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Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.

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Retroviruses.

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Course of Infection with HIV and SIV

Primary Infection

Primary infection of humans with HIV-1 is associated with an acute mononucleosis-like clinical syndrome (Table 1) which appears approximately 3–6 weeks following infection. The severity and persistence of the symptoms vary considerably. Although the majority of infected individuals fail to report such symptoms to their physicians, upon careful questioning, approximately 50–70% can recall some symptoms appropriately associated with their estimated time of infection (Tindall and Cooper 1991). Although lymphadenopathy and malaise may persist, other symptoms usually subside within 1–2 weeks. Significant declines in the levels of CD4+ T lymphocytes in the peripheral blood occur in the first 2–8 weeks following HIV-1 infection (Gaines et al. 1990). These levels may rebound toward normal as the patient enters the clinically latent stage of disease (see below); however, they rarely if ever return to preinfection levels. Although the acute syndrome associated with primary SIV infection in monkeys has not been carefully described, rapid declines in the numbers of CD4+ T lymphocytes have been documented within the first few weeks of infection.

Table 1. Pathologic Conditions Associated with AIDS.

Table 1

Pathologic Conditions Associated with AIDS.

The acute syndrome associated with primary HIV-1 infection is accompanied by a burst of viral replication that can be detected in the blood approximately 3 weeks following infection (Fig. 4) (Clark et al. 1991; Daar et al. 1991; Tindall and Cooper 1991). During this period, infectious virus and viral proteins can be readily detected in the cell-free plasma as well as in cerebrospinal fluids, and the number of virions in cell-free plasma can reach 106 to 107 per milliliter. However, as for all retroviruses, only a small percentage of the virions are infectious. The concentration of viral antigen in plasma can be quantitated using commercial antigen capture assays directed against the CA (p24) protein. These assays are valuable because they detect viral particles but give erratic results due to circulating antibodies. More reproducible values can be obtained using quantitative assays that measure the level of viral RNA (Piatak et al. 1993).

Figure 4. Pathogenesis of HIV infection.

Figure 4

Pathogenesis of HIV infection. A schematic diagram of the pathogenic events that occur from initial infection with HIV to the development of clinical disease. (Modified from Pantaleo et al. 1993a.) (more...)

The early stages of infection have also been carefully measured during pathogenic infection of macaque monkeys with SIV; the results are similar to what is known for HIV in humans. Peaks of plasma antigenemia and viremia occur around week 2. Replicating SIV has been detected in the brains of rhesus monkeys 2 weeks after experimental intravenous infection (Chakrabarti et al. 1991).

Approximately 3–6 weeks after the infection of macaques with SIV and humans with HIV-1, specific antiviral immune responses can be detected (Ho et al. 1985; Cooper et al. 1987, 1988; Gaines et al. 1987). These antiviral immune responses are associated with a precipitous decline in plasma viremia and plasma antigenemia, a decline in the viral burden in PBMCs, resolution of the clinical syndrome, and a temporary stabilization of the number of CD4+ T cells. Both humoral and cellular immune responses can be detected. Multiple factors probably contribute to the decline in viral titer, including the responses of the two arms of the immune system, the secretion of virus-suppressing cytokines, and the possible exhaustion of suitable CD4+ target cells (Phillips 1996). Recent studies have indicated that the initial decline in plasma viremia is associated with the appearance of HIV-specific, CD8+ cytolytic T cells, whereas the first neutralizing antibody is not detected for several additional weeks (Koup et al. 1994). The vast majority of infected individuals develop detectable antibody responses within 3 months of infection. Some macaques experimentally infected with SIV develop little or no free anti-SIV antibodies, and these animals die with an acute AIDS-like disease 3–7 months following infection (Daniel et al. 1987).

It has been demonstrated that antiretroviral therapy administered to patients during primary HIV infection improves the clinical course and increases the CD4+ T-cell count compared to individuals who remain untreated during the period of primary HIV infection (Kinloch-de Loes et al. 1995). However, it remains to be determined whether treatment of primary infection alters the long-term clinical course.

