1519CHAPTER 200 Influenza

pneumonia is characterized by increasing dyspnea, persistent fever,

and—in more severe cases—cyanosis. Primary influenza pneumonia

was typical in the 1918 pandemic and occurs with H5N1 virus, as

initially described in Hong Kong in 1997. Pathologically, a marked

inflammatory reaction in the alveolar septa is characterized by infiltration of monocytes, lymphocytes, and macrophages, with variable

numbers of neutrophils. Destruction and hemorrhage are seen in the

respiratory epithelium. Large amounts of virus can be recovered from

the lungs.

In secondary bacterial pneumonia or mixed viral and bacterial

pneumonia, illness may be biphasic, with evidence of recovery from

the primary influenza illness followed by recrudescence of fever and

pulmonary symptoms. Localizing findings may be detected on pulmonary examination and/or x-ray. The development of secondary

bacterial infection is not surprising, as influenza de-epithelializes the

airways and destroys ciliary function, allowing bacterial contamination. Another proposed mechanism for bacterial/viral enhancement is

the production by Staphylococcus and Pseudomonas of proteases that

enhance cleavage of the influenza hemagglutinin and thereby facilitate

viral replication. The risk of secondary bacterial disease is greatest in

elderly patients and those with chronic obstructive pulmonary disease

(COPD).

Some influenza strains cause laryngotracheobronchitis, bronchiolitis, or croup in children. Otitis media—a common accompaniment to

influenza in children—may also be due to a combination of influenza

virus and bacteria.

Extrapulmonary Complications Although influenza is believed

to spread only rarely beyond the respiratory epithelial cells, where

unique endogenous proteases facilitate hemagglutinin cleavage and

productive infection, this disease causes not only prominent systemic

complaints but also a variety of extrapulmonary manifestations. The

most common extrapulmonary manifestation of influenza is myositis,

which is seen more often in influenza B and is characterized by severe

muscle pain, elevated creatinine phosphokinase levels, and myoglobinuria that can lead to renal failure. The muscles are extremely tender

to touch. Myo/pericarditis is seen less frequently. However, a consistent

epidemiologic link exists between influenza epidemics and excess cardiovascular hospitalizations.

Neurologic involvement, while rare, does occur following influenza infection. Influenza-associated encephalopathy or encephalitis

is characterized by rapid progression within a few days of influenza

infection. Transverse myelitis and Parkinsonian symptoms have been

reported. Postinfectious acute demyelinating encephalomyelitis can

follow influenza as well as other viral infections. The literature is

mixed on the benefit and reliability of efforts to establish a polymerase

chain reaction (PCR)–based diagnosis in this condition. MRI shows

distinctive multifocal, symmetric brain lesions affecting the thalamus,

brainstem tegmentum, cerebral periventricular white matter, and

cerebellar medulla. Neurologic manifestations are more frequent in

children as compared to adults. Children most commonly present with

febrile seizures, increased seizure frequency among those with seizure

disorders, or self-limited encephalopathy. More serious manifestations

of meningitis, encephalitis, and focal brain lesions may occur, particularly in children with preexisting neurologic conditions.

Guillain-Barré syndrome can develop after influenza and was

reported after a widespread influenza vaccination effort in the fall of

1976 that was undertaken in anticipation of a swine influenza epidemic

(which never materialized). Until aspirin was recognized as a cofactor

in its precipitation, Reye syndrome, an acute hepatic decompensation,

was seen commonly in children and adolescents with influenza, particularly those infected with influenza B virus. Subsequently, the use

of aspirin for fever control and symptom relief in children with viral

infections was strongly discouraged, and Reye syndrome has virtually

disappeared from clinical practice.

■ LABORATORY FINDINGS AND DIAGNOSIS

There is a strong argument for establishing a microbiologic diagnosis

from both an individual-patient and a public-health perspective. This

information is particularly valuable early in the season, when the

extent of influenza and the precise circulating strain(s) are uncertain;

in the management of high-risk or hospitalized patients; in settings

such as long-term-care facilities and hospitals, where the institution of

specific infection-control measures is appropriate; and in any patient

with influenza-like illness if the test results will influence clinical

management.

Influenza virus is most easily recovered from nasopharygeal specimens. If nasopharyngeal specimens are not available, nasal and throat

swab specimens should be collected and combined together for influenza testing over single specimens from either site. These samples are

most effectively collected with a flocked swab.

When available, rapid molecular assays (i.e., nucleic acid amplification test [NAAT]) are preferred over rapid influenza diagnostic

tests and immunofluorescence assays in inpatients and outpatients to

improve detection of influenza virus infection. Not only is this the most

sensitive and specific method, it also provides opportunities to identify

the strain with some specificity. Many such NAATs are multiplex, and

target a panel of common respiratory pathogens—influenza, respiratory syncytial virus, parainfluenzavirus, and coronaviruses including

SARS-CoV-2—an advantage in the ill hospitalized patient and during

outbreaks of other respiratory pathogens. Clinicians should not use

viral culture for initial or primary diagnosis of influenza because

results will not be available in a timely manner to inform clinical management, but viral culture can be considered to confirm negative test

results from rapid influenza diagnostic tests and immunofluorescence

assays, such as during an institutional outbreak, and to provide isolates

for further characterization.

Serologic confirmation of infection is also possible but requires

paired serum samples, with the convalescent-phase sample obtained

2 weeks after infection. Mucosal antibody assays that are now being

developed can detect strain-specific antibodies in paired mucosal specimens and yield insights into the importance of mucosal immunity in

protection against influenza.

Other laboratory tests are of limited value. Mild leukopenia is seen

in influenza, and a white blood cell count above 15,000/μL suggests a

secondary bacterial component in influenzal pneumonia.

