1526 PART 5 Infectious Diseases

autoimmune destruction of neural cells by T cells with specificity for

viral components such as Tax or Env proteins. One theory is that susceptibility to HAM may be related to the presence of human leukocyte

antigen (HLA) alleles capable of presenting viral antigens in a fashion

that leads to autoimmunity. Insufficient data are available to confirm

an HLA association. However, antibodies in the sera of HAM patients

have been shown to bind a neuron-specific antigen (heteronuclear

ribonuclear protein A1 [hnRNP A1]) and to interfere with neurotransmission in vitro.

It is unclear what factors influence whether HTLV-1 infection will

cause disease and, if it does, whether it will induce a neoplasm (ATL)

or an autoimmune disorder (HAM). Differences in viral strains, the

susceptibility of particular MHC haplotypes, the route of HTLV-1

infection, the viral load, and the nature of the HTLV-1-related immune

response are putative factors, but few definitive data are available.

OTHER PUTATIVE HTLV-1-RELATED DISEASES Even in the absence of

the full clinical picture of HAM, bladder dysfunction is common in

HTLV-1-infected women. In areas where HTLV-1 is endemic, diverse

inflammatory and autoimmune diseases have been attributed to the

virus, including uveitis, dermatitis, pneumonitis, rheumatoid arthritis,

and polymyositis. However, a causal relationship between HTLV-1 and

these illnesses has not been established.

Prevention Women in endemic areas should not breast-feed their

children, and blood donors should be screened for serum antibodies to

HTLV-1. As in the prevention of HIV infection, the practice of safe sex

and the avoidance of needle sharing are important.

TREATMENT

HTLV-1 Infection

For the small number of patients who develop HTLV-1–related

disease, therapies are not curative. In patients with the acute and

lymphomatous types of ATL, the disease progresses rapidly. Hypercalcemia is generally controlled by glucocorticoid administration

and cytotoxic therapy directed against the neoplasm. The tumor

is highly responsive to combination chemotherapy that is used

against other forms of lymphoma; however, patients are susceptible

to overwhelming bacterial and opportunistic infections, and ATL

relapses within 4–10 months after remission in most cases. The

combination of interferon α and zidovudine may extend survival.

Because viral replication is not clearly associated with ATL progression, zidovudine is probably effective through its cytotoxic

effects (as a chain-terminating thymidine analogue) rather than

its antiviral effects. Selected series have reported high rates of

response and a 40% rate of 5-year survival; however, this level of

response has not been universal. LSG15, a multidrug chemotherapy

program developed in Japan, induces complete responses in about

one-third of patients, about half of whom survive for >2 years;

however, the median survival time is about 13 months. High-dose

therapy with bone marrow transplantation has been widely tested

in Japan. Median survival has not been influenced by this treatment; however, up to 25% of patients survive free of disease for

4 years. Lenalidomide has been reported to have a 42% response

rate in patients with relapsed ATL, extending median survival to

20 months despite a short 4-month progression-free survival period.

Mogamulizumab, an antibody to CCR4 (a receptor for a number of

chemokines, including RANTES and TARC), improved response

rates when added to chemotherapy. An experimental approach

using an yttrium-90-labeled or toxin-conjugated antibody to the

IL-2 receptor appears promising but is not widely available. Patients

with the chronic or smoldering form of ATL may be managed with

an expectant approach: treat any infections, and watch and wait for

signs of progression to acute disease.

Patients with HAM may obtain some benefit from the use of

glucocorticoids to reduce inflammation. Antiretroviral regimens

have not been effective. In one study, danazol (200 mg three times

daily) produced significant neurologic improvement in five of six

treated patients, with resolution of urinary incontinence in two cases,

decreased spasticity in three, and restoration of the ability to walk

after confinement to a wheelchair in two. Antibody to IL-15 receptor

β chain has been tested with some promising clinical effects in small

numbers of patients. Physical therapy and rehabilitation are important components of management.

■ FEATURES OF HTLV-2 INFECTION

Epidemiology HTLV-2 is endemic in certain Native American

tribes and in Africa. It is generally considered to be a New World virus

that was brought from Asia to the Americas 10,000–40,000 years ago

during the migration of infected populations across the Bering land

bridge. The mode of transmission of HTLV-2 is probably the same as

that of HTLV-1 (see above). HTLV-2 may be less readily transmitted

sexually than HTLV-1.

Studies of large cohorts of injection drug users with serologic assays

that reliably distinguish HTLV-1 from HTLV-2 indicated that the vast

majority of HTLV-positive cohort members were infected with HTLV-2.

The seroprevalence of HTLV in a cohort of 7841 injection drug users

from drug treatment centers in Baltimore, Chicago, Los Angeles, New

Jersey (Asbury Park and Trenton), New York City (Brooklyn and

Harlem), Philadelphia, and San Antonio was 20.9%, with >97% of

cases due to HTLV-2. The seroprevalence of HTLV-2 was higher in

the Southwest and the Midwest than in the Northeast. In contrast, the

seroprevalence of HIV-1 was higher in the Northeast than in the Southwest or the Midwest. Approximately 3% of the cohort members were

infected with both HTLV-2 and HIV-1. The seroprevalence of HTLV-2

increased linearly with age. Women were significantly more likely

than men to be infected with HTLV-2; the virus is thought to be more

efficiently transmitted from male to female than from female to male.

