certain studies, deworming of the infected host has resulted in a decrease in plasma viremia.

Two diseases of extraordinary global health significance, malaria and

tuberculosis (TB), have been shown to increase HIV viral load in dually

infected individuals. Globally, Mycobacterium tuberculosis is the most

common opportunistic infection in HIV-infected individuals (Chap.

178). In addition to the fact that individuals with HIV are more likely to

develop active TB after exposure and to reactivate latent TB, it has been

demonstrated that active TB can accelerate the course of HIV infection.

It has also been shown that levels of plasma viremia are greatly elevated

in individuals with HIV who have active TB and who are not receiving

ART, compared with pre-TB levels and levels of viremia after successful

treatment of the active TB. The situation is similar in the interaction

between HIV and malaria parasites (Chap. 224). Acute infection with

Plasmodium falciparum of individuals with HIV increases viral load,

and the increased viral load is reversed by effective treatment of malaria.

MICROBIAL TRANSLOCATION AND PERSISTENT IMMUNE ACTIVATION

One proposed mechanism of persistent immune activation involves

the disruption of the mucosal barrier in the gut due to HIV replication

in submucosal lymphoid tissue. As a result of this disruption, there is

an increase in the products of bacteria, particularly lipopolysaccharide

(LPS), that translocate from the bowel lumen through the damaged

mucosa to the circulation, leading to persistent systemic immune

activation and inflammation. This effect can persist even after the

HIV viral load is brought to <50 copies/mL by ART. Other related

factors that are thought to contribute to the pathogenesis of HIV

include depletion in the GALT of IL-17–producing T cells, which are

responsible for defense against extracellular bacteria and fungi, as well

as alterations in gut microbiota and the metabolic pathways involved.

PERSISTENT IMMUNE ACTIVATION AND INFLAMMATION INDUCE

IMMUNE DYSFUNCTION The immune activated state in HIV infection

is reflected by hyperactivation of B cells leading to hypergammaglobulinemia; increased lymphocyte turnover; activation of monocytes;

expression of activation markers and immune checkpoint receptors

on CD4+ and CD8+ T cells; increased activation-associated cellular

apoptosis and pyroptosis; lymph node hyperplasia, particularly during

the chronic phase prior to disease progression; increased secretion of

proinflammatory cytokines, particularly IL-6 and type I interferons;

elevated levels of high-sensitivity C-reactive protein, CXC chemokine

ligand 10 (CXCL10), d-dimer, neopterin, β2

-microglobulin, soluble

(s) CD14, sTNFR, sCD27, sCD163, and sCD40L; and autoimmune

phenomena (see “Autoimmune Phenomena,” below). Even in the

absence of direct infection of a target cell, HIV envelope proteins can

interact with cellular receptors (CD4 molecules and chemokine receptors) to deliver potent activation signals resulting in calcium flux, the

phosphorylation of certain proteins involved in signal transduction,

co-localization of cytoplasmic proteins including those involved in

cell trafficking, immune dysfunction, and, under certain circumstances, apoptosis and pyroptosis. From an immunologic standpoint,

chronic exposure of the immune system to a particular antigen over

an extended period may ultimately lead to an inability to sustain an

adequate immune response to the antigen in question. In many chronic

viral infections, including HIV infection, persistent viremia is associated with “functional exhaustion” of virus-specific T cells, decreasing

their capacity to proliferate and perform effector functions. It has been

demonstrated that this phenomenon of immune exhaustion may be

mediated, at least in part, by the upregulation of inhibitory receptors on

HIV-specific T cells, such as PD-1, LAG-3 and Tim-3 that are shared

by both CD4+ and CD8+ T cells, as well as CTLA-4 on CD4+ and 2B4

and CD160 on CD8+ T cells. Furthermore, the ability of the immune

system to respond to a broad spectrum of non-HIV antigens may be

compromised if immunocompetent bystander cells are maintained in

a state of chronic activation.

The deleterious effects of chronic immune activation on the progression of HIV disease are well established. As in most conditions of

persistent antigen exposure, the host must maintain sufficient activation of antigen (HIV)-specific responses but must also prevent excessive activation and potential immune-mediated damage to tissues.

Certain studies suggest that normal immunoregulatory mechanisms

that act to keep hyperimmune activation in check, particularly CD4+,

FoxP3+, and CD25+ regulatory T cells (T-regs), may be dysfunctional

or depleted in the context of advanced HIV disease. One possibility is

a role for the inhibitory receptor LAG-3 (see below), overexpressed on

exhausted T cells and shown to inhibit the proliferation of T-regs.

Apoptosis Apoptosis is a form of programmed cell death that is a

normal mechanism for the elimination of effete cells in organogenesis

as well as in the cellular proliferation that occurs during a normal

immune response (Chap. 349). Apoptosis can occur by intrinsic or

extrinsic pathways, the latter of which is largely dependent on cellular

activation, and in this regard the aberrant cellular activation associated

with HIV disease is correlated with a heightened state of apoptosis.

HIV can trigger activation-induced cell death through the upregulation of the death receptors, such as Fas/CD95, TNFR1, or TNF-related

apoptosis-inducing ligand (TRAIL) receptors 1 and 2. Their corresponding ligands FasL, TNF, and TRAIL also are upregulated in HIV

disease. HIV-induced stress and alterations in homeostasis also can

trigger intrinsic apoptosis due to the downregulation of antiapoptotic

proteins such as Bcl-2. Other mechanisms of HIV-induced cell death

have been described, including autophagy, necrosis, necroptosis, and

pyroptosis. The phenomenon of pyroptosis, an inflammatory form of

cell death involving the upregulation of the proinflammatory enzyme

caspase 1 and release of the proinflammatory cytokines IL-1β and

IL-18, has been linked to a bystander effect of HIV replication on

TABLE 202-4 Conditions Associated with Persistent Immune

Activation and Inflammation in Patients with HIV Infection

Accelerated aging syndrome

Bone fragility

Cancers

Cardiovascular disease

Diabetes

Kidney disease

Liver disease

Neurocognitive dysfunction

1546 PART 5 Infectious Diseases

depletion of CD4+ T cells (see “Pathophysiology and Pathogenesis,”

above). The process of pyroptosis generates multimeric complexes

called inflammasomes, which can also be activated by LPS. Certain

viral gene products have been associated with enhanced susceptibility

to apoptosis; these include Env, Tat, and Vpr. In contrast, Nef has been

shown to possess antiapoptotic properties. The intensity of apoptosis

correlates with the general state of activation of the immune system

and not with the stage of disease or with viral burden. A number of

studies, including those examining lymphoid tissue, have demonstrated that the rate of apoptosis is elevated in HIV infection and that

apoptosis is seen in “bystander” cells such as CD8+ T cells and B cells

as well as in uninfected CD4+ T cells. It is likely that this bystander

apoptosis of immunocompetent cells related to immune activation

contributes to the general immunologic abnormalities in HIV disease.

MEDICAL CONDITIONS ASSOCIATED WITH PERSISTENT IMMUNE ACTIVATION AND INFLAMMATION IN HIV DISEASE It has become clear, as

the survival of HIV-infected individuals has increased, that a number

of previously unrecognized medical complications are associated with

HIV disease—and that these complications relate to chronic immune

activation and inflammation (Table 202-4). These complications can

appear even after patients have experienced years of ART-induced adequate control of viral replication (plasma viremia < 50 copies per milliliter of plasma) for several years. Other chronic conditions that have

been reported include bone fragility, certain cancers, diabetes, kidney

and liver disease, and neurocognitive dysfunction, thus presenting an

overall picture of accelerated aging.