■ DIFFERENTIAL DIAGNOSIS

Influenza may be diagnosed clinically based on an acute presentation

of a febrile respiratory illness during high periods of influenza circulation. However, less common presentations of influenza, and cases

occurring outside of peak influenza season, are frequently misdiagnosed on the basis of symptoms alone. Influenza symptoms and signs

may overlap with symptoms of other respiratory viruses. Respiratory

syncytial virus often co-circulates with influenza virus; it particularly

affects the youngest children, causing bronchiolitis, but it can also

infect the elderly, leading to an influenza-like nonspecific respiratory

illness and a decline in mobility, nutrition, and pulmonary function,

with resultant hospitalization.

Patients with COVID-19 have a wide range of symptoms reported,

ranging from mild to severe illness. Many of these symptoms—fever,

chills, cough, shortness of breath, fatigue, muscle aches, headaches,

congestion, or runny nose—overlap with the symptoms of influenza.

While new loss of taste (ageusia) or smell (anosmia) may distinguish

COVID-19 from influenza, they are reported in the minority of

infected persons. When SARS-CoV-2 and influenza viruses are cocirculating, clinicians should consider both viruses, as well as co-infection,

in patients with acute respiratory illness symptoms. The similar clinical

presentations reiterate the importance of testing in order to inform

treatment decisions.

■ IMMUNIZATION

Vaccination is the best approach to prevent influenza. The vaccines

currently available in the United States are increasing in number and

diversity (Table 200-4). These vaccines fall into two broad categories:

parenterally administered inactivated influenza vaccines and intranasally administered live-attenuated influenza vaccines. Current vaccines are further classified based on production substrate (eggs, cell),

1520 PART 5 Infectious Diseases

antigen dose and valence (trivalent or quadrivalent), and the presence

or absence of adjuvants. Current inactivated influenza vaccines are

designed with the common goal to induce immunity to the hemagglutinin surface glycoprotein of the influenza virus. No effort is made to

standardize the neuraminidase content.

As the viral surface hemagglutinin undergoes frequent antigenic

drift, the seasonal influenza vaccine is reformulated as often as twice

annually to match the strains projected to circulate in the following

influenza season. The decision about vaccine composition must be

made approximately 10 months before the seasonal peak in influenza

virus circulation; this decision is made by committees at the World

Health Organization (WHO). Subsequently, the US Food and Drug

Administration (FDA), which has regulatory authority over vaccines

in the United States, convenes an advisory committee that considers

the recommendations of WHO, reviews and discusses similar data, and

makes a final decision regarding vaccine virus composition of influenza vaccines licensed and marketed in the United States. This timing

can result in a mismatch of vaccine composition with the viral strains

that are actually prevalent in the upcoming season. Influenza vaccine

is unique in being given seasonally in the months immediately preceding an outbreak in temperate climates. In the United States, vaccine is

typically available starting in August or September.

The performance of current influenza vaccines varies by year, vaccine formulation, and the underlying age, health condition, and prior

virus and vaccine exposure of the recipient. Unfortunately, the relative

contribution of each of these factors has not been well elucidated,

given the many variables involved and the complex interplay of infection and host response. Depending upon the degree to which vaccine

strains match circulating strains, seasonal influenza vaccines will

confer more or less protection, as antibody against influenza is for the

most part strain-specific. A meta-analysis of randomized controlled

trials of influenza vaccine efficacy over 12 influenza seasons showed

inactivated influenza vaccines had a pooled efficacy of 59% (95% CI,

51%−67%) among those aged 18−65 years. Since 2004−2005, the CDC

has estimated the effectiveness of seasonal influenza vaccine to prevent

laboratory-confirmed influenza associated with medically attended

respiratory illness. During that period, effectiveness ranged from

approximately 40%−60% across all age groups during seasons when

most circulating influenza vaccines are antigenically similar to the recommended influenza vaccine components; effectiveness was lower in

years with strain mismatch. Importantly, studies support that influenza

vaccine mitigates disease severity. For example, observational studies in

children support that influenza vaccination reduces intensive care unit

hospitalizations and deaths by an estimated 74% and 65%, respectively.

Newer technologies have been developed to overcome some of the

limitations of current vaccines. The first fully recombinant vaccine

was approved by the FDA in 2017. Both recombinant and cell-based

vaccines may overcome the egg-adaptation of vaccine strains that

may contribute to diminished vaccine effectiveness. Oil-in-water

adjuvanted vaccines and high-dose vaccines elicit greater immune

responses than traditional inactivated influenza vaccines and are

approved in the United States for persons ≥65 years of age. In most

head-to-head comparisons, high-dose vaccines have shown superior

effectiveness to standard dose. While evidence is more limited, select

comparisons of recombinant and adjuvanted vaccines with standard

vaccines likewise show improved effectiveness.

In head-to-head comparisons in pediatric populations in the 1990s,

a live, attenuated, intranasally administered vaccine (LAIV) exhibited

an efficacy exceeding that of injected inactivated vaccines. LAIV is a

desirable option in children given the ease of intranasal administration

and theoretical advantage of stimulating mucosal immunity by the

topical route. However, in the 2014−2016 influenza seasons, LAIV had

lower replicative fitness and no demonstrable efficacy assignable to

the vaccine’s H1N1 component. Consequently, advisory committees in

the United States and elsewhere suspended the recommendations for

use of LAIV until manufacturing improvements allowed reinstatement

of recommendations for its use in 2018. Since that time, LAIV has

performed comparably to inactivated influenza vaccines in annual

effectiveness assessments.

Inactivated influenza vaccines have been licensed for more than

60 years and have a robust safety and tolerability profile. While local

reactions are most common following inactivated influenza vaccines,

rare adverse events may occur. These include Guillain-Barré syndrome,

identified in 1976 and less frequently during other years; oculorespiratory syndrome, first recognized in 2000; and febrile seizures first

reported in young children in Australia in 2010. Adjuvanted vaccines

in general cause more local pain and erythema than unadjuvanted

vaccines. LAIVs have been associated with excess wheezing and hospitalizations in children younger than 2 years, and thus are not licensed

for use in this age group.