Associated Diseases Although HTLV-2 was isolated from a

patient with a T cell variant of hairy cell leukemia, this virus has not

been consistently associated with a particular disease and in fact has

been thought of as “a virus searching for a disease.” However, evidence

is accumulating that HTLV-2 may play a role in certain neurologic,

hematologic, and dermatologic diseases. These data require confirmation, particularly in light of the previous confusion regarding the relative prevalences of HTLV-1 and HTLV-2 among injection drug users.

Prevention Avoidance of needle sharing, adherence to safe-sex

practices, screening of blood (by assays for HTLV-1, which also detect

HTLV-2), and avoidance of breast-feeding by infected women are

important principles in the prevention of spread of HTLV-2.

HUMAN IMMUNODEFICIENCY VIRUS

HIV-1 and HIV-2 are members of the lentivirus subfamily of Retroviridae and are the only lentiviruses known to infect humans. The

lentiviruses are slower-acting than viruses that cause acute infection

(e.g., influenza virus) but not than other retroviruses. The features of

acute primary infection with HIV resemble those of more classic acute

infections. The characteristic chronicity of HIV disease is consistent

with the designation lentivirus. For a detailed discussion of HIV,

see Chap. 202.

■ FURTHER READING

El Hajj H et al: Novel treatments of adult T cell leukemia lymphoma.

Front Microbiol 11:1062, 2020.

Katsuya H et al: Treatment and survival among 1594 patients with

ATL. Blood 126:2570, 2015.

Ma G et al: Multifaceted functions and roles of HBA in HTLV-1

pathogenesis. Retrovirology 13:16, 2016.

Moir S et al: Pathogenic mechanisms of HIV disease. Annu Rev Pathol

6:223, 2011.

Tsukasaki K et al: Diagnostic approaches and established treatments

for adult T-cell leukemia lymphoma. Front Microbiol 11:1207, 2020.

Yamauchi J et al: An update on human T-cell leukemia virus type I

(HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/

TSP) focusing on clinical and laboratory biomarkers. Pharmacol

Ther 218:107669, 2021.

1527CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

The Acquired Immune Deficiency Syndrome (AIDS) was first recognized in the United States in the summer of 1981, when the U.S.

Centers for Disease Control and Prevention (CDC) reported the

unexplained occurrence of Pneumocystis jirovecii (formerly P. carinii)

pneumonia in five previously healthy homosexual men in Los Angeles

and of Kaposi’s sarcoma (KS) with or without P. jirovecii pneumonia

and other opportunistic infections in 26 previously healthy homosexual men in New York, San Francisco, and Los Angeles. The disease was

soon recognized in male and female injection drug users; in hemophiliacs and blood transfusion recipients; among female sexual partners

of men with AIDS; and among infants born to mothers with AIDS.

In 1983, human immunodeficiency virus (HIV) was isolated from

a patient with lymphadenopathy, and by 1984 it was demonstrated

clearly to be the causative agent of AIDS. In 1985, a sensitive enzymelinked immunosorbent assay (ELISA) was developed; this led to an

appreciation of the scope and evolution of the HIV epidemic at first in

the United States and other developed nations and ultimately among

developing nations throughout the world (see “HIV Infection and

AIDS Worldwide,” below). The staggering worldwide evolution of the

HIV pandemic has been matched by an explosion of information in the

areas of HIV virology, pathogenesis (both immunologic and virologic),

treatment of HIV disease, treatment and prophylaxis of the opportunistic diseases associated with HIV infection, and prevention of HIV

infection. The information flow related to HIV disease is enormous

and continues to expand, and it has become almost impossible for the

health care generalist to stay abreast of the literature. The purpose of

this chapter is to present the most current information available on the

scope of the pandemic; on its pathogenesis, treatment, and prevention;

and on prospects for vaccine development. Above all, the aim is to

provide a solid scientific basis and practical clinical guidelines for a

state-of-the-art approach to the care of persons with HIV.

■ DEFINITION

The current CDC classification system for HIV infection and AIDS

categorizes patients based on clinical conditions associated with HIV

infection together with the level of the CD4+ T lymphocyte count.

A confirmed HIV case can be classified in one of five HIV infection

stages (0, 1, 2, 3, or unknown). If there was a negative HIV test within

6 months of the first HIV infection diagnosis, the stage is 0 and remains

0 until 6 months after diagnosis. Advanced HIV disease (AIDS) is classified as stage 3 if one or more specific opportunistic illness has been

diagnosed (Table 202-1). Otherwise, the stage is determined by CD4+

T lymphocyte test results and immunologic criteria (Table 202-2). If

none of these criteria apply (e.g., because of missing information on

CD4+ T lymphocyte test results), the stage is U (unknown).

The definition and staging criteria of AIDS are complex and comprehensive and were established for surveillance purposes rather than

for the practical care of patients. Thus, the clinician should not focus

on whether the patient fulfills the strict definition of AIDS, but should

view HIV disease as a spectrum ranging from primary infection, with

or without the acute syndrome, to the relatively asymptomatic stage,

to advanced stages associated with opportunistic diseases (see “Pathophysiology and Pathogenesis,” below).