Autoimmune Phenomena Autoimmune phenomena are commonly observed in HIV-infected individuals and they reflect, at least

in part, chronic immune activation and the dysregulation of B and

T cells. Although these phenomena usually occur in the absence

of autoimmune disease, a wide spectrum of clinical manifestations

that may be associated with autoimmunity have been described (see

“Immunologic and Rheumatologic Diseases,” below). Autoimmune

phenomena include antibodies against autoantigens expressed on

intact lymphocytes and other cells, or against proteins released from

dying cells. Antiplatelet and anti-erythrocyte antibodies have some

clinical relevance in that they may contribute to thrombocytopenia

and autoimmune hemolytic anemia, respectively, in HIV disease (see

below). Antibodies to nuclear and cytoplasmic components of cells

have been reported, as have antibodies to cardiolipin and phospholipids, as well as surface receptors, including CD4, and serum proteins.

However, these manifestations are relatively low in the era of ART.

Molecular mimicry, either from opportunistic pathogens or from HIV

itself, also is a trigger or cofactor in autoimmunity. Antibodies against

the HIV envelope proteins, especially gp41, often cross-react with host

proteins; the best-known examples are antibodies directed against the

membrane-proximal external region (MPER) of gp41 that also react

with phospholipids and cardiolipin. The phenomenon of polyreactive

HIV-specific antibodies may be beneficial to the host (see “Immune

Response to HIV,” below).

The increased occurrence and/or exacerbation of certain autoimmune diseases have been reported in HIV infection; these diseases

include psoriasis, idiopathic thrombocytopenic purpura, autoimmune

hemolytic anemia, Graves’ disease, antiphospholipid syndrome, and

primary biliary cirrhosis. Most of these manifestations were described

prior to the advent of ART and have decreased in frequency since

its widespread use. However, with increasing availability of ART, an

immune reconstitution inflammatory syndrome (IRIS) has been increasingly observed in infected individuals, particularly those with low

CD4+ T-cell counts (see below). IRIS is an autoimmune-like phenomenon characterized by a paradoxical deterioration of clinical condition,

which is usually compartmentalized to a particular organ system, in

individuals in whom ART has recently been initiated. It is associated

with a decrease in viral load and at least partial recovery of immune

competence, which is usually associated with increases in CD4+ T-cell

counts. The immunopathogenesis of this syndrome is felt to be related

to an increase in immune response against the presence of residual

antigens that are usually microbial and is most commonly seen with

underlying mycobacterial (Mycobacterium tuberculosis [TB] or avium

complex [MAC]), fungal (cryptococcal) and viral (CMV, HHV) infections. This syndrome is discussed in more detail below.

■ CYTOKINES AND OTHER SOLUBLE FACTORS IN

HIV PATHOGENESIS

The immune system is homeostatically regulated by a complex network

of immunoregulatory cytokines, which are pleiotropic and redundant and operate in an autocrine and paracrine manner. They are

expressed continuously, even during periods of apparent quiescence

of the immune system. On perturbation of the immune system by

antigenic challenge, the expression of cytokines increases to varying

degrees (Chap. 349). Cytokines that are important components of

this immunoregulatory network are thought to play major roles in

HIV disease, during both the early and chronic phases of infection.

A potent proinflammatory “cytokine storm” is induced during the

acute phase of HIV infection, likely a response by inflammatory cells

to virus replicating at very high levels. Cytokines and chemokines that

are induced during this early phase include the type I interferon IFN-α,

IL-15, and CXCL10, followed by IL-6, IL-12, and TNF-α, and a delayed

peak of the anti-inflammatory cytokine IL-10. Soluble factors of innate

immunity also are induced shortly after infection, including neopterin

and β-microglobulin. Several of these early-expressed cytokines and

factors are not downregulated following the early phase of HIV infection, as seen in other self-resolving viral infections, and persist during

the chronic phase of infection and contribute to maintaining high

levels of immune activation. Among the cytokines and factors associated with early innate immune responses, they are intended to contain

viral replication, although paradoxically most are potent inducers of

HIV expression/replication because of their ability to induce immune

activation that leads to enhanced viral production and an increase in

readily available target cells for HIV (activated CD4+ T cells). The

induction of IFN-α, one of the first cytokines induced during primary

HIV infection and an important element of innate immune sensing,

is thought to play a particularly important role in HIV pathogenesis

by inducing a large number of IFN-associated genes that activate the

immune system, alter the homeostasis of CD4+ T cells, and influence

the virus variants that are selected during the HIV transmission bottleneck. Other cytokines that are elevated during the chronic phase

of HIV infection and linked to immune activation include IFN-γ, the

CC-chemokine RANTES (CCL5), macrophage inflammatory protein

(MIP)-1β (CCL4), and IL-18.

Several specific cytokines and soluble factors have been associated

with HIV pathogenesis at various stages of disease, in various tissues or

organs, and in the regulation of HIV replication. Plasma levels of IP-10

are predictive of disease progression, whereas the proinflammatory

cytokine IL-6, marker of monocyte/macrophage activation soluble

CD14 (sCD14), and coagulation marker d-dimer are associated with

increased risk of all-cause mortality in HIV-infected individuals. In

particular, IL-6, sCD14, and d-dimer are associated with increased risk

of cardiovascular disease and other causes of death, even in individuals

receiving ART. IL-18 has also been shown to play a role in the development of the HIV-associated lipodystrophy syndrome. Elevated levels of

TNF-α and IL-6 have been demonstrated in plasma and cerebrospinal

fluid (CSF), and increased expression of TNF-α, IL-1β, IFN-γ, and IL-6

has been demonstrated in the lymph nodes of HIV-infected individuals

prior to disease progression and a shift to TGF-β in advanced disease

(see “Lymphoid Organs and HIV Pathogenesis, above). RANTES

(CCL5), MIP-1α (CCL3), and MIP-1β (CCL4) (Chap. 349) inhibit

infection by and spread of R5 HIV-1 strains, while stromal cell–derived

factor (SDF) 1 inhibits infection by and spread of X4 strains. The

mechanisms whereby the CC-chemokines RANTES (CCL5), MIP-1α

(CCL3), and MIP-1β (CCL4) inhibit infection of R5 strains of HIV, or

SDF-1 blocks X4 strains of HIV, involve blocking of the binding of the

virus to its co-receptors, the CC-chemokine receptor CCR5 and the

CXC-chemokine receptor CXCR4, respectively. Other soluble factors

that have not yet been fully characterized, such as soluble CD8 antiviral

factor (CAF), also have been shown to suppress HIV replication, independent of co-receptor usage.