A number of factors, such as route of infection (mucosal vs. blood vs. mother to fetus/infant), preexisting genital ulcerative disease (due to sexually transmitted disease), and level of viremia, affect the efficiency of transmission of HIV (see above). In this regard, the issue has been raised as to whether some strains of HIV are transmitted preferentially. A number of groups have observed considerable sequence homogeneity in an individual in the weeks immediately following infection (McNearney et al. 1992; Pang et al. 1992; Zhang et al. 1993). Since most sexual encounters with an infected partner do not result in HIV-1 infection, infection may involve a single or a few infectious particles. This conclusion is supported by the homogeneity of the virus population in many individuals soon after infection. It is more surprising that for most cases of sexual and mother-offspring transmissions, the transmitted virus appears to be a minor variant present in the blood of the donor (Wike et al. 1992; Clark and Shaw 1993; Zhu et al. 1993). The mechanisms responsible for this selective transmission remain to be elucidated.

Clinical Latency: The HIV Steady State

Following the induction of an immune response to HIV-1 in humans and to SIV in macaques, there is usually a relatively long period that is characterized by few, if any, clinical manifestations. When present, clinical symptoms are usually mild (see Table 1). Current estimates for the average time from infection with HIV-1 to the development of the clinical conditions that define AIDS (see below) vary from 8 to 12 years (Moss and Bacchetti 1989; Lemp et al. 1990b). The time interval from infection to development of opportunistic disease varies greatly from one individual to another; however, the estimated time has gradually increased since AIDS was first recognized. This may be due both to better detection of infection and to antiretroviral therapies and effective prophylaxis for life-threatening opportunistic infections (Lemp et al. 1990a, 1992; Seage et al. 1993). Throughout the latent period, there is usually a steady decline in the numbers of CD4+ lymphocytes (Fig. 5). This decline is not seen in the small percentage of individuals who are long-term nonprogressors. The asymptomatic phase may be either much shorter or absent in infants infected at birth (Auger et al. 1988; Jones et al. 1992). According to the 1993 revised definition of AIDS by the Centers for Disease Control and Prevention (see below), even if the individual is otherwise completely asymptomatic, a diagnosis of AIDS is made if the CD4+ T-cell count falls below 200 per microliter.

Figure 5. Typical course of HIV infection.

Figure 5

Typical course of HIV infection. Patterns of CD4+ T-cell decline and virus load increase vary greatly from one patient to another, as do the actual values of viral RNA load. (Modified from Pantaleo (more...)

Although the long-term asymptomatic phase can be called clinical latency, there are numerous clear lines of evidence to show that there is continual, rapid viral replication in the progression to disease. Cells positive for SIV and HIV RNAs can be found in lymph nodes by in situ hybridization at all stages of infection: early, asymptomatic, and late (Wyand et al. 1989; Pantaleo et al. 1993c). Sequence changes occur in the viral genome at a rate of about 1% per year in env (Balfe et al. 1990; Burns and Desrosiers 1991; Simmonds et al. 1991); the only way this can occur is through continued viral replication. Antibody responses to HIV-1 are strong, and remain high for years (see below, Immune Responses to HIV and SIV, Humoral Immune Responses), indicating constant antigenic stimulation. Virus can be recovered and/or detected month after month, year after year from peripheral blood cells of most infected individuals. Using sensitive and reproducible assays for virion RNA, such as quantitative competitive (QC) polymerase chain reaction (PCR), HIV virions can be detected in cell-free plasma of virtually all HIV-1-infected individuals at all stages of infection (Piatak et al. 1993). Furthermore, the level of virus is remarkably constant, exhibiting relatively small day to day fluctuations, increasing only gradually during the course of infection. Simple modeling suggests that this relatively stable viral load reflects both a constant rate of new infection and death of the infected cells throughout most of the course of the infection (Coffin 1995).

These observations show that the clinical latency does not imply viral latency. Rather, they indicate that there is continual viral replication during the long asymptomatic stage. Recent studies not only confirmed previous results documenting chronic viral replication (Pantaleo et al. 1993c; Piatak et al. 1993), but have also provided an accurate quantitative picture of the dynamics of viral production and turnover (Ho et al. 1995; Wei et al. 1995; Perelson et al. 1996). These measurements were made using inhibitors of HIV reverse transcriptase and protease in patients. Treatment of HIV-1-infected individuals with effective inhibitors of HIV replication results in rapid and precipitous declines in the levels of plasma viremia. Levels of plasma virus typically fall by 99% within 2 weeks (Fig. 6). Coincident with the decline in circulating virus are parallel increases in the numbers of CD4+ T lymphocytes.