ETIOLOGIC AGENT

HIV is the etiologic agent of AIDS; it belongs to the family of

human retroviruses (Retroviridae) and the subfamily of lentiviruses

(Chap. 201). Nononcogenic lentiviruses cause disease in other animal

202

species, including sheep, horses, goats, cattle, cats, and monkeys. The

four retroviruses known to cause human disease belong to two distinct

groups: the human T lymphotropic viruses (HTLV)-1 and HTLV-2,

which are transforming retroviruses; and the human immunodeficiency viruses, HIV-1 and HIV-2, which cause cytopathic effects either

directly or indirectly (Chap. 201). The most common cause of HIV

disease throughout the world, and certainly in the United States, is

HIV-1, which comprises several subtypes with different geographic

distributions (see “Molecular Heterogeneity of HIV-1,” below). HIV-2

was first identified in 1986 in West African patients and was originally

confined to West Africa. However, cases traced to West Africa or to

sexual contacts with West Africans have been identified throughout

the world. The currently defined groups of HIV-1 (M, N, O, P) and

the HIV-2 groups A through H each are likely derived from a separate

transfer to humans from a nonhuman primate reservoir. HIV-1 viruses

likely came from chimpanzees and/or gorillas, and HIV-2 from sooty

mangabeys. The AIDS pandemic is primarily caused by the HIV-1 M

group viruses. Although HIV-1 group O and HIV-2 viruses have been

found in numerous countries, including those in the developed world,

they have caused much more localized epidemics. Reported infections

with group N and group P viruses are rare and confined almost entirely

to residents of Cameroon or travelers from Cameroon. The taxonomic

relationship between primate lentiviruses is shown in Fig. 202-1.

■ MORPHOLOGY OF HIV

Electron microscopy shows that the HIV virion is an icosahedral

structure (Fig. 202-2) containing numerous external spikes formed

Human Immunodeficiency

Virus Disease: AIDS and

Related Disorders

Anthony S. Fauci, Gregory K. Folkers,

H. Clifford Lane

TABLE 202-1 CDC Stage 3 (AIDS)-Defining Opportunistic Illnesses in

HIV Infection

Bacterial infections, multiple or recurrenta

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasiveb

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at

age >1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV

Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis,

or esophagitis (onset at age >1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month’s duration)

Kaposi’s sarcoma

Lymphoma, Burkitt’s (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or

extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary,b

 disseminated, or

extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or

extrapulmonary

Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia

Pneumonia, recurrentb

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age >1 month

Wasting syndrome attributed to HIV

a

Only among children age <6 years. b

Only among adults, adolescents, and children

age ≥6 years.

Source: MMWR 63(RR-03), April 11, 2014.

1528 PART 5 Infectious Diseases

by the two major envelope proteins, the external gp120 and the transmembrane gp41. The HIV envelope exists as a trimeric heterodimer.

The virion buds from the surface of the infected cell (Fig. 202-2A) and

incorporates a variety of host cellular proteins into its lipid bilayer. The

structure of HIV-1 is schematically diagrammed in Fig. 202-2B.

■ REPLICATION CYCLE OF HIV

HIV is an RNA virus whose hallmark is the reverse transcription of its

genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with the high-affinity binding via surfaceexposed residues within the gp120 protein to its receptor on the host

cell surface, the CD4 molecule (Fig. 202-3). The CD4 molecule is a

55-kDa protein found predominantly on a subset of T lymphocytes that

are responsible for helper function in the immune system (Chap. 349).

Once it binds to CD4, the gp120 protein undergoes a conformational

change that facilitates binding to one of two major co-receptors.

The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both

receptors belong to the family of seven-transmembrane-domain G

protein–coupled cellular receptors, and the use of one or the other or

both receptors by the virus for entry into the cell is an important determinant of the cellular tropism of the virus. Cell-to-cell spread is also

facilitated by accessory molecules such as the C-type lectin receptor

DC-SIGN expressed on certain dendritic cells (DCs) that bind to the

HIV gp120 envelope protein, allowing virus captured on DCs to spread

to CD4+ T cells. Following binding of the envelope protein to the CD4

molecule associated with the above-mentioned conformational change

in the viral envelope gp120, fusion with the host cell membrane occurs

via the newly exposed gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion

and target cell together (Fig. 202-4). Following fusion, uncoating of

the capsid protein shell is initiated—a step that facilitates reverse transcription and leads to formation of the preintegration complex, composed of viral RNA, enzymes, and accessory proteins and surrounded

by capsid and matrix proteins (Fig. 202-3). All these post-fusion viral

components constitute the HIV replication complex, including the

outer capsid shell, which plays an integral role in supporting reverse

transcription of viral RNA. As the preintegration complex traverses

the cytoplasm to reach the nucleus, the viral reverse transcriptase

enzyme catalyzes the reverse transcription of the genomic RNA into

DNA, resulting in the formation of double-stranded HIV proviral

DNA. At several steps of the replication cycle, the virus is vulnerable

to various cellular factors that can block the progression of infection.