1547CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

■ LYMPHOCYTE TURNOVER IN HIV INFECTION

The immune systems of patients with HIV infection are characterized

by a profound increase in lymphocyte turnover that is immediately

reduced with effective ART. Studies utilizing in vivo or in vitro labeling of lymphocytes in the S-phase of the cell cycle have demonstrated

a tight correlation between the degree of lymphocyte turnover and

plasma viremia. This increase in turnover is seen in CD4+ and CD8+

T lymphocytes as well as B lymphocytes and can be observed in peripheral blood and lymphoid tissue. Mathematical models derived from

these data suggest that one can view the lymphoid pool as consisting

of dynamically distinct subpopulations of cells that are differentially

affected by HIV infection. A major consequence of HIV infection

appears to be a shift in cells from a more quiescent pool to a pool with

a higher turnover rate. It is likely that a consequence of a higher rate

of turnover is a higher rate of cell death. It has been suggested that

the more rapid decline in CD4+ compared with CD8+ T cells may

be linked to alterations in inflammatory and homeostatic cytokines

that cause increased activation-induced death without replenishment

of CD4+ T cells. (See Table 202-5 for additional mechanisms of

depletion.)

■ THE ROLE OF VIRAL RECEPTORS AND

CO-RECEPTORS IN HIV PATHOGENESIS

CCR5 AND CXCR4 As mentioned above, HIV-1 utilizes two major

co-receptors along with CD4 to bind to, fuse with, and enter target

cells; these co-receptors are CCR5 and CXCR4, which are also receptors for certain endogenous chemokines. Strains of HIV that utilize

CCR5 as a co-receptor are referred to as R5 viruses. Strains of HIV that

utilize CXCR4 are referred to as X4 viruses. Many virus strains are dual

tropic in that they utilize both CCR5 and CXCR4; these are referred to

as R5X4 viruses.

The natural chemokine ligands for the major HIV co-receptors can

readily block entry of HIV. For example, the CC-chemokines RANTES

(CCL5), MIP-1α (CCL3), and MIP-1β (CCL4), which are the natural

ligands for CCR5, block entry of R5 viruses, whereas SDF-1, the natural ligand for CXCR4, blocks entry of X4 viruses. The mechanism

of inhibition of viral entry is a steric inhibition of binding that is not

dependent on signal transduction (Fig. 202-25).

The transmitting virus is almost invariably an R5 virus that predominates during the early stages of HIV disease, although in the era

of deep sequencing, more X4 variants have been detected in early disease than previously reported. In the absence of ART or in therapeutic

failures, there is a transition to a predominantly X4 virus in approximately half of individuals infected with subtype B virus. The transition

is often preceded by dual R5X4 strains, and detection of X4 variants

is associated with a relatively rapid decline in CD4+ T-cell counts,

increased HIV plasma viremia, and progression of disease. However,

the other half of infected individuals progress in their disease while

maintaining predominance of an R5 virus, and individuals infected

with non-subtype B clades more rarely switch from CCR5 tropism to

CXCR4 tropism than those infected with subtype B. The reason for this

difference is unclear.

The basis for the tropism of different envelope glycoproteins for

either CCR5 or CXCR4 relates to the ability of the HIV envelope,

including the third variable region (V3 loop) of gp120, to interact with

these co-receptors. In this regard, binding of gp120 to CD4 induces

a conformational change in gp120 that increases its affinity for the

relevant co-receptor. Finally, R5 viruses are more efficient in infecting

monocytes/macrophages and microglial cells of the brain (see “Neuropathogenesis in HIV Disease,” below).

THE INTEGRIN a4a7 The integrin α4β7 is an accessory receptor for

HIV. It is not essential for the binding and infection of a CD4+ T cell

by HIV; however, it likely plays an important role in the transmission

of HIV at mucosal surfaces such as the genital tract and gut and contributes somewhat to the pathogenesis of HIV disease. The integrin

α4β7, which is the gut homing receptor for peripheral T cells, binds

in its activated form to a specific tripeptide in the V2 loop of gp120,

resulting in rapid activation of leukocyte function–associated antigen 1

(LFA-1), the central integrin in the establishment of virologic synapses,

which facilitate efficient cell-to-cell spread of HIV. It has been demonstrated that α4β7high CD4+ T cells are more susceptible to productive

infection than are α4β7low–neg CD4+ T cells because this cellular subset

TABLE 202-5 Proposed Mechanisms of CD4+ T-Cell Dysfunction and

Depletion

DIRECT MECHANISMS INDIRECT MECHANISMS

Loss of plasma membrane

integrity due to viral budding

Aberrant intracellular signaling events

Accumulation of unintegrated

viral DNA

Activation of DNA-dependent

protein kinase during viral

integration into host genome

Autoimmunity

Interference with cellular RNA

processing

Innocent bystander killing of viral antigen–

coated cells

Intracellular gp120-CD4

autofusion events

Apoptosis, pyroptosis (caspase 1–associated

inflammation), autophagy

Syncytia formation Inhibition of lymphopoiesis from reduced

survival cytokines and lymphoid tissue

integrity

Activation-induced cell death

Elimination of HIV-infected cells by virusspecific immune responses

CC-Chemokine

(RANTES,

MIP-1α,

MIP-1β)

ENV

CD4

CXCR4

SDF-1

ENV

CD4

CCR5

HIV

HIV

CD4+

Target Cell

HIV

HIV

CD4+

Target Cell

A

B

FIGURE 202-25 Model for the role of co-receptors CXCR4 and CCR5 in the efficient

binding and entry of X4 (A) and R5 (B) strains of HIV-1, respectively, into CD4+ target

cells. Blocking of this initial event in the virus life cycle can be accomplished by

inhibition of binding to the co-receptor by the normal ligand for the receptor in

question. The ligand for CXCR4 is stromal cell–derived factor (SDF-1); the ligands for

CCR5 are RANTES, MIP-1α, and MIP-1β.

1548 PART 5 Infectious Diseases

is enriched with metabolically active CD4+ T cells that are CCR5high.

These cells are present in the mucosal surfaces of the gut and genital

tract. Importantly, it has been demonstrated that the virus that is transmitted during sexual exposure binds much more efficiently to α4β7

than does the virus that diversifies from the transmitting virus over

time by mutation, particularly involving the accumulation of glycogens

on the surface of the HIV envelope (see “Early Events in HIV Infection:

Primary Infection and Initial Dissemination of Virus,” above).

■ CELLULAR TARGETS OF HIV

CD4+ T lymphocytes and to a lesser extent CD4+ cells of the myeloid

lineage are the principal targets of HIV and are the only cells that can

be productively infected with HIV. Circulating DCs have been reported

to express low levels of CD4, although high expression of the restriction factor SAMHD1 in myeloid (mDC) and plasmacytoid (pDC) DCs

limits HIV replication in these cells by depleting intracellular pools

of dNTPs and directly degrading viral RNA. Epidermal Langerhans

cells express CD4 and have been infected by HIV in vivo, although

they too restrict replication by high expression of the host restriction

factor, langerin. As has been shown in vivo for DCs, FDCs, and B cells,

Langerhans cells are more likely to bind and transfer virus to activated

CD4+ T cells than to be productively infected themselves.

Of potential clinical relevance is the demonstration that thymic

precursor cells, which were assumed to be negative for CD3, CD4,

and CD8 molecules, express low levels of CD4 and can be infected

with HIV in vitro. In addition, human thymic epithelial cells transplanted into an immunodeficient mouse can be infected with HIV

by direct inoculation of virus into the thymus. Since these cells may

play a role in the normal regeneration of CD4+ T cells, it is possible

that their infection and depletion contribute, at least in part, to

the impaired ability of the CD4+ T-cell pool to completely reconstitute

itself in certain infected individuals in whom ART has suppressed

plasma viremia to below the level of detection (see below). In addition,

CD34+ monocyte precursor cells have been shown to be infected in

vivo in patients with advanced HIV disease. It is likely that these cells

express low levels of CD4, and therefore it is not essential to invoke

CD4-independent mechanisms to explain the infection. The clinical

relevance of this finding is unclear.