Vaccine-specific recommendations for use, the approved age range

of each product, the route of administration, and the anticipated side

effects are updated annually by the CDC (https://www.cdc.gov/vaccines/

hcp/acip-recs/vacc-specific/flu.html). In the United States, routine

annual influenza vaccination is recommended for all persons 6 months

of age and older. No preferential recommendation is made for one

influenza vaccine product over another for persons for whom more

than one licensed, recommended, and appropriate product is available.

Two doses of vaccine should be given to children <9 years of age who

are getting their first or second yearly vaccination. Groups at special

risk of experiencing or transmitting influenza and for whom influenza

immunization is a particularly high priority are listed in Table 200-2.

In general, influenza vaccine is not recommended for persons with

a history of severe allergic reaction to the vaccine or to components

other than egg. Manufacturer package inserts and updated CDC guidance should be consulted for information on contraindications and

precautions for individual influenza vaccines, including specific guidance for persons with a history of egg allergy. A history of Guillain-Barré

syndrome within 6 weeks of a previous dose of influenza vaccine is

considered a precaution for the use of all influenza vaccines.

TREATMENT

Influenza

Antiviral therapy for influenza has been limited by the paucity of

available drugs, the short duration of symptoms in uncomplicated

influenza, and the changing patterns of drug resistance in influenza

viral strains. In the past, influenza A infection could be treated with

the M-2 channel blockers amantadine and rimantadine. Widespread resistance has currently relegated these compounds to historical interest only.

TABLE 200-4 Categories of Vaccines Licensed for Prevention of Seasonal Influenza, United States

LIVE ATTENUATED

NONREPLICATING VACCINES

STANDARD INACTIVATED HIGH-DOSE INACTIVATED RECOMBINANT ADJUVANTED INACTIVATED

ROUTE Intranasal Intramuscular Intramuscular Intramuscular Intramuscular

APPROVED AGES 2–49 years ≥6 months ≥65 years ≥18 years ≥65 years

HAa 15 15 60 45 15

SUBSTRATE Eggs Eggs/cell culture Eggs Cell culture Eggs

NUMBER OF STRAINS 4 4 4 4 3/4

a

Hemagglutinin content in micrograms per strain.

1521CHAPTER 201 The Human Retroviruses

Neuraminidase inhibitors have been the mainstay for treatment

of influenza A and B viruses for many years. As their name implies,

these drugs inhibit the influenza neuraminidase and thus limit

the egress of influenza virus from an infected cell. They are most

effective in patients whose influenza illness is recognized early and

confirmed by rapid diagnostic testing or on the basis of clinical and

epidemiologic evidence. In experimental trials, these drugs hasten

the resolution of symptoms if given within 48 h of infection. There

are indications for their use both prophylactically—either throughout the season or, when a case is recognized in a close contact,

in the short term—and therapeutically. The anticipated effect of

early administration is the resolution of symptoms 1–2 days sooner

than without treatment. The use of neuraminidase inhibitors is

recommended for complicated influenza infections in hospitalized patients in the absence of formal proof of efficacy and when

diagnosis may have been delayed. All the available neuraminidase

inhibitors carry a risk of development of resistance, particularly

with prolonged administration (e.g., to an immunodeficient individual with persistent recovery of influenza virus). Resistance

to neuraminidase inhibitors is not widespread among currently

circulating influenza A or B strains, but its development has been

demonstrated in the laboratory, and clinical resistance could influence the utility of these drugs.

The defined risk groups who can benefit from neuraminidase

inhibitors include children <2 years of age, adults >65 years of age,

patients with chronic conditions, immunosuppressed individuals,

pregnant women, women who have delivered infants ≤2 weeks previously, patients <19 years old who are receiving long-term aspirin

treatment, Native Americans (including Alaska Natives), morbidly

obese individuals, and residents of nursing homes or chronic-care

facilities. This list resembles that of candidates whose vaccination is a

high priority (Table 200-2). Use of neuraminidase inhibitors should be

considered in selected high-risk cases despite a history of vaccination.

The available neuraminidase inhibitors are oral oseltamivir,

nasal-spray zanamivir, and intravenous peramivir. Oseltamivir,

which is most widely used, is an orally absorbed drug that is converted to its active component, oseltamivir carboxylate, in the liver.

Gastrointestinal symptoms, especially nausea, may accompany

the administration of oseltamivir. Because zanamivir is not orally

bioavailable, it is given as an inhaled dry powder dispersed through

a Diskhaler device.

The usual duration of therapy with either oral oseltamivir or

intranasal zanamivir is 5 days, with twice-a-day dosing. Oseltamivir is preferred for treatment of pregnant women and is approved

for treatment at any age, beginning at 14 days of life in infants.

Poor oral intake or absorption is a contraindication to the use

of oseltamivir, although this drug can also be given by oro/nasal

tube. Asthma and COPD are relative contraindications to the use

of intranasal zanamivir; this agent is approved for treatment in

persons 7 years and older. For hospitalized patients with suspected

or confirmed influenza, initiation of antiviral treatment with oral

or enterically administered oseltamivir is recommended as soon

as possible. For patients who cannot tolerate or absorb oral or

enterically administered oseltamivir, the use of a single infusion of

intravenous peramivir should be considered. Peramivir is licensed

for individuals ≥2 years of age. The most current recommendations

and details on influenza antiviral drug use and release are available

through the CDC (https://www.cdc.gov/flu/professionals/antivirals/

summary-clinicians.htm#summary).

In 2018, a first-in-class compound, baloxavir marboxil

(XOFLUZA), was approved by the FDA for persons 12 years and

older for prophylaxis or treatment of uncomplicated influenza

within 2 days of onset of illness. Baloxavir inhibits cap-dependent

endonuclease, has activity against influenza A and B, and is a singledose formulation. In clinical studies, if given within 48 hours of

symptoms, baloxavir decreased symptom duration, viral shedding, and antibiotic use in healthy individuals with uncomplicated

influenza. However, development of resistance is a concern with

2−10% of the trial participants who received baloxavir showing

viral escape with reduced drug susceptibility. CDC does not recommend use of baloxavir in pregnant women, breastfeeding mothers, outpatients with complicated or progressive illness, severely

immunosuppressed patients, or hospitalized patients because of

lack of information on use of baloxavir for these groups.