The cytoplasmic tripartite motif-containing protein 5-α (TRIM5-α)

is a host restriction factor that interacts with retroviral capsids, causing their premature disassembly and induction of innate immune

responses. The apolipoprotein B mRNA editing enzyme (catalytic

polypeptide-like 3 [APOBEC3]) family of cellular proteins also inhibits progression of virus infection after virus

has entered the cell and prior to entering

the nucleus. APOBEC3 proteins, which are

incorporated into virions and released into

the cytoplasm of a newly infected cell, bind

to the single minus-strand DNA intermediate

and deaminate viral cytidine, causing hypermutation of retroviral genomes. HIV has

evolved a powerful strategy to protect itself

from APOBEC. The viral protein Vif targets APOBEC3 for proteasomal degradation.

SAMHD1 is another post-entry host factor

that prevents reverse transcription by depleting pools of deoxynucleotides (dNTPs). The

type I interferon (IFN)-induced myxovirus

resistance protein 2 (MX2) is another restriction factor associated with innate immunity

that inhibits HIV-1 nuclear entry.

With activation of the cell, the viral DNA

accesses the nuclear pore and is transferred

from the cytoplasm to the nucleus, where it

is integrated into the host cell chromosomes

through the action of another virally encoded

enzyme, integrase (Fig. 202-3). HIV proviral

DNA integrates into the host genomic DNA

preferentially in regions of active transcription and regional hotspots. This provirus may

remain transcriptionally inactive (latent) or it

may manifest varying levels of gene expression, up to active transcription and production of virus depending on the metabolic state

of the infected cell.

Cellular activation plays an important

role in the replication cycle of HIV and is

critical to the pathogenesis of HIV disease

(see “Pathogenesis and Pathophysiology,”

below). Following initial binding, fusion, and

HIV-2 and SIV-SMM/MAC

SIV-CPZ

Pan troglodytes

schweinfurthii

SIV-OLC

SIV-WRC

SIV-COL

SIV_LST

SIV-SUN

SIV-MND1

SIV-SAB

SIV-RCM

SIV-MND2

SIV-DRL

SIV-VER

SIV-GRI

SIV-TAN

SIV-SYK

SIV-TAL

SIV-MUS

SIV-GSN

SIV-MON

SIV-ASC

SIV-DEN

SIV-DEB

0.25

HIV-1 M and N

groups and SIV-CPZ

Pan troglodytes

troglodytes

HIV-1 P and O

groups and

SIV_Gorilla

A

B

FIGURE 202-1 A phylogenetic tree based on the nearly complete genomes (gag through nef genes) of primate

immunodeficiency viruses. The scale (0.25) indicates a 25% phylogenetically corrected genetic distance at the

nucleotide level. Clades in color represent viruses (HIV-1, HIV-2) identified in humans after relatively recent

transfers from chimpanzee, gorilla, and sooty mangabey reservoirs. (Prepared by Brian Foley, PhD, of the HIV

Sequence Database, Theoretical Biology and Biophysics Group, Los Alamos National Laboratory; additional

information at www.hiv.lanl.gov/content/sequence/HelpDocs/subtypes.html.)

TABLE 202-2 CDC HIV Infection Stages 1–3 Based on Age-Specific

CD4+ T Lymphocyte Count or CD4+ T Lymphocyte Percentage of Total

Lymphocytesa

AGE ON DCATE OF CD4 T+ LYMPHOCYTE TEST

<1 YEAR 1–5 YEARS

6 YEARS

THROUGH ADULT

STAGEa CELLS/µL % CELLS/µL % CELLS/µL %

1 ≥1500 ≥34 ≥1000 ≥30 ≥500 ≥26

2 750–1499 26–33 500–999 22–29 200–499 14–25

3 <750 <26 <500 <22 <200 <14

a

The stage is based primarily on the CD4+ T lymphocyte count; the CD4+

T lymphocyte count takes precedence over the CD4+ T lymphocyte percentage, and

the percentage is considered only if the count is missing.

Source: MMWR 63(RR-03), April 11, 2014.

1529CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

internalization of the nucleic acid contents of virions into the target

cell, incompletely reverse-transcribed DNA intermediates are labile in

quiescent cells and do not integrate efficiently into the host cell genome

unless cellular activation occurs shortly after infection. Furthermore,

some degree of activation of the host cell is required for the initiation

of transcription of the integrated proviral DNA into either genomic

RNA or mRNA. This latter process may not necessarily be associated

with the detectable expression of the classic cell-surface markers of

activation, especially given that cell-associated HIV RNA transcribed

from competent or defective proviruses can be detected in infected

resting CD4+ T cells. In this regard, activation of HIV expression from

the latent state depends on the interaction of various cellular and viral

factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristoylation,

phosphorylation, and cleavage. The viral particle is formed by the

assembly of HIV proteins, enzymes, and genomic RNA at the plasma

membrane of the cells. Budding of the progeny virion through the

lipid bilayer of the host cell membrane is the point at which the core

acquires its external envelope and where the host restriction factor

tetherin can inhibit the release of budding particles. Tetherin is an

IFN-induced type II transmembrane protein that interferes with virion

detachment, although the HIV accessory protein Vpu counteracts this

effect through direct interactions with tetherin. During or soon after

budding, the virally encoded protease catalyzes the cleavage of the

gag-pol precursor to yield the mature virion. Progression through the

virus replication cycle is profoundly influenced by a variety of viral

regulatory gene products. Likewise, each point in the replication cycle

of HIV is a real or potential target for therapeutic intervention. Thus

far, the reverse transcriptase, protease, and integrase enzymes as well

as the process of virus–target cell binding and fusion have proved to be

susceptible to pharmacologic disruption.