■ QUALITATIVE AND QUANTITATIVE

ABNORMALITIES OF MONONUCLEAR CELLS

CD4+ T Cells The primary immunopathogenic lesion in HIV

infection involves CD4+ T cells, and the range of CD4+ T-cell abnormalities in advanced HIV infection is broad. The defects are both

quantitative and qualitative and ultimately impact virtually every limb

of the immune system, indicating the critical dependence of the integrity of the immune system on the inducer/helper function of CD4+ T

cells. In advanced HIV disease, most of the observed immune defects

can ultimately be explained by the quantitative depletion of CD4+ T

cells. However, T-cell dysfunction can be demonstrated in patients

early in the course of infection, even when the CD4+ T-cell count is

in the low-normal range. The degree and spectrum of dysfunctions

increase as the disease progresses, reflecting the range of CD4+ T-cell

functional heterogeneity, especially in lymphoid tissues. One of the

first sites of intense HIV replication is in the GALT where CD4+ TH17

cells reside; they are important for host defense against extracellular

pathogens in the intestinal mucosa and help maintain the integrity of

the gut epithelium. In HIV infection, they are depleted by direct and

indirect effects of viral replication and cause loss of gut homeostasis

and integrity, as well as a shift toward a TH1 phenotype. Studies have

shown that even after many years of ART, normalization of the CD4+ T

cells in the GALT remains incomplete. In lymph nodes, HIV perturbs

another important subset of the CD4+ helper T lineage, namely TFH

cells (see “Lymphoid Organs and HIV Pathogenesis,” above). TFH cells,

which are derived either directly from naïve CD4+ T cells or from

other TH precursors, migrate into B-cell follicles during germinal center

reactions and provide help to antigen-specific B cells through cell–cell

interactions and secretion of cytokines to which B cells respond, the

most important of which is IL-21. In addition, it has been shown that

HIV-infected individuals with broadly neutralizing antibodies have

higher frequencies of memory TFH CD4+ T cells. As with TH17 cells,

TFH cells are highly susceptible to HIV infection. However, in contrast to

TH17 and most other CD4+ T-cell subsets, the number of TFH cells

is increased in lymph nodes of HIV-infected individuals, especially

those who are viremic. It is unclear whether this increase is helpful to

responding B cells, although the likely outcome is that the increase in

numbers is detrimental to the quality of the humoral immune response

against HIV (see “Immune Response to HIV,” below). In addition,

defects of central memory cells are a critical component of HIV immunopathogenesis. The progressive loss of antigen-specific CD4+ T cells

has important implications for the control of HIV infection. In this

regard, there is a correlation between the maintenance of HIV-specific

CD4+ T-cell proliferative responses and improved control of infection.

Essentially every T-cell function has been reported to be abnormal

at some stage of HIV infection. Loss of polyfunctional HIV-specific

CD4+ T cells, especially those that produce IL-2, occurs early in disease, whereas IFN-producing CD4+ T cells are maintained longer and

do not correlate with control of HIV viremia. Other abnormalities

include impaired expression of IL-2 receptors, defective IL-2 production, reduced expression of the IL-7 receptor (CD127), and a decreased

proportion of CD4+ T cells that express CD28, a major co-stimulatory

molecule necessary for the normal activation of T cells, which is also

depleted as a result of aging. Cells lacking expression of CD28 do not

respond normally to activation signals and may express markers of

terminal activation including HLA-DR, CD38, and CD45RO. As mentioned above (“The Role of Immune Activation and Inflammation in

HIV Pathogenesis”), a subset of CD4+ T cells referred to as T regulatory

cells, or T-regs, may be involved in damping aberrant immune activation that propagates HIV replication. The presence of these T-reg cells

correlates with lower viral loads and higher CD4+/CD8+ T-cell ratios.

A loss of this T-reg capability with advanced disease may be detrimental to the control of virus replication.

It is difficult to explain completely the profound immunodeficiency

noted in HIV-infected individuals solely based on direct infection and

quantitative depletion of CD4+ T cells. This is particularly apparent

during the early stages of HIV disease, when CD4+ T-cell numbers

may be only marginally decreased. In this regard, it is likely that CD4+

T-cell dysfunction results from a combination of depletion of cells due

to direct infection of the cell and a number of virus-related but indirect

effects on the cell such as elimination of “innocent bystander cells”

(Table 202-5). Several of these effects have been demonstrated ex vivo

and/or by the analysis of cells isolated from the peripheral blood. Soluble viral proteins, particularly gp120, can bind with high affinity to the

CD4 molecules on uninfected T cells and monocytes; in addition, virus

and/or viral proteins can bind to DCs or FDCs. HIV-specific antibody

can recognize these bound molecules and potentially collaborate in the

elimination of the cells by ADCC. HIV envelope glycoproteins gp120

and gp160 manifest high-affinity binding to the CD4 molecule as well

as to various chemokine receptors. Intracellular signals transduced by

gp120 through both CD4 and CCR5/CXCR4 have been associated with

a number of immunopathogenic processes including anergy, apoptosis, and abnormalities of cell trafficking. The molecular mechanisms

responsible for these abnormalities include dysregulation of the T-cell

receptor–phosphoinositide pathway, p56lck activation, phosphorylation of focal adhesion kinase, activation of the MAP kinase and ras signaling pathways, and downregulation of the co-stimulatory molecules

CD40 ligand and CD80.

The inexorable decline in CD4+ T-cell counts that occurs in most

untreated HIV-infected individuals may result in part from the inability of the immune system to regenerate over an extended period of time

the rapidly turning over CD4+ T-cell pool efficiently enough to compensate for both HIV-mediated and naturally occurring attrition of

cells. In this regard, the degree and duration of decline of CD4+ T cells

at the time of initiation of therapy is an important predictor of the restoration of these cells. A person who maintains a very low CD4+ T-cell

count for a considerable period before the initiation of ART almost

invariably has an incomplete reconstitution of such cells. At least two

major mechanisms may contribute to the failure of the CD4+ T-cell

1549CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

pool to reconstitute itself adequately over the course of HIV infection.

The first is the destruction of lymphoid precursor cells, including

thymic and bone marrow progenitor cells; the other is the gradual

disruption of the lymphoid tissue architecture and microenvironment,

which is essential for efficient regeneration of immunocompetent cells.

Finally, during the advanced stages of CD4+ T lymphopenia, there are

increased serum levels of the homeostatic cytokine IL-7. It was initially

felt that this elevation was a homeostatic response to the lymphopenia;

however, recent findings suggest that the increase in serum IL-7 was a

result of reduced utilization of the cytokine related to the loss of cells

expressing the IL-7 receptor, CD127, which serves as a normal physiologic regulator of IL-7 production.