Figure 6. Decay of circulating virus and infected cells, after strongly suppressive antiviral drug treatment.

Figure 6

Decay of circulating virus and infected cells, after strongly suppressive antiviral drug treatment. (Data from Perelson et al. 1997.) These results imply the presence of at least three classes of (more...)

Mathematical modeling suggests that the half-life of the virus is less than 6 hours in blood, and the lifetime of infected cells is about 1.5 days (Perelson et al. 1996). Since the plasma virus level and the number of infected cells are approximately constant, large numbers of virus and infected cells are produced and destroyed each day (Fig. 7). By the onset of frank AIDS, virus may be 1000 generations or more removed from the initial infecting virus. The rapid initial increase in the number of CD4+ T lymphocytes after drug treatment also suggests that CD4+ T-cell killing is linked to the levels of replicating virus (see below, Immunopathogenic Mechanisms of HIV Infection), although a redistribution of cells among body compartments has not been completely ruled out.

Figure 7. The HIV steady state.

Figure 7

The HIV steady state. (A) The lifetimes of various kinetic classes of infected cells are illustrated schematically by the arrows. Starting from a common pool of uninfected cells (more...)

These kinetic studies were performed with individuals whose CD4+ T lymphocyte concentrations were less than 500 cells/μl of blood, compared to a normal value of 600–1200 cells/μl. It is still unclear whether identical kinetic phenomena will occur in individuals earlier in the course of infection. However, within the range of CD4+ T cells studied (2–500 per milliliter), there is only a small variation in the calculated kinetic parameters, and the variations do not correlate with clinical status.

In monotherapy with most antiviral agents, the dramatic declines in circulating virus are followed by the rapid appearance of mutant viruses resistant to the drug. In fact, with many drugs, viremia usually returns to pretreatment levels within a few weeks or months. The appearance of drug resistance is coincident with the appearance of viruses carrying specific mutations in reverse transcriptase or protease. The large decreases in plasma viremia and the increases in CD4+ T-cell counts argue strongly that these drugs are initially very effective in limiting viral replication and cell killing. Drug resistance clearly represents the major barrier to the development of effective antiviral therapy. Recent studies imply that certain combinations of antiviral drugs may reduce this problem considerably (see Chapter 12.

More recently, therapies using combinations of antiviral agents—typically a protease inhibitor and two reverse transcriptase inhibitors—have been developed and brought into widespread use (see Chapter 12. In many patients, treatment with such combinations of inhibitors gives rise to significant and long-lived suppression of viral load, implying that such strategies may effectively block viral replication, preventing overgrowth of resistant mutants. Careful analysis of viral load in such patients reveals a second phase decline from about 1% of the viral load down to the limit of detection of the assay (Fig. 6) (Perelson et al. 1997). The half-life of this second phase of decline is about tenfold the half-life of the first phase of decline, implying a second population of latently or chronically infected cells that die with a half-life of about 2 weeks. Such cells account for about 10% of the total infected cell population, but contribute only 1–5% of the virus in the blood at any one time. Although these cells are probably not important to pathogenesis, they are very important in therapy, because they provide a long-lived reservoir potentially capable of rekindling infection even after prolonged suppressive therapy.

It is not well understood how the balance between the production and clearance of virus and infected cells is maintained for such a long period of time. Two general mechanisms can be envisioned. In the first, the host immune response keeps the virus under control but is unable to completely clear it. In the second, viral replication is limited by the availability of suitable targets, particularly activated CD4+ T cells. On the basis of studies in other viral systems, one would expect the host immune response to limit the extent of viral replication. Several observations are consistent with this concept. SIV-infected monkeys and HIV-infected infants with poor immune responses to the virus progress faster than those with more robust immune responses. Furthermore, the appearance of specific escape mutants suggests that the immune response—particularly the cellular arm—has at least some effect on viral replication, although the extent of this effect cannot be accurately estimated (see below, Immune Responses to HIV and SIV). However, the absence of episodic peaks of antibody and viremia which occur in infections with nonprimate lentiviruses (Chapter 10 is inconsistent with simple immune-response-escape models. The transient increases in viral loads that are observed after immune stimulation suggest that the availability of activated T lymphocytes also serves to limit replication (Phillips 1996; for review, see Stanley et al. 1996).