■ HIV GENOME

Figure 202-5 illustrates schematically the arrangement of the HIV

genome. Like other retroviruses, HIV-1 has genes that encode the

structural proteins of the virus: gag encodes the proteins that form the

core of the virion (including p24 antigen); pol encodes the enzymes

responsible for protease processing of viral proteins, reverse transcription, and integration; and env encodes the envelope glycoproteins.

However, HIV-1 is more complex than other retroviruses, particularly

those of the nonprimate group, in that it also contains at least six

other regulatory genes (tat, rev, nef, vif, vpr, and vpu), which code for

proteins involved in the modification of the host cell to enhance virus

growth and the regulation of viral gene expression. Several of these

gp120

Capsid

Matrix

RNA

gp41

Reverse

transcriptase

Lipid

membrane

A B

C

FIGURE 202-2 A. Electron micrograph of HIV. Figure illustrates a typical virion following budding from the surface of a CD4+ T lymphocyte, together with two additional

incomplete virions in the process of budding from the cell membrane. B. Structure of HIV-1, including the gp120 envelope, gp41 transmembrane components of the envelope,

genomic RNA, enzyme reverse transcriptase, p18(17) inner membrane (matrix), and p24 core protein (capsid). (Courtesy by George V. Kelvin.) (Adapted from RC Gallo: Sci

Am 256:46, 1987.) C. Scanning electron micrograph of HIV-1 virions infecting a human CD4+ T lymphocyte. The original photograph was imaged at 20,000× magnification. Cell

is approximately 10 microns in diameter, and the HIV particles are approximately 120 nanometers. (Courtesy of Elizabeth R. Fischer, Rocky Mountain Laboratories, National

Institute of Allergy and Infectious Diseases.)

1530 PART 5 Infectious Diseases

 New viral RNA

and proteins move to

the cell surface and

an immature virion

begins to form.

6

7

 HIV RNA, reverse

transcriptase, integrase,

and other viral proteins

enter the host cell.

 Viral DNA is

formed by reverse

transcription.

 Viral DNA is

transported across the

nucleus and integrates

into the host DNA.

 New viral RNA is

used as genomic RNA

and to make viral

proteins.

Preintegration

complex

2

3

4

5

Viral RNA

Reverse

transcriptase

Viral DNA

Integrase

Host DNA

New viral RNA

Protease

CD4

Co-receptor

(CCR5 or CXCR4)

gp120

HIV

Host Cell

Mature Virion

1 Binding and

fusion to the

host cell

surface.

 The virus matures

after protease

cleaves long

precursor proteins

FIGURE 202-3 The replication cycle of HIV. See text for description. (From the National Institute of Allergy and Infectious Diseases.)

FIGURE 202-4 Binding and fusion of HIV-1 with its target cell.

HIV-1 binds to its target cell via the CD4 molecule, leading to a

conformational change in the gp120 molecule that allows it to bind

to the co-receptor CCR5 (for R5-using viruses). The virus then firmly

attaches to the host cell membrane in a coiled-spring fashion via

the newly exposed gp41 molecule. Virus-cell fusion occurs as the

transitional intermediate of gp41 undergoes further changes to

form a hairpin structure that draws the two membranes into close

proximity (see text for details). (Adapted from Montefiori D, Moore

JP: HIV vaccines. Magic of the occult? Science 283:336, 1999.)

CCR5/

CXCR4

CD4

gp120

gp41

CD4+ T cell

HIV virion

Receptor binding

Membrane fusion

1531CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

proteins are thought to play a role in the pathogenesis of HIV disease;

their various functions are listed in Fig. 202-5. Flanking these genes are

the long terminal repeats (LTRs), which contain regulatory elements

involved in gene expression (Fig. 202-5). The major difference between

the genomes of HIV-1 and HIV-2 is the fact that HIV-2 lacks the vpu

gene and has a vpx gene not contained in HIV-1.

■ MOLECULAR HETEROGENEITY OF HIV-1

Molecular analyses of HIV isolates reveal varying levels of sequence

diversity over all regions of the viral genome. For example, the degree

of difference in the coding sequences of the viral envelope protein

ranges from a few percent (very close, among isolates from the same

infected individual) to more than 50% (extreme diversity, between

isolates from the different groups of HIV-1: M, N, O, and P). The

changes tend to cluster in hypervariable regions. HIV can evolve by

several means, including simple base substitution, insertions and

deletions, recombination, and gain and loss of glycosylation sites. HIV

sequence diversity arises directly from the limited fidelity of the reverse

transcriptase, i.e., a tendency toward copying errors. The balance of

immune pressure and functional constraints on proteins influences

the regional level of variation within proteins. For example, Envelope,

which is exposed on the surface of the virion and is under immune

selective pressure from both antibodies and cytolytic T lymphocytes,

is extremely variable, with clusters of mutations in hypervariable

domains. In contrast, reverse transcriptase, with important enzymatic

functions, is relatively conserved, particularly around the active site.