CD8+ T Cells A relative CD8+ T lymphocytosis is generally

associated with high levels of HIV plasma viremia and likely reflects

an immune response to the virus as well as dysregulated homeostasis

associated with generalized immune activation. During the late stages

of HIV infection, there may be a significant reduction in the numbers of CD8+ T cells despite the presence of high levels of viremia.

HIV-specific CD8+ CTLs have been demonstrated in HIV-infected

individuals early in the course of disease, and their emergence often

coincides with a decrease in plasma viremia—an observation that is a

factor in the proposal that virus-specific CTLs can control HIV disease

for a finite period of time in a certain percentage of infected individuals. However, emergence of HIV escape mutants that ultimately

evade these HIV-specific CD8+ T cells has been described in most

HIV-infected individuals who are not receiving ART. In addition, as

the disease progresses, the functional capability of these cells gradually

decreases, at least in part due to the persistent nature of HIV infection

that causes functional exhaustion via the upregulation of inhibitory

receptors such as PD-1, TIGIT, LAG-3, and TIM-3 on HIV-specific

CD8+ T cells (see “The Role of Immune Activation and Inflammation

in HIV Pathogenesis,” above). As chronic immune activation persists,

there are also systemic effects on CD8+ T cells, such that as a population they assume an abnormal phenotype characterized by expression

of activation markers such as co-expression of HLA-DR and CD38

with an absence of expression of the IL-2 receptor (CD25) and a

reduced expression of the IL-7 receptor (CD127). In addition, CD8+ T

cells lacking CD28 expression are increased in HIV disease, reflecting

a skewed expansion of a less differentiated CD8+ T-cell subset. This

skewing of subsets is also associated with diminished polyfunctionality, a qualitative difference that distinguishes elite controllers from

progressors. Elite controllers can also be distinguished from progressors by the maintenance in the former of a high proliferative capacity

of their HIV-specific CD8+ T cells coupled to increases in perforin

expression and elimination of infected targets, characteristics that are

markedly diminished in advanced HIV disease. It has been reported

that the phenotype of CD8+ T cells in HIV-infected individuals may

be of prognostic significance. Those individuals whose CD8+ T cells

developed a phenotype of HLA-DR+/CD38– following seroconversion

had stabilization of their CD4+ T-cell counts, whereas those whose

CD8+ T cells developed a phenotype of HLA-DR+/CD38+ had a more

aggressive course and a poorer prognosis. In addition to the defects in

HIV-specific CD8+ CTLs, functional defects in other MHC-restricted

CTLs, such as those directed against influenza and CMV, have been

demonstrated. CD8+ T cells secrete a variety of soluble factors that

inhibit HIV replication, including the CC-chemokines RANTES

(CCL5), MIP-1α (CCL3), and MIP-1β (CCL4) and potentially several

yet-unidentified factors. The presence of high levels of HIV viremia in

vivo as well as exposure of CD8+ T cells in vitro to HIV envelope, both

of which are associated with aberrant immune activation, have been

shown to be associated with a variety of cellular functional abnormalities. Furthermore, since the integrity of CD8+ T-cell function depends

in part on adequate inductive signals from CD4+ T cells, the defect in

CD8+ CTLs is likely compounded by the quantitative loss and qualitative dysfunction of CD4+ T cells.

B Cells The predominant defect in B cells from HIV-infected

individuals is one of aberrant cellular activation, which is reflected by

increased propensity to terminal differentiation and immunoglobulin

secretion, as well as increased expression of markers of activation

and exhaustion. As a result of activation and differentiation in vivo

and induction of inhibitory pathways of regulation, B cells from HIV

viremic patients manifest a decreased capacity to undergo cell signaling

and mount a proliferative response ex vivo. B cells from HIV-infected

individuals manifest enhanced spontaneous secretion of immunoglobulins in vitro, a process that reflects their highly differentiated state in

vivo. There is also an increased incidence of EBV-related B-cell lymphomas in HIV-infected individuals that are likely due to combined

effects of defective T-cell immune surveillance and increased B-cell

turnover that increases the risk of oncogenesis. Untransformed B cells

cannot be infected with HIV, although HIV or its products can activate

B cells directly. B cells from patients with high levels of viremia bind

virions to their surface via the CD21 complement receptor. It is likely

that in vivo activation of B cells by replication-competent or defective virus as well as viral products during the viremic state accounts

at least in part for their activated phenotype. B-cell subpopulations

from HIV-infected individuals undergo a number of changes over the

course of HIV disease, including the attrition of resting memory B

cells and replacement with several aberrant memory and differentiated

B-cell subpopulations that collectively express reduced levels of CD21

and either increased expression of activation markers or inhibitory

receptors associated with functional exhaustion. The more activated

and differentiated B cells are also responsible for increased secretion

of immunoglobulins and increased susceptibility to Fas-mediated

apoptosis. In more advanced disease, there is also the appearance of

immature B cells associated with CD4+ T-cell lymphopenia. Despite

increased frequencies of germinal center B cells and CD4+ TFH cells,

both of which are required for effective humoral immunity, cognate

B-cell–CD4+ T-cell interactions in lymphoid tissues are perturbed in

HIV-infected individuals, especially those with persistent viremia. In

vivo, the aberrant activated state of B cells manifests itself by hypergammaglobulinemia and by the presence of circulating immune complexes

that bind the B cells and restrict their capacity to respond to further

stimulation. HIV-infected individuals respond poorly to primary and

secondary immunizations with protein and polysaccharide antigens.

Using immunization with influenza vaccine, it has been demonstrated

that there is a memory B-cell defect in HIV-infected individuals, particularly those with high levels of HIV viremia. There is also evidence

that responses to HIV and non-HIV antigens in infected individuals,

especially those who remain viremic, are enriched in abnormal subsets

of B cells that either are highly prone to apoptosis or show signs of

functional exhaustion. Taken together, these B-cell defects are likely

responsible at least in part for the inadequate humoral response to

HIV as well as to decreased response to vaccinations and the increase

in certain bacterial infections seen in advanced HIV disease in adults.

In addition, they likely contribute to the inadequacy of host defenses

against bacterial infections that play a role in the increased morbidity

and mortality of HIV-infected children. The absolute number of circulating B cells also may be depressed in HIV infection; this phenomenon likely reflects increased activation-induced apoptosis as well as

a redistribution of cells out of the circulation and into the lymphoid

tissue—phenomena that are associated with ongoing viral replication.

Monocytes/Macrophages Circulating monocytes are generally

normal in number in HIV-infected individuals; however, there is evidence of increased activation within this lineage. The increased level

of sCD14 and other biomarkers (see above) reported in HIV-infected

individuals is an indirect marker of monocyte activation in vivo.