Other critical aspects of treatment include maintenance of fluid

and electrolyte balance, oxygen supplementation, fever control with

nonsteroidal anti-inflammatory drugs, and treatment of suspected

secondary bacterial complications with antibiotics. Appropriate

respiratory isolation of patients should be practiced in accordance

with local hospital guidelines.

■ FURTHER READING

Barry JM: The Great Influenza: The Story of the Deadliest Pandemic in

History. New York, Penguin Books, 2005.

Chung JR: Effects of influenza vaccination in the United States during

the 2018−2019 influenza season. Clin Infect Dis 71:e368, 2020.

Erbelding EJ: A universal influenza vaccine: The strategic plan for

the National Institute of Allergy and Infectious Diseases. J Infect Dis

218:347, 2018.

Fineberg HV: Pandemic preparedness and response—lessons from

the H1N1 influenza of 2009. N Engl J Med 370:1335, 2014.

Kash JC, Taubenberger JK: The role of viral, host, and secondary

bacterial factors in influenza pathogenesis. Am J Pathol 185:1528,

2015.

Osterholm MT et al: Efficacy and effectiveness of influenza vaccines:

A systemic review and meta-analysis. Lancet Infect Dis 12:36, 2012.

Treanor JJ: Influenza vaccination. N Engl J Med 375:1261, 2016.

Uyeki TM et al: Novel influenza A viruses and pandemic threats. Lancet 398:2172, 2017.

Watanabe T et al: 1918 influenza virus hemagglutinin (HA) and the

viral RNA polymerase complex enhance viral pathogenicity, but only

HA induces aberrant host responses in mice. J Virol 87:5239, 2013.

Wright PF et al: Correlates of immunity to influenza as determined

by challenge of children with live, attenuated influenza vaccine. Open

Forum Infect Dis 3:108, 2016.

Section 14 Infections Due to Human

Immunodeficiency Virus and Other

Human Retroviruses

201

The retroviruses, which make up a large family (Retroviridae), infect

mainly vertebrates. These viruses have a unique replication cycle

whereby their genetic information is encoded by RNA rather than

DNA. Retroviruses contain an RNA-dependent DNA polymerase

(a reverse transcriptase) that directs the synthesis of a DNA form of

the viral genome after infection of a host cell. The designation retrovirus denotes that information in the form of RNA is transcribed into

DNA in the host cell—a sequence that overturned a central dogma of

molecular biology: that information passes unidirectionally from DNA

to RNA to protein. The observation that RNA was the source of genetic

information in the causative agents of certain animal tumors led to a

number of paradigm-shifting biologic insights regarding not only the

direction of genetic information passage but also the viral etiology of

certain cancers and the concept of oncogenes as normal host genes

scavenged and altered by a viral vector.

The Human

Retroviruses

Dan L. Longo, Anthony S. Fauci

1522 PART 5 Infectious Diseases

The family Retroviridae includes seven subfamilies (Table 201-1).

Members of two of the families infect humans with pathologic consequences: the deltaretroviruses, of which human T-cell lymphotropic

virus (HTLV) type 1 is the most important in humans; and the lentiviruses, of which HIV is the most important in humans.

The wide variety of interactions of a retrovirus with its host range

from completely benign events (e.g., silent carriage of endogenous

retroviral sequences in the germline genome of many animal species)

to rapidly fatal infections (e.g., exogenous infection with an oncogenic

virus such as Rous sarcoma virus in chickens). The ability of retroviruses to acquire and alter the structure and function of host cell genetic

sequences has revolutionized our understanding of molecular carcinogenesis. The viruses can insert into the germline genome of the host

cell and behave as a transposable or movable genetic element. They can

activate or inactivate genes near the site of integration into the genome.

They can rapidly alter their own genome by recombination and mutation under selective environmental stimuli.

Most human viral diseases occur as a consequence of tissue destruction either directly by the virus itself or indirectly by the host’s response

to the virus. Although these mechanisms are operative in retroviral

infections, retroviruses have additional mechanisms of inducing disease, including the malignant transformation of an infected cell and the

induction of an immunodeficiency state through selective destruction

or dysfunction of immune-competent cells that renders the host susceptible to opportunistic diseases (infections and neoplasms; Chap. 202).

STRUCTURE AND LIFE CYCLE

All retroviruses are similar in structure, genome organization, and

mode of replication. Retroviruses are 70–130 nm in diameter and

have a lipid-containing envelope surrounding an icosahedral capsid

with a dense inner core. The core contains two identical copies of the

single-strand RNA genome. The RNA molecules are 8–10 kb long

and are complexed with reverse transcriptase and tRNA. Other viral

proteins, such as integrase, are also components of the virion particle.

The RNA has features usually found in mRNA: a cap site at the 5′ end

of the molecule, which is important in the initiation of mRNA translation, and a polyadenylation site at the 3′ end, which influences mRNA

turnover (i.e., messages with shorter polyA tails turn over faster than

messages with longer polyA tails). However, the retroviral RNA is not

translated; instead, it is transcribed into DNA. The DNA form of the

retroviral genome is called a provirus.