The extraordinary variability of HIV-1 contrasts markedly with the

relative stability of HTLV-1 and 2.

The four groups (M, N, O and P) of HIV-1 are the result of four separate chimpanzee-to-human (or possibly gorilla-to-human for groups

O and P) transfers. Group M (major), which is responsible for most of

the infections in the world, has diversified into subtypes and intersubtype recombinant forms, due to “sub-epidemics” within humans after

one of those transfers.

Among primate lentiviruses, HIV-1 is most closely related to viruses

isolated from chimpanzees and gorillas (Fig. 202-1). The chimpanzee

subspecies Pan troglodytes troglodytes has been established to be the

natural reservoir of the HIV-1 M and N groups. The rare viruses of

the HIV-1 O and P groups are most closely related to viruses found

in Cameroonian gorillas. The M group comprises ten subtypes, or

clades, designated A, B, C, D, F, G, H, J, K and L, as well as more than

100 known circulating recombinant forms (CRFs) and numerous

unique recombinant forms. Intersubtype recombinants are generated

by infection of an individual with two subtypes that then recombine

and create a virus with a selective advantage. These CRFs range from

highly prevalent forms such as CRF01_AE, common in southeast Asia,

and CRF02_AG from west and central Africa, to a large number of

CRFs that are relatively rare, either because they are of a more recent

origin (newly recombined) or because they have not broken out into

a major population. The subtypes and CRFs create the major lineages

of the M group of HIV-1. HIV-1 M group subtype C dominates the

global pandemic, and although there is much speculation that it is

LTR

Long terminal repeat

Contains control regions

that bind host transcription

factors (NF-κβ, NFAT,

Sp. 1, TBP)

Required for the initiation

of transcription

Contains RNS trans-acting

response element (TAR)

that binds Tat

vif

Viral infectivity

factor (p23)

Overcomes inhibitory

effects of APOBEC3,

preventing hypermutation

and viral DNA degradation

vpu

Viral protein U

Promotes CD4

degradation and

influences virion

release

Overcomes

inhibitory effects

of tetherin

env

gp160 envelope protein

Cleaved in endoplasmic

reticulum to gp120 (SU)

and gp 41 (TM)

gp120 mediates CD4

and chemokine receptor

binding, while gp41

mediates fusion

Contains RNA response

element (RRE) that

binds Rev

nef

Negative effector (p27)

Promotes downregulation of surface

CD4 and MHC 1

expression

Blocks apoptosis

Enhances viron

activity

Alters state of

cellular activation

Progression to disease

slowed significantly in

absence of Nef

gag

Pr55gag

Polyprotein processed by PR

MA, matrix (p17)

Undergoes myristoylation that

helps target gag polyprotein

to lipid rafts

CA capsid (p24)

Binds cyclophilin A and CPSF6

Target of TRIM5α

NC, nucleocapsid (p7)

Zn finger, RNA-binding protein

p6

Regulates the terminal steps in

virion budding through

interactions with TSG101 and

ALIX 1

Incorporates Vpr into viral

particles

5

pol

Polymerase

Encodes a variety

of viral enzymes,

including PR (p10),

RT and RNAase H

(p66/51), and IN (p32)

all processed by PR

vpr

Viral protein R (p15)

Promotes G2

cell-cycle arrest

Facilitates HIV

infection of

macrophages

rev

Regulator of viral

gene expression (p19)

Binds RRE

Inhibits viral RNA

splicing and promotes

nuclear export of

incompletely spliced

viral RNAs

tat

Transcriptional

activator (p14)

Binds TAR

In presence of host

cyclin T1 and CDK9

enhances RNA Pol II

elongation on the viral

DNA template

R U5U3 R U5U3 3

FIGURE 202-5 Organization of the genome of the HIV provirus together with a summary description of its 9 genes encoding 15 proteins. (Reproduced with permission from

WC Greene et al: Charting HIV’s remarkable voyage through the cell: Basic science as a passport to future therapy. Nat Med 8:673, 2002.)

1532 PART 5 Infectious Diseases

more transmissible than other subtypes, solid data on variations in

transmissibility between subtypes are lacking. Human population densities, access to prevention and treatment, prevalence of genital ulcers,

iatrogenic transmissions, and other confounding host factors are all

possible reasons why one subtype has spread more than another.

Figure 202-6 schematically diagrams the worldwide distribution

of HIV-1 subtypes by region. Nine strains account for the vast majority

of HIV infections globally: HIV-1 subtypes A, B, C, D, F, G and three of

the CRFs, CRF01_AE, CRF02_AG, and CRF07_BC. Subtype C viruses

(of the M group) are by far the most common form worldwide, likely

accounting for ~50% of prevalent infections worldwide. In sub-Saharan

Africa, home to approximately two-thirds of all individuals living with

HIV/AIDS, most infections are caused by subtype C, with smaller

proportions of infections caused by subtype A, subtype D, CRF02_AG,

and other subtypes and recombinants. In South Africa, the country

with the largest number of prevalent infections (7.8 million in 2020),

98% of the HIV-1 isolates sequenced are of subtype C. In Asia, HIV-1

isolates of the CRF01_AE lineage and subtypes B and C predominate.