Levels of sCD14 can remain elevated in individuals whose plasma

viremia has been suppressed by ART for several years, an indicator of

the residual immune activation and inflammation observed in HIV

infection and effects on the monocyte/macrophage lineage. A number

of other abnormalities of circulating monocytes have been reported

in HIV-infected individuals, many of which may be related directly

or indirectly to aberrant in vivo immune activation. In this regard,

increased levels of lipopolysaccharide (LPS) are found in the sera of

HIV-infected individuals due, at least in part, to translocation across

1550 PART 5 Infectious Diseases

the gut mucosal barrier (see above). LPS is a highly inflammatory bacterial product that preferentially binds to macrophages through CD14

and Toll-like receptors, resulting in cellular activation. In the peripheral blood, expansion of monocytes that express the intermediate

and non-classical marker CD16 and markers of activation (HLA-DR)

and stimulation (CD40 and CD86) has been described, especially

in viremic individuals. Activated monocytes are also responsible for

secretion of inflammatory cytokines and chemokines observed in HIV

infection, including CXCL10, IL-1β, and IL-6. Monocytes express the

CD4 molecule and several co-receptors for HIV on their surface, and

thus are potential targets of HIV infection. However, in vivo infection

of circulating monocytes is difficult to demonstrate, although infection

of tissue macrophages and macrophage-lineage cells in the brain (infiltrating macrophages or resident microglial cells) and lung (pulmonary

alveolar macrophages) can be demonstrated easily. Tissue macrophages

are an important source of HIV during the inflammatory response

associated with opportunistic infections and can serve as persistent

reservoirs of HIV infection, thus representing an obstacle to the eradication of HIV by antiretroviral drugs.

Dendritic and Langerhans Cells DCs and Langerhans cells are

not productively infected with HIV, likely in part due to their expression of host restriction factors, including APOBEC3G and SAMHD1

(see above). However, they are thought to play an important role in the

initiation of HIV infection by virtue of the ability of HIV to bind to

cell-surface C-type lectin receptors, particularly DC-SIGN (see above)

and langerin. However, while langerin provides a host barrier for replication by trafficking HIV to acidic compartments for degradation,

DC-SIGN retains HIV in early endosomal compartments. This allows

efficient presentation of intact virus to CD4+ T-cell targets that become

infected; complexes of infected CD4+ T cells and DCs provide an

optimal microenvironment for virus replication. Furthermore, pDCs

secrete large amounts of IFN-α in response to viral infections and

as such play an important role in innate sensing of HIV during early

phase of infection. The numbers of circulating pDCs and mDCs are

decreased in HIV infection through mechanisms that remain unclear,

although several studies have shown increased lymphoid tissue recruitment of DCs associated with lymphoid hyperplasia and inflammation.

The mDCs are also involved in the initiation of adaptive immunity

in draining lymph nodes by presenting antigen to T cells and B cells,

as well as by secreting cytokines such as IL-12, IL-15, and IL-18 that

activate other immune cells, although these functions are perturbed in

HIV infection.

Natural Killer Cells and Innate Lymphoid Cells NK cells

represent the prototypical member of innate lymphoid cells (ILCs)

that collectively provide tissue homeostasis and immunosurveillance

against virus-infected cells, certain tumor cells, and allogeneic cells

(Chap. 349). There are no convincing data that HIV productively

infects NK cells in vivo; however, functional abnormalities in NK cells

have been observed throughout the course of HIV disease, and the

severity of these abnormalities increases as disease progresses. NK

cells are part of the innate immune system and act by direct killing of

infected cells and secretion of antiviral cytokines and chemokines. In

early HIV infection there is an increase in the activation of NK cells,

and the capacity to secrete IFN-γ is maintained, although they manifest

reduced cytotoxic function as a result of altered maturation. During

chronic HIV infection, both NK cell cytotoxicity and cytokine secretion become impaired. Given that HIV infection of target cells downregulates HLA-A and B, but not HLA-C and D molecules, this may

explain in part the relative inability of NK cells to kill HIV-infected

target cells. However, the NK cell impairments, especially in patients

with high levels of virus replication, are associated with an expansion

of an “anergic” CD56–/CD16+ NK cell subset. This abnormal subset

of NK cells manifests an increased expression of inhibitory NK cell

receptors (iNKRs) and a substantial decrease in expression of natural

cytotoxicity receptors (NCRs) and shows a markedly impaired lytic

activity. The overrepresentation of this abnormal subset of NK cells

may explain in part the observed defects in NK cell function in HIVinfected individuals and likely begins to occur during primary

infection. The relative expression of iNKRs and NCRs—as well as

their ligands, which include HLA class I molecules—has an impact

on the antiviral functions associated with NK cells, including direct

killing and ADCC. Polymorphisms in iNKR and NCR alleles have been

linked to HIV-1 disease outcomes, and there are indications that the

early control of HIV may be mediated by cytotoxic NK cell-mediated

responses. NK cells may also serve as sources of HIV-inhibitory soluble

factors, including CC-chemokines such as MIP-1α (CCL3), MIP-1β

(CCL4), and RANTES (CCL5). Finally, both inflammatory cytokines

and alterations in the GALT of HIV infected individuals disrupt NK

cells and other ILCs.

■ GENETIC FACTORS IN HIV-1 AND AIDS

PATHOGENESIS

Candidate gene approaches and genome-wide association studies

(GWAS) have identified polymorphisms in host genes that contribute

to inter-individual variation in (1) the risk of acquiring HIV, (2) the

steady-state levels of HIV that are established soon after infection

(virologic set point), (3) the rate at which untreated HIV infection

progresses to AIDS defined by a CD4+ T-cell count that is lower

than  200  cells/mm3

 and/or development of AIDS-defining illnesses,

(4) the level of immune reconstitution (e.g., CD4+ cell counts) achieved

and risk of non-AIDS-associated diseases after initiation of virally

suppressive antiretroviral therapy (ART), and (5) adverse reactions to

antiretroviral agents. The key polymorphisms that influence these five

outcomes are summarized in Table 202-6, and their identification has

greatly advanced our understanding of the genes that influence HIVAIDS pathogenesis and ART-associated immune reconstitution. Of

particular interest are polymorphisms in two chromosomal regions,

as they are associated with consistent effects on HIV acquisition, virologic set point, and/or rates of HIV disease progression: the region in

chromosome 3 that includes the gene that encodes the HIV co-receptor

CC chemokine receptor 5 (CCR5) and the major histocompatibility locus

(MHC) in chromosome 6 (Fig. 202-26).

GENETICS OF CCR5: FROM BENCH TO BEDSIDE While the discovery

of CCR5 as a major co-receptor for cell entry of HIV-1 was established

by in vitro studies, genetic association studies established its seminal

role in HIV pathogenesis. Initial in vitro studies revealed that a 32-bp

deletion (Δ32) in the coding region of CCR5 contributes to resistance

to CCR5 using R5 strains of HIV. The CCR5 Δ32 allele encodes a truncated protein that is not expressed on the cell surface. Congruently,

genotype-phenotype association studies in large cohorts demonstrated

that individuals homozygous for the CCR5 Δ32 allele (Δ32/Δ32) lack

CCR5 surface expression and are highly resistant to acquiring HIV

infection; heterozygosity for the CCR5 Δ32 allele is associated with a

lower risk of acquiring HIV.

The distribution of the CCR5 Δ32 allele is population specific.

Approximately 1% of individuals of European ancestry are homozygous for the CCR5 Δ32 allele. Depending on the geographic region in

Europe, up to 18% of individuals are heterozygous for the CCR5 Δ32

allele. The CCR5 Δ32 allele is rare in other populations. The evolutionary pressure that resulted in the emergence of the CCR5 Δ32 allele in

the European population remains unknown and has been speculated to

be secondary to an ancestral pandemic, such as the plague.