The replication cycle of retroviruses proceeds in two phases

(Fig. 201-1). In the first phase, the virus enters the cytoplasm after

binding to one or more specific cell-surface receptors; the viral RNA

and reverse transcriptase synthesize a double-strand DNA version

of the RNA template; and the provirus moves into the nucleus and

integrates into the host cell genome. This proviral integration is permanent. Although some animal retroviruses integrate into a single

specific site of the host genome in every infected cell, the human retroviruses integrate randomly. This first phase of replication depends

entirely on gene products in the virus. The second phase includes the

synthesis and processing of viral genomes, mRNAs, and proteins using

TABLE 201-1 Classification of Retroviruses: The Family Retroviridae

GENUS EXAMPLE(S) FEATURE

Alpharetrovirus Rous sarcoma virus Contains src oncogene

Betaretrovirus Mouse mammary

tumor virus

Exogenous or endogenous

Gammaretrovirus Abelson murine

leukemia virus

Contains abl oncogene

Deltaretrovirus HTLV-1 Causes T-cell lymphoma and

neurologic disease

Epsilonretrovirus Walleye dermal sarcoma

virus

Not known to be pathogenic

in humans

Lentivirus HIV-1, HIV-2 Causes AIDS

Spumavirus Simian foamy virus Not known to be pathogenic

in humans

Adsorption to

specific receptor

Reverse

transcription

Transcription

Provirus

Proteins

Splicing

Genomes

gag

gag pol env

gag pol env

gag pol env

gag pol env

gag pol env

gag pol env

gag pol mRNA

env mRNA

env proteins

m7G

m7G

m7G

m7G

m7G

m7G

m7G pol

Penetration

Integration Translation

Transcription

Polyadenylation

Capsid

assembly

Budding

A

B

FIGURE 201-1 The life cycle of retroviruses. A. Overview of virus replication. The

retrovirus enters a target cell by binding to a specific cell-surface receptor; once

the virus is internalized, its RNA is released from the nucleocapsid and is reversetranscribed into proviral DNA. The provirus is inserted into the genome and then

transcribed into RNA; the RNA is translated; and virions assemble and are extruded

from the cell membrane by budding. B. Overview of retroviral gene expression. The

provirus is transcribed, capped, and polyadenylated. Viral RNA molecules then have

one of three fates: they are exported to the cytoplasm, where they are packaged

as the viral RNA in infectious viral particles; they are spliced to form the message

for the envelope polyprotein; or they are translated into Gag and Pol proteins. Most

of the messages for the Pol protein fail to initiate Pol translation because of a stop

codon before its initiation; however, in a fraction of the messages, the stop codon is

missed, and the Pol proteins are translated. (Reproduced with permission from JM

Coffin, in BN Fields, DM Knipe [eds]: Fields Virology. New York, Raven, 1990.)

host cell machinery, often under the influence of viral gene products.

Virions are assembled and released from the cell by budding from the

membrane; host cell membrane proteins are frequently incorporated

into the envelope of the virus. Proviral integration occurs during the

S-phase of the cell cycle; thus, in general, nondividing cells are resistant

to retroviral infection. Only the lentiviruses are able to infect nondividing cells. Once a host cell is infected, it is infected for the life of the cell.

Retroviral genomes include both coding and noncoding sequences

(Fig. 201-2). In general, noncoding sequences are important recognition signals for DNA or RNA synthesis or processing events

and are located in the 5′ and 3′ terminal regions of the genome. All

retroviral genomes are terminally redundant, containing identical

sequences called long terminal repeats (LTRs). The ends of the retroviral RNA genome differ slightly in sequence from the integrated retroviral DNA. In the latter, the LTR sequences are repeated in both the 5′

and the 3′ terminus of the virus. The LTRs contain sequences involved

in initiating the expression of the viral proteins, the integration of the

provirus, and the polyadenylation of viral RNAs. The primer binding

site, which is critical for the initiation of reverse transcription, and the

1523CHAPTER 201 The Human Retroviruses

viral packaging sequences are located outside the LTR sequences. The

coding regions include the gag (group-specific antigen, core protein),

pol (RNA-dependent DNA polymerase), and env (envelope) genes. The

gag gene encodes a precursor polyprotein that is cleaved to form three

to five capsid proteins; a fraction of the Gag precursor proteins also

contain a protease responsible for cleaving the Gag and Pol polyproteins. A Gag-Pol polyprotein gives rise to the protease that is responsible for cleaving the Gag-Pol polyprotein. The pol gene encodes three

proteins: the reverse transcriptase, the integrase, and the protease. The

reverse transcriptase copies the viral RNA into the double-strand DNA

provirus, which inserts itself into the host cell DNA via the action of

integrase. The protease cleaves the Gag-Pol polyprotein into smaller

protein products. The env gene encodes the envelope glycoproteins:

one protein that binds to specific surface receptors and determines

what cell types can be infected and a smaller transmembrane protein

that anchors the complex to the envelope. Fig. 201-3 shows how the

retroviral gene products make up the virus structure.

HTLVs have a region between env and the 3′ LTR that encodes

several proteins and transcripts in overlapping reading frames

(Fig. 201-2). Tax is a 40-kDa protein that does not bind to DNA but

induces the expression of host cell transcription factors that alter host

cell gene expression and is capable of inducing cell transformation

under certain circumstances. Rex is a 27-kDa protein that regulates the

expression of viral mRNAs. Other transcripts from this region (p12,

p13, and p30) tend to restrict expression of viral genes and diminish

the immunogenicity of infected cells. The protein of HBZ, a product of

the complementary proviral DNA strand, interacts with many cellular

transcription factors and signaling proteins. It stimulates proliferation

of infected cells and is the only viral product universally expressed in

HTLV-1-infected tumor cells. These proteins are produced from messages that are similar but that are spliced differently from overlapping

but distinct exons.