CRF01_AE accounts for most infections in south and southeast Asia,

while >95% of infections in India, home to an estimated 2.3 million

HIV-infected individuals, are of subtype C (see “HIV Infection and

AIDS Worldwide,” below). Subtype B viruses are overwhelmingly

predominant in the United States, Canada, certain countries in South

America, western Europe, and Australia. It is thought that, purely by

chance, subtype B was seeded into the United States and Europe in the

late 1970s, thereby establishing an overwhelming founder effect. Many

countries have co-circulating viral subtypes that are giving rise to new

CRFs. Sequence analyses of HIV-1 isolates from infected individuals

indicate that recombination among viruses of different clades likely

occurs when an individual is infected with viruses of more than one

subtype, particularly in geographic areas where subtypes overlap, and

more often in sub-epidemics driven by injection drug use than in those

driven by sexual transmission.

The extraordinary diversity of HIV, reflected by the presence of

multiple subtypes, circulating recombinant forms, and continuous

viral evolution, has implications for possible differential rates of

transmission, rates of disease progression, and the development of

resistance to antiretroviral drugs. This diversity may also prove to be a

formidable obstacle to HIV vaccine development, as a broadly useful

vaccine would need to induce protective responses against a wide range

of viral strains.

TRANSMISSION

HIV is transmitted primarily by sexual contact (both heterosexual

and male to male); by blood and blood products; and by infected

mothers to infants intrapartum, perinatally, or via breast milk. After

four decades of experience and observations, there is no evidence that

HIV is transmitted by any other modality. Table 202-3 lists the estimated risk of HIV transmission for various types of exposures.

■ SEXUAL TRANSMISSION

HIV infection is predominantly a sexually transmitted infection (STI)

worldwide. By far the most common mode of infection, particularly

in developing countries, is heterosexual transmission, although in

many western countries male-to-male sexual transmission dominates.

Although a wide variety of factors including viral load and the presence

of ulcerative genital diseases influence the efficiency of heterosexual

transmission of HIV, such transmission is generally inefficient. A

recent systemic review found a low per-act risk of heterosexual transmission in the absence of antiretrovirals: 0.04% for female-to-male

transmission and 0.08% for male-to-female transmission during vaginal intercourse in the absence of antiretroviral therapy or condom use

(Table 202-3).

HIV has been demonstrated in seminal fluid both within infected

mononuclear cells and in cell-free material. The virus appears to

concentrate in the seminal fluid, particularly in situations where there

are increased numbers of lymphocytes and monocytes in the fluid, as

seen in genital inflammatory states such as urethritis and epididymitis,

conditions closely associated with other STIs. The virus has also been

demonstrated in cervical smears and vaginal fluid. There is an elevated

risk of HIV transmission associated with unprotected receptive anal

intercourse (URAI) among both men and women compared to the risk

01_AE

02_AG

07_BC

A

B

C

D

F

G

Other

FIGURE 202-6 Global geographic distribution of HIV-1 subtypes and recombinant forms. Distributions derived from relative frequency of subtypes among >860,000 HIV

genomic sequences in the Los Alamos National Laboratory HIV Sequence Database. (Additional information available at www.hiv.lanl.gov/components/sequence/HIV/geo/

geo.comp.)

1533CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

associated with unprotected receptive vaginal intercourse. Although

data are limited, the per-act risk for HIV transmission via URAI has

been estimated to be ~1.4% (Table 202-3). The risk of HIV acquisition

associated with URAI is higher than that seen in penile-vaginal intercourse probably because only a thin, fragile rectal mucosal membrane

separates the deposited semen from potentially susceptible cells in and

beneath the mucosa, and micro-trauma of the mucosal membrane has

been associated with anal intercourse. Anal douching and sexual practices that traumatize the rectal mucosa also increase the likelihood of

infection. It is likely that anal intercourse provides at least two modalities of infection: (1) direct inoculation into blood in cases of traumatic

tears in the mucosa; and (2) infection of susceptible target cells, such as

Langerhans cells, in the mucosal layer in the absence of trauma. Insertive anal intercourse also confers an increased risk of HIV acquisition

compared to insertive vaginal intercourse in the receptive partner since

the vaginal mucosa is several layers thicker than the rectal mucosa and

less likely to be traumatized during intercourse. Nonetheless, the virus

can be transmitted to either partner through vaginal intercourse. As

noted in Table 202-3, male-to-female HIV transmission is more efficient than female-to-male transmission. The differences in reported

transmission rates between men and women may be due in part to

the prolonged exposure of the vaginal and cervical mucosa to infected

seminal fluid; the endometrium also can be exposed to virus when

semen enters through the cervical os. By comparison, the penis and

urethral orifice of the uninfected male partner are exposed relatively

briefly to infected vaginal fluid.