Subsequent studies identified single nucleotide variants (SNVs) in

the promoter (regulatory) region of CCR5 that influence gene expression levels. Alleles bearing specific cassettes of linked polymorphisms

(haplotypes) were identified and designated as human haplogroups A

to G*2 (HHA to HHG*2) (Fig. 202-26). The CCR5 Δ32 polymorphism

is found on the HHG*2 haplotype. CCR5 haplotypes A–D versus E–G*2

differ by bearing GT versus AC at polymorphic sites rs1799987 and

rs1799988 (Fig. 202-26). CCR5-HHA haplotype represents the ancestral haplotype (found in chimpanzees) and is associated with lower

CCR5 gene expression, whereas the CCR5-HHE haplotype is associated with higher CCR5 expression. Methylation of DNA is a common

epigenetic signaling mechanism that cells use to lock genes in the “off ”

position, and polymorphisms in CCR5 haplotypes may mediate their

effects by influencing DNA methylation levels in the CCR5 locus.

The CCR5-HHE and CCR5-HHA haplotypes are more sensitive and

1551CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

TABLE 202-6 Host Genetic Factors Influencing HIV/AIDS Pathogenesis and Therapy Responses

GENEa GENETIC VARIATION MECHANISMSb GENETIC ASSOCIATIONSc

Genes in MHC Locus

HLA-B B*27 and B*57 Altered presentation of specific HIV antigens Slower progression to AIDS; lower viral load

B*35 Restriction of specific HIV peptide presentation Faster progression to AIDS; higher viral load

HLA-Bw4 Providing ligands for activating KIR Slower progression to AIDS

B*57:01 Altered presentation of specific HIV antigens (as

above). Possible abacavir-specific activation of

cytokine-producing CD8+ T cells in carriers of this

allele

Slower progression to AIDS. Higher risk of

abacavir-associated hypersensitivity

HLA-B −21M allele −21M allele enhances HLA-E expression levels,

which correlates with higher HLA-A expression and

inhibition of NKG2A-expressing cells

The −21M allele associates with higher viral load,

reduced CD4+ counts, and accelerated disease

progression

B*57:03 bearing the rs2523608-A allele Altered presentation of specific HIV antigens Variant overexpressed in HIV-1 controllers of

African descent

HLA class I allele Homozygosity of HLA-class I alleles Reduced repertoire for epitope recognition Faster progression to AIDS; increased risk of

mother-to-child transmission

Shared donor-recipient HLA alleles Preadaptation of HIV strains Faster disease progression to AIDS

Rare HLA alleles Limited adaptation of HIV strains; less frequent

escape mutants

Protection against HIV infection

HLA class II allele HLA-DRB1 alleles Influence protein specificity of CD4+ T-cell

responses to HIV Gag and Nef proteins

HLA-DRB1*15:02—lower viral load

HLA-DRB1*03:01—higher viral load

HLA extended

haplotype

A1-B8-DR3-DQ2

(AH 8.1)

Increased proinflammatory responses; higher

TNF-α production

Faster progression to AIDS

HLA-C rs9264942-C allele (35 kb upstream of

HLA-C) in linkage with rs67384697-Del

Increased expression of HLA-C by reducing binding

of miRNA-148a

Decreased viral load set point

rs5010528-G (1 kb upstream of HLA-C) Unknown Higher risk of developing nevirapine-associated

hypersensitivity

HCP5 rs2395029-G Linkage disequilibrium with HLA-B*57:01 Lower viral load and slower progression to AIDS

MICA Noncoding SNV near MICA, rs4418214-T May affect HLA class I peptide presentation—

linkage with protective HLA-B alleles

Enriched in HIV-1 controllers

PSORS1C3 rs3131018-A May affect HLA class I peptide presentation Enriched in HIV-1 controllers

ZNRD1 rs9261174-C Possible interference in processing of HIV

transcripts; influence ZNRD1 expression

Slower disease progression to AIDS

Chemokine Receptors

CCR5 rs333: 32-bp deletion in the ORF (Δ32)

found in persons of European descent

Truncated CCR5 protein; reduced co-receptor

activity of R5 HIV strain

Δ32/Δ32: CCR5-null state associated with

resistance to acquiring HIV infection

Δ32/wild type: slower progression to AIDS; better

CD4+ T-cell recovery during ART

Promoter SNVs, haplotypes (HHA to

HHG*2)

Altered CCR5 expression, e.g., HHE haplotype

correlates with high CCR5 expression

HHE/HHE: increased HIV susceptibility and faster

progression to AIDS

rs1015164 G→ A

(34kb downstream from CCR5 and close

to CCRL2)

Increases expression of the lncRNA RP11-24-11.2,

which corresponds to an antisense transcript that

overlaps CCR5 (CCR5AS); results in increased CCR5

expression

rs1015164A allele associated with higher viral load

CCR2 rs1799864: SNV in ORF (64 V→I) Linkage with polymorphisms in CCR5 promoter 64I-bearing haplotype associated with delayed

progression to AIDS

CCRL2 rs3204849: SNV in ORF (167 Y→F) SNV in linkage with CCR5 haplotype 167F associated with accelerated progression to

AIDS and PCP

CXCR6 rs2234358 G→T in the 3’UTR Trafficking of effector T cells and activation of NK T

cells; minor HIV co-receptor

Prevalence of rs2234358-T lower in long-term

nonprogressors and viremic controllers of African

descent

CX3CR1 SNVs in ORF: rs3732379 (249 V→I) and

rs3732378 (280 T→M)

Alleles bearing 249I and 280M reduce receptor

expression and binding of fractalkine, the CX3CR1

ligand

249I and 280M associated with faster AIDS

progression in persons of European descent

DARC rs2814778: promoter SNV (–46T→C)

found in persons of African descent

–46C/C associated with absent DARC expression

(Duffy null), low neutrophil counts, and altered

circulating chemokine levels as well as HIV binding

to RBCs and trans-infection of HIV-1

–46C/C: increased risk of acquiring HIV but slower

HIV disease progression; Duffy null–associated

low neutrophil trait associated with increased

HIV risk

Chemokines

CCL3L, CCL4L Gene copy number of CCL3L and CCL4L High numbers of CCL3L and CCL4L gene-containing

segmental duplications correlate with high CCL3L

and CCL4L levels

Gene copy number lower than population median

associated with increased HIV-AIDS susceptibility

and lower CD4+ T-cell recovery during ART

CCL5 Promoter SNVs Altered gene expression Influence HIV-AIDS susceptibility

CCL2 rs1024611: Promoter SNV (–2578 T→G) –2578G allele: increased CCL2 expression and

monocyte recruitment

–2578G/G associated with increased risk of

developing HIV-1–associated dementia and faster

AIDS onset

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1552 PART 5 Infectious Diseases

TABLE 202-6 Host Genetic Factors Influencing HIV/AIDS Pathogenesis and Therapy Responses

GENEa GENETIC VARIATION MECHANISMSb GENETIC ASSOCIATIONSc

CXCL12 rs7919208: promoter SNV (G→A) rs7919208A creates a new transcription factor

binding site associated with increased CXCL12

expression

rs7919208A associated with higher susceptibility

to HIV-related non-Hodgkin lymphoma

Cytokines

IL-6 rs1800795: Promoter SNV (–174 G→C) –174G/G associated with increased IL-6 and CRP

levels

–174G/G associated with high risk of KS

development and variable recovery of CD4+ T cells

during ART

IL-7RA rs6897932: Coding SNV (244 T→I) 244 I/I associated with increased signal

transduction and proliferation in response to IL-7

244 I/I associated with faster CD4+ T-cell recovery

during ART

IL-10 rs1800872: Promoter SNV (–592 C→A), –592A associated with decreased IL-10 levels –592A associated with increased HIV infection risk

and AIDS progression rate

Drug-Metabolizing Enzyme Gene

CYP2B6 Multiple variants (e.g., rs3745274 [516

G→ T], i.e., CYP2B6*6)