The lentiviruses in general, and HIV-1 and -2 in particular, contain

a larger genome than other pathogenic retroviruses. They contain

an untranslated region between pol and env that encodes portions

of several proteins, varying with the reading frame into which the

mRNA is spliced. Tat is a 14-kDa protein that augments the expression

of virus from the LTR. The Rev protein of HIV-1, similar to the Rex

protein of HTLV, regulates RNA splicing and/or RNA transport. The

Nef protein downregulates CD4, the cellular receptor for HIV; alters

host T cell–activation pathways; and enhances viral infectivity. The Vif

protein is necessary for the proper assembly of the HIV nucleoprotein

core in many types of cells; without Vif, proviral DNA is not efficiently

produced in these infected cells. In addition, the Vif protein targets

APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide, a cytidine deaminase that mutates the viral sequence) for proteasomal degradation, thus blocking its virus-suppressing effect. Vpr,

LTR

LTR

LTR

LTR

MuLV

HTLV-I,II

HIV-1

HIV-2

ENV

GAG POL

POL

LTR

LTR

p19 p24 p15

GAG

MA CA NC PR RT

p14 p95

GP46 p21

SU TM

TAX, p40

REX, p27

TAT, p14

REV, p19

p30

p12

p13

HBZ

MA CA

GAG

NC

p17 p24 p7

p10

PR

RT IN

POL

p66 p32

p23

VIF

VPR VPU

p15 p16

GP120 GP41

SU ENV TM

NEF

p27 LTR

GAG

POL

VIF

VPX VPR

ENV

NEF

LTR

TAT

REV

FIGURE 201-2 Genomic structure of retroviruses. The murine leukemia virus MuLV has the typical three structural genes: gag, pol, and env. The gag region gives rise to

three proteins: matrix (MA), capsid (CA), and nucleic acid–binding (NC) proteins. The pol region encodes both a protease (PR) responsible for cleaving the viral polyproteins

and a reverse transcriptase (RT). In addition, HIV pol encodes an integrase (IN). The env region encodes a surface protein (SU) and a small transmembrane protein (TM).

The human retroviruses have additional gene products translated in each of the three possible reading frames. HTLV-1 and HTLV-2 have tax and rex genes with exons on

either side of the env gene. HIV-1 and HIV-2 have six accessory gene products: tat, rev, vif, nef, vpr, and either vpu (in HIV-1) or vpx (in HIV-2). The genes for these proteins

are located mainly between the pol and env genes. GP, glycoprotein; HBZ, HTLV-1 basic leucine zipper domain–containing protein; LTR, long terminal repeat.

HTLV-I HIV-1

SU

TM

NC

PR

RT

IN

MA

CA

RNA

gp46

p21

p15

p14

p95

 ––

p19

p24

9kb

gp120

gp41

p7

p10

p66

p32

p17

p24

10kb

FIGURE 201-3 Schematic structure of human retroviruses. The surface glycoprotein

(SU) is responsible for binding to receptors of host cells. The transmembrane

protein (TM) anchors SU to the virus. NC is a nucleic acid–binding protein found in

association with the viral RNA. A protease (PR) cleaves the polyproteins encoded

by the gag, pol, and env genes into their functional components. RT is reverse

transcriptase, and IN is an integrase present in some retroviruses (e.g., HIV-1) that

facilitates insertion of the provirus into the host genome. The matrix protein (MA) is

a Gag protein closely associated with the lipid of the envelope. The capsid protein

(CA) forms the major internal structure of the virus, the core shell.

1524 PART 5 Infectious Diseases

Vpu (HIV-1 only), and Vpx (HIV-2 only) are viral proteins encoded by

translation of the same message in different reading frames. As noted

above, oncogenic retroviruses depend on cell proliferation for their

replication; lentiviruses can infect nondividing cells, largely through

effects mediated by Vpr. Vpr facilitates transport of the provirus into

the nucleus and can induce other cellular changes, such as G2

 growth

arrest and differentiation of some target cells. Vpx is structurally related

to Vpr, but its functions are not fully defined. Vpu promotes the degradation of CD4 in the endoplasmic reticulum and stimulates the release

of virions from infected cells.

Retroviruses can be either exogenously acquired (by infection with

an infected cell or a free virion capable of replication) or transmitted

in the germline as endogenous virus. Endogenous retroviruses are

often replication defective. The human genome contains endogenous

retroviral sequences, but there are no known replication-competent

endogenous retroviruses in humans.

In general, viruses that contain only the gag, pol, and env genes

either are not pathogenic or take a long time to induce disease; these

observations indicate the importance of the other regulatory genes in

viral disease pathogenesis. The pathogenesis of neoplastic transformation by retroviruses relies on the chance integration of the provirus at a

spot in the genome resulting in the expression of a cellular gene (protooncogene) that becomes transforming by virtue of its unregulated

expression. For example, avian leukosis virus causes B-cell leukemia

by inducing the expression of myc. Some retroviruses possess captured

and altered cellular genes near their integration site, and these viral

oncogenes can transform the infected host cell. Viruses that have

oncogenes often have lost a portion of their genome that is required

for replication. Such viruses need helper viruses to reproduce, a feature

that may explain why these acute transforming retroviruses are rare in

nature. All human retroviruses identified to date are exogenous and

are not acutely transforming (i.e., they lack a transforming oncogene).

These remarkable properties of retroviruses have led to experimental efforts to use them as vectors to insert specific genes into particular

cell types, a process known as gene therapy or gene transfer. The process

could be used to repair a genetic defect or to introduce a new property

that could be used therapeutically; for example, a gene (e.g., thymidine

kinase) that would make a tumor cell susceptible to killing by a drug

(e.g., ganciclovir) could be inserted. One source of concern about

the use of retroviral vectors in humans is that replication-competent

viruses might rescue endogenous retroviral replication, with unpredictable results. This concern is not merely hypothetical: the detection

of proteins encoded by endogenous retroviral sequences on the surface

of cancer cells implies that the genetic events leading to the cancer were

able to activate the synthesis of these usually silent genes.

HUMAN T-CELL LYMPHOTROPIC VIRUS

HTLV-1, a delta retrovirus, was isolated in 1980 from a T-cell lymphoma cell line from a patient originally thought to have cutaneous

T-cell lymphoma. Later it became clear that the patient had a distinct

form of lymphoma (originally reported in Japan) called adult T-cell

leukemia/lymphoma (ATL). Serologic data have determined that

HTLV-1 is the cause of at least two important diseases: ATL and

tropical spastic paraparesis, also called HTLV-1-associated myelopathy

(HAM). HTLV-1 may also play a role in infective dermatitis, arthritis,

uveitis, and Sjögren’s syndrome.