Among various cofactors examined in studies of heterosexual HIV

transmission, the presence of other STIs has been strongly associated

with HIV transmission. In this regard, there is a close association

between genital ulcerations and transmission, owing to both susceptibility to infection and infectivity. Infections with microorganisms such

as Treponema pallidum (Chap. 182), Haemophilus ducreyi (Chap. 157),

and herpes simplex virus (HSV; Chap. 192) are important causes of

genital ulcerations linked to transmission of HIV. In addition, pathogens responsible for non-ulcerative inflammatory STIs such as those

caused by Chlamydia trachomatis (Chap. 189), Neisseria gonorrhoeae

(Chap. 156), and Trichomonas vaginalis (Chap. 229) also are associated with an increased risk of transmission of HIV infection. Bacterial

vaginosis, an infection related to sexual behavior, but not strictly an

STI, also may be linked to an increased risk of transmission of HIV

infection. Several studies have suggested that treating STIs and genital

tract syndromes may help prevent transmission of HIV. This effect

is most prominent in populations in which the prevalence of HIV

infection is relatively low. It is noteworthy that this principle may not

apply to the treatment of HSV infections since it has been shown that

even following anti-HSV therapy with resulting healing of HSV-related

genital ulcers, HIV acquisition is not reduced. Biopsy studies revealed

that the likely explanation is that HIV receptor–positive inflammatory

cells persisted in the genital tissue despite the healing of ulcers, and so

HIV-susceptible targets remained at the site.

The quantity of HIV-1 in plasma (viral load) is a primary determinant of the risk of HIV-1 transmission. In a cohort of heterosexual

couples in Uganda discordant for HIV infection and not receiving

antiretroviral therapy, the mean serum HIV RNA level was significantly higher among HIV-infected subjects whose partners seroconverted than among those whose partners did not seroconvert. In fact,

transmission was rare when the infected partner had a plasma level of

<1700 copies of HIV RNA per milliliter, even when genital ulcer disease was present (Fig. 202-7). The rate of HIV transmission per coital

act was highest during the early stage of HIV infection when plasma

HIV RNA levels were high and in advanced disease with high viral set

points.

Antiretroviral therapy dramatically reduces plasma viremia in most

HIV-infected individuals (see “Antiretroviral Therapy” and “HIV

Prevention,” below) and is associated with a dramatic reduction in

risk of transmission, an approach widely referred to as treatment as

prevention or TasP. Multiple studies have demonstrated that if the viral

load of a person with HIV is reduced by antiretroviral therapy to below

detectable levels as measured by conventional commercial assays, there

is essentially no chance of sexual transmission to the person’s sexual

partner. This is true for heterosexuals as well as men who have sex with

men, leading to the commonly used description of this phenomenon as

“undetectable equals untransmittable” or “U=U.”

Multiple studies including large, randomized, controlled trials

clearly have indicated that male circumcision is associated with a lower

risk of acquisition of HIV infection for heterosexual men. Studies also

suggest that circumcision is protective against HIV acquisition for

men who have sex with men reporting mainly or only insertive sex.

The benefit of circumcision may be due to increased susceptibility of

uncircumcised men to ulcerative STIs, as well as to other factors such

as microtrauma to the foreskin and glans penis. In addition, the highly

vascularized inner layer of foreskin tissue contains a high density of

Langerhans cells as well as increased numbers of CD4+ T cells, macrophages, and other cellular targets for HIV. Finally, the moist environment under the foreskin may promote the presence or persistence of

microbial flora that, via inflammatory changes, may lead to even higher

concentrations of target cells for HIV in the foreskin. In addition, randomized clinical trials have demonstrated that male circumcision also

reduces herpes simplex virus (HSV) type 2, human papillomavirus

virus (HPV), and genital ulcer disease in men as well as HPV, genital

ulcer disease, bacterial vaginosis, and Trichomonas vaginalis infections

among female partners of circumcised men. Thus, there may be an

TABLE 202-3 Estimated Per-Act Probability of Acquiring HIV from an

Infected Source, By Exposure Act

TYPE OF EXPOSURE RISK PER 10,000 EXPOSURES

Parenteral

Blood transfusion 9250

Needle-sharing during injection drug use 63

Percutaneous (needle-stick) 23

Sexual

Receptive anal intercourse 138

Insertive anal intercourse 11

Receptive penile-vaginal intercourse 8

Insertive penile-vaginal intercourse 4

Receptive oral intercourse Low

Insertive oral intercourse Low

Othera

Biting Negligible

Spitting Negligible

Throwing body fluids (including semen or saliva) Negligible

Sharing sex toys Negligible

a

HIV transmission through these exposure routes is technically possible but unlikely

and not well documented.

Source: CDC, www.cdc.gov/hiv/risk/estimates/riskbehaviors.html.

0

10

20

30

40

50

Probability of transmission

per 10,000 coital acts

<1700 <1700–

12,499

12,500–

38,499

≥38,500

HIV load of infected partner, RNA copies/mL

No genital ulcer disease

Genital ulcer disease

FIGURE 202-7 Probability of HIV transmission per coital act among monogamous,

heterosexual, HIV-serodiscordant couples in Uganda. (From RH Gray et al: Lancet

357:1149, 2001.)