CYP2B6 variants influence enzyme activity 516T/T associated with higher risk of adverse

reactions to efavirenz

Innate Immunity Genes

MBL Alleles defined by 3 coding SNVs Low plasma concentration and structural variation

of MBL protein

Slow progression to AIDS with heterozygosity for

coding SNVs

X allele (promoter SNV –221) Decreased levels of MBL protein Faster progression to AIDS with X/X genotype

APOBEC3G rs8177832: ORF SNV (186 H→R) Reduced anti–HIV-1 activity 186R associated with rapid AIDS progression in

persons of African descent

APOBEC3F Haplotype tagged by rs2076101 in ORF

(231 I→V)

231V variant may influence Vif-mediated APOBEC3F

degradation

231V associated with lower viral load, slower

progression to AIDS and PCP

TLR7 rs179008: ORF SNV (32A→T) on Chr. X Lower TLR7 mRNA translation efficiency and

impaired TLR7-dependent IFN-α production

rs179008-T associated with lower viral load and

cell-associated HIV-1 DNA in women

PARD3B rs11884476 near exon 20 (C→G) Direct interaction with HIV signaling through SMAD

family of proteins

rs11884476-G associated with slower progression

to AIDS

IFNL4 rs368234815: Frameshift mutation

(TT→ΔG)

Polymorphism in IFNL4 gene in linkage with a IFNL3

variant; this haplotype influences IFNL3 levels

rs368234815-ΔG associated with higher prevalence

of AIDS-defining illnesses and potentially

increased HIV-1 infection risk

rs8099917 T→G Unknown rs8099917-G associated with higher susceptibility

to KS

Others

ApoE E4 allele defined by two coding SNVs ApoE is an HIV-1–inducible inhibitor of HIV-1

replication and infectivity in macrophages

E4/E4 associated with rapid AIDS progression and

HIV-associated dementia

ApoL1/MYH9 Several risk haplotypes, including G1 Overexpression of the ApoL1 kidney risk variants

may increase kidney cell death

Increased risk for HIV-associated nephropathy

RYR3 rs2229116: ORF SNV (A →G) Unknown; potential impact on calcium signaling and

homeostasis

rs2229116-G associated with subclinical

atherosclerosis during ART

PROX1 rs17762192-G; 36kb upstream of PROX1 Unknown; presumably due to its impact on PROX1

expression, which is a negative regulator of IFN-γ

rs17762192-G associated with reduced rate of HIV

disease progression

Gene–Gene Interaction

KIR+HLA KIR3DS1 interaction with HLA-Bw4-80Ile Altered NK cell activity required to eliminate HIVinfected cells

KIR3DS1/HLA-Bw4-80Ile associated with delayed

AIDS onset

KIR2DL3 interaction with HLA-C1 Reduction of inhibitory KIR likely results in

increased immune activation, impaired killing of

latently infected cells, and a higher proviral burden

HLA-C1+

 KIR2DL+

 associated with better immune

recovery during ART

KIR3DL1 I47V interaction with

HLA-B*57:01

Variation in an immune NK cell receptor that binds

B*57:01, modifying the protective effect of B*57:01

Increasing copy numbers of 47V associated with

lower viral load in persons carrying HLA-B*57

LILRB2+HLA LILRB2 interaction with HLA class I Regulation of dendritic cells by LILRB2-HLA

engagement

Control of HIV-1

CCL3L1+ CCR5 Low CCL3L1 gene copies + detrimental

CCR5 genotypes

Low CCL3L1 and high CCR5 expression Increased HIV/AIDS susceptibility and reduced

immune reconstitution during ART

a

Representative genes and polymorphisms and b

possible mechanisms are listed. c

Some of the associations are population specific and may display cohort-specific effects.

Most of the associations were derived from persons of European descent.

Note: APOBEC, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; ApoE, apolipoprotein E; ApoL1, apolipoprotein L1; ART, antiretroviral therapy; CCL,

CC ligand; CCL3L, CCL3-like; CCR5, CC chemokine receptor 5; CCR5AS, CCR5 antisense RNA; CCRL2, CC chemokine receptor like 2; CRP, C-reactive protein; CYP2B6,

cytochrome P450 family 2 subfamily B member 6; CXCL12, chemokine (C-X-C motif) ligand 12; CXCR6, chemokine (C-X-C motif) receptor 6; CX3CR1, chemokine (C-X3-C motif)

receptor 1; DARC, Duffy antigen receptor for chemokines; Del, deletion; HCP5, HLA class I histocompatibility antigen protein P5; HHE, human haplogroup E; HLA, human

leukocyte antigen; IFN, interferon; IFNL4, interferon λ4 gene; IFNL3, interferon λ3 gene; IL, interleukin; IL-7RA, interleukin 7 receptor-α; KIR, killer cell immunoglobulin-like

receptors; KS, Kaposi sarcoma; LILRB2, leukocyte immunoglobulin-like receptor B2; MBL, mannose-binding lectin; MHC, major histocompatibility complex; MICA, MHC

class I polypeptide-related sequence A; MYH9, myosin heavy chain 9; NK, natural killer; ORF, open reading frame; PARD3B, par-3 family cell polarity regulator beta; PCP,

Pneumocystis jirovecii pneumonia; PROX1, prospero homeobox 1; PSORS1C3, psoriasis susceptibility 1 candidate 3; RYR3, ryanodine receptor 3; SMAD, mothers against

decapentaplegic homolog; SNV, single nucleotide variant; rs#, SNV identification number; TLR7, toll-like receptor 7; TNF-α, tumor necrosis factor α; UTR, untranslated

region; VL, viral load; ZNRD1, zinc ribbon domain containing 1; +, present; –, absent.

Sources: Sunil K. Ahuja, MD, Weijing He, MD, Reviews for additional information: P An et al: Trends Genet 26:119, 2010; J Fellay: Antivir Ther 14:731, 2009; RA Kaslow et al:

J Infect Dis 191:S68, 2005; D van Manen et al: Retrovirology 9:70, 2012; MP Martin et al: Immunol Rev 254:245, 2013; S Limou et al: Front Immunol 4:118, 2013; PJ McLaren et al:

Curr Opin HIV AIDS 10:110, 2015; PJ McLaren et al: Proc Natl Acad Sci USA 112:14658, 2015; PJ McLaren, M Carrington: Nat Immunol 16:577, 2015; P An et al: PLoS Genet

12:e1005921, 2016; F Pereyra et al: Science 330:1551, 2010; I Bartha et al: PLoS Comput Biol 13:e1005339, 2017; S Kulkarni et al: Nat Immunol 20:824, 2019; S Le Clerc et al:

Front Genet 10:799 2019; V Kalidasan et al: Front Microbiol 11:46 2020; SN Gingras et al: Hum Genet 139:865 2020.

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