Two years after the isolation of HTLV-1, HTLV-2 was isolated from

a patient with an unusual form of hairy cell leukemia that affected

T cells. Epidemiologic studies of HTLV-2 failed to reveal a consistent

disease association. Similarly, HTLV-3 and HTLV-4 have been identified but have no known disease association.

■ BIOLOGY AND MOLECULAR BIOLOGY

Because the biology of HTLV-1 and that of HTLV-2 are similar, the

following discussion will focus on HTLV-1.

Human glucose transporter protein 1 (GLUT-1) functions as a receptor for HTLV-1, probably acting together with neuropilin-1 (NRP1)

and heparan sulfate proteoglycans. The heparan sulfate proteoglycans

do not appear to be involved with HTLV-2 cell entry. Generally, only

T cells are productively infected, but infection of B cells and other cell

types is occasionally detected. The most common outcome of HTLV-1

infection is latent carriage of randomly integrated provirus in CD4+ T

cells. HTLV-1 does not contain an oncogene and does not insert into a

unique site in the genome. Indeed, most infected cells express no viral

gene products. The only viral gene product that is routinely expressed

in tumor cells transformed by HTLV-1 in vivo is hbz. The tax gene is

thought to be critical to the transformation process but is not expressed

in the tumor cells of many ATL patients, possibly because of the immunogenicity of tax-expressing cells. Cells transformed in vitro, by contrast, actively transcribe HTLV-1 RNA and produce infectious virions.

Most HTLV-1-transformed cell lines are the result of the infection of a

normal host T cell in vitro. It is difficult to establish cell lines derived

from authentic ATL cells.

Although tax does not itself bind to DNA, it is located in the nucleus

and induces the expression of a wide range of host cell gene products,

including transcription factors (especially c-rel/nuclear factor κB

[NF-κB], ets-1 and -2, and members of the fos/jun family), cytokines

(e.g., interleukin [IL] 2, granulocyte-macrophage colony-stimulating

factor, and tumor necrosis factor), membrane proteins and receptors

(major histocompatibility [MHC] molecules and IL-2 receptor α), and

chromatin remodeling complexes. The genes activated by tax are generally controlled by transcription factors of the c-rel/NF-κB and cyclic

AMP response element binding (CREB) protein families. It is unclear

how this induction of host gene expression leads to neoplastic transformation; tax can interfere with G1

 and mitotic cell-cycle checkpoints,

block apoptosis, inhibit DNA repair, and promote antigen-independent

T cell proliferation. Induction of a cytokine-autocrine loop has been

proposed; however, IL-2 is not the crucial cytokine. The involvement

of IL-4, IL-7, and IL-15 has been proposed.

In light of the irregular expression of tax in ATL cells, it has been

suggested that tax is important in the early phases of transformation

but is not essential for the maintenance of the transformed state. The

maintenance role is thought to be due to hbz expression. As is clear

from the epidemiology of HTLV-1 infection, transformation of an

infected cell is a rare event and may depend on heterogeneous second,

third, or fourth genetic hits. No consistent chromosomal abnormalities have been described in ATL; however, aneuploidy is common,

and individual cases with p53 mutations and translocations involving

the T cell receptor genes on chromosome 14 have been reported. Tax

may repress certain DNA repair enzymes, permitting the accumulation of genetic damage that would normally be repaired. However,

the molecular pathogenesis of HTLV-1-induced neoplasia is not fully

understood.

■ FEATURES OF HTLV-1 INFECTION

Epidemiology HTLV-1 infection is transmitted in at least three

ways: from mother to child, especially via breast milk; through sexual activity, more commonly from men to women; and through the

blood—via contaminated transfusions or contaminated needles. The

virus is most commonly transmitted perinatally. Compared with HIV,

which can be transmitted in cell-free form, HTLV-1 is less infectious,

and its transmission usually requires cell-to-cell contact.

HTLV-1 is endemic in southwestern Japan and Okinawa, where

>1 million persons are infected. Antibodies to HTLV-1 are present in

the serum of up to 35% of Okinawans, 10% of residents of the Japanese

island of Kyushu, and <1% of persons in nonendemic regions of Japan.

Despite this high prevalence of infection, only ~500 cases of ATL

are diagnosed in this area each year. Clusters of infection have been

noted in other areas of eastern Asia, such as Taiwan; in the Caribbean

basin, including northeastern South America; in northwestern South

America; in central and southern Africa; in Italy, Israel, Iran, and

Papua New Guinea; in the Arctic; and in the southeastern part of the

United States (Fig. 201-4). An estimated 5–10 million persons have

HTLV-1 infection worldwide.

Progressive spastic or ataxic myelopathy developing in an individual

who is HTLV-1 positive (i.e., who has serum antibodies to HTLV-1)

may be due to direct infection of the nervous system with the virus, but

1525CHAPTER 201 The Human Retroviruses

FIGURE 201-4 Global distribution of HTLV-1 infection. Countries with a prevalence of HTLV-1 infection of 1–5% are

shaded darkly. Note that the distribution of infected patients is not uniform in endemic countries. For example, the

people of southwestern Japan and northeastern Brazil are more commonly affected than those in other regions of

those countries.

destruction of the pyramidal tracts appears to involve HTLV-1-infected

CD4+ T cells; a similar disorder may result from infection with HIV

or HTLV-2. In rare instances, patients with HAM are seronegative but

have detectable antibody to HTLV-1 in cerebrospinal fluid (CSF).

The cumulative lifetime risk of developing ATL is 3% among HTLV1-infected patients, with a threefold greater risk among men than

among women; a similar cumulative risk is projected for HAM (4%),

but with women more commonly affected than men. The distribution

of these two diseases overlaps the distribution of HTLV-1, with >95%

of affected patients showing serologic evidence of HTLV-1 infection.

The latency period between infection and the emergence of disease is

20–30 years for ATL. For HAM, the median latency period is ~3.3 years

(range, 4 months to 30 years). The development of ATL is rare among

persons infected by blood products; however, ~20% of patients with

HAM acquire HTLV-1 from contaminated blood. ATL is more common among perinatally infected individuals, whereas HAM is more

common among persons infected via sexual transmission.

Associated Diseases •  ATL Four clinical types of HTLV-1-

induced neoplasia have been described: acute, lymphomatous, chronic,

and smoldering. All of these tumors are monoclonal proliferations of

CD4+ postthymic T cells with clonal proviral integrations and clonal

T cell receptor gene rearrangements.

ACUTE ATL About 60% of patients who develop malignancy have

classic acute ATL, which is characterized by a short clinical prodrome

(~2 weeks between the first symptoms and the diagnosis) and an

aggressive natural history (median survival period, 6 months). The

clinical picture is dominated by rapidly progressive skin lesions, pulmonary involvement, hypercalcemia, and lymphocytosis with cells

containing lobulated or “flower-shaped” nuclei (see Fig. 108-7). The

malignant cells have monoclonal proviral integrations and express

CD4, CD3, and CD25 (low-affinity IL-2 receptors) on their surface.

Serum levels of CD25 can be used as a tumor marker. Anemia and

thrombocytopenia are rare. The skin lesions may be difficult to distinguish from those in mycosis fungoides. Lytic bone lesions, which are

common, do not contain tumor cells but rather are composed of osteolytic cells, usually without osteoblastic activity. Despite the leukemic

picture, bone marrow involvement is patchy in most cases.

The hypercalcemia of ATL is multifactorial; the tumor cells produce

osteoclast-activating factors (tumor necrosis factor α, IL-1, lymphotoxin) and can also produce a parathyroid hormone–like molecule.

Affected patients have an underlying immunodeficiency that makes

them susceptible to opportunistic infections similar to those seen in

patients with AIDS (Chap. 202). The pathogenesis of the immunodeficiency is unclear. Pulmonary infiltrates in ATL patients reflect leukemic

infiltration half the time and opportunistic infections with organisms

such as Pneumocystis and other fungi the other half. Gastrointestinal

symptoms are nearly always related to

opportunistic infection. Strongyloides stercoralis is a gastrointestinal parasite that has

a pattern of endemic distribution similar to

that of HTLV-1. HTLV-1-infected persons

also infected with this parasite may develop

ATL more often or more rapidly than those

without Strongyloides infections. Serum

concentrations of lactate dehydrogenase

and alkaline phosphatase are often elevated

in ATL. About 10% of patients have leptomeningeal involvement leading to weakness, altered mental status, paresthesia,

and/or headache. Unlike other forms of

central nervous system (CNS) lymphoma,

ATL may be accompanied by normal CSF

protein levels. The diagnosis depends on

finding ATL cells in the CSF (Chap. 108).

LYMPHOMATOUS ATL The lymphomatous

type of ATL occurs in ~20% of patients and

is similar to the acute form in its natural

history and clinical course, except that circulating abnormal cells are

rare and lymphadenopathy is evident. The histology of the lymphoma

is variable but does not influence the natural history. In general, the

diagnosis is suspected on the basis of the patient’s birthplace (see “Epidemiology,” above) and the presence of skin lesions and hypercalcemia.

The diagnosis is confirmed by the detection of antibodies to HTLV-1

in serum.

CHRONIC ATL Patients with the chronic form of ATL generally have

normal serum levels of calcium and lactate dehydrogenase and no

involvement of the CNS, bone, or gastrointestinal tract. The median

duration of survival for these patients is 2 years. In some cases, chronic

ATL progresses to the acute form of the disease.

SMOLDERING ATL Fewer than 5% of patients have the smoldering

form of ATL. In this form, the malignant cells have monoclonal proviral

integration; <5% of peripheral-blood cells exhibit typical morphologic

abnormalities; hypercalcemia, adenopathy, and hepatosplenomegaly

do not develop; the CNS, the bones, and the gastrointestinal tract are

not involved; and skin lesions and pulmonary lesions may be present.

The median survival period for this small subset of patients appears to

be ≥5 years.

HAM (TROPICAL SPASTIC PARAPARESIS) In contrast to ATL, in which

there is a slight predominance of male patients, HAM affects female

patients disproportionately. HAM resembles multiple sclerosis in certain

ways (Chap. 444). The onset is insidious. Symptoms include weakness

or stiffness in one or both legs, back pain, and urinary incontinence.

Sensory changes are usually mild, but peripheral neuropathy may

develop. The disease generally takes the form of slowly progressive and

unremitting thoracic myelopathy; one-third of patients are bedridden

within 10 years of diagnosis, and one-half are unable to walk unassisted

by this point. Patients display spastic paraparesis or paraplegia with

hyperreflexia, ankle clonus, and extensor plantar responses. Cognitive

function is usually spared; cranial nerve abnormalities are unusual.

MRI reveals lesions in both the white matter and the paraventricular

regions of the brain as well as in the spinal cord. Pathologic examination of the spinal cord shows symmetric degeneration of the lateral

columns, including the corticospinal tracts; some cases involve the

posterior columns as well. The spinal meninges and cord parenchyma

contain an inflammatory infiltrate that includes CD8+ T cells with

myelin destruction.

HTLV-1 is not usually found in cells of the CNS but may be detected

in a small population of lymphocytes present in the CSF. In general,

HTLV-1 replication is greater in HAM than in ATL, and patients

with HAM have a stronger immune response to the virus. Antibodies

to HTLV-1 are present in the serum and appear to be produced in

the CSF of HAM patients, where titers are often higher than in the

serum. The pathophysiology of HAM may involve the induction of