The remarkable genetic variation in the virus population in a single individual (Hahn et al. 1986; Burns and Desrosiers 1991) is a direct consequence of this continuous viral replication (Coffin 1995). The rate at which mutants accumulate in the population is determined not only by the error rate of replication, but also by the fitness of the mutants that appear. Any mutation that increases the fitness of the virus will tend to accumulate in the population, whereas the frequency of mutations that decrease the survival of the virus will remain low. Selective forces that could increase the survival of particular mutants include the humoral and cellular immune responses of the host, adaptation to a new host with a novel genetic background, and adaptation to a particular tissue or cell type in which the virus happens to find itself, as well as any therapeutic protocol used to treat the patient.

In env, nucleotide substitutions and amino acid substitutions accumulate at an average rate of about 1% and 2.5% per year, respectively. Deletions, duplications, and insertions contribute to genetic variation. Mutations in env are not randomly distributed but tend to be localized to discrete variable domains within which a remarkably high percentage (>95%) of the nucleotide substitutions change an amino acid. This extremely nonrandom pattern of sequence variation indicates that there is, in vivo, a strong selection for changes in distinct variable regions of env. Selective pressure from neutralizing antibodies is almost certainly one of the driving forces responsible for this nonrandom pattern of sequence variation (see below, Immune Responses to HIV and SIV) as is selection for variation in tropism. A major goal of HIV and SIV research is to understand the selective forces driving variation in each of the variable domains of env. It is not the replication error rates that are remarkable for HIV and SIV, but rather the capacity of their envelope proteins to tolerate changes (Coffin 1986). Although rates of sequence change can be reasonably measured over the course of years, the numbers are too high to permit extrapolation to an evolutionary time scale.

Recombination between HIV variants can also contribute significantly to genetic variation in vivo. As with other retroviruses (see Chapter 4, recombination can be readily observed in cell culture between variants of HIV carrying different mutations (for example, mutations that confer resistance to different antiviral agents) (Moutouh et al. 1996). Recombinants occur frequently among the progeny from cells infected with two different viruses, which implies that recombination is likely to be limited by the frequency of doubly infected cells. Viral genomes containing sequences from HIVs of different clades have been isolated from a number of individuals, indicating both a high frequency of coinfection of individuals with different viruses (presumably at approximately the same time) and sufficient coinfection of cells within an infected individual to allow recombination (Robertson et al. 1995; Carr et al. 1996). Progressive evolution by sequential recombination events has also been seen in HIV-infected individuals (J. Mullins, pers. comm.). Recombination in vivo can also be directly observed in monkeys infected simultaneously with two variant SIVs (D. Wooley and R. Desrosiers, unpubl.). As with mutation, the appearance of recombinants in vivo is most likely a function of selective forces, and it is therefore impossible to estimate the underlying rates.

In the large majority of infected individuals, the apparent steady state gradually breaks down, leading to the low numbers of CD4+ T cells and high viral loads characteristic of AIDS. All of the available evidence indicates that disease progression is directly linked to viral load and to the extent of viral replication (for review, see Pantaleo et al. 1993a; Mellors et al. 1996, 1997). Infected monkeys and humans with a relatively low steady-state viral burden clearly do better (as determined by CD4 counts and clinical status) than individuals with a high viral burden (Fig. 8). Infection of rhesus monkeys with a variety of infectious molecular clones and mutant forms of SIV has shown a complete concordance of disease progression with levels of replicating virus.

Figure 8. Relationship between viral load and clinical progression.

Figure 8

Relationship between viral load and clinical progression. Shown are Kaplan-Meier plots of AIDS-free survival time divided into quartiles according to viral load (A) or CD4+ T-cell (more...)

A similar concordance of viral load and progression can be seen in other lentiviral infections. For example, severe arthritis in goats is associated with higher levels of CAEV replication in joints (Narayan and Cork 1985; Narayan et al. 1988; Straub 1989). Prior vaccination of monkeys can sometimes reduce SIV viral burden. This reduction is associated with slower progression to disease (Shafferman et al. 1992, 1993). Although mechanisms that are only indirectly related to viral burden and viral replication and that have yet to be fully delineated may be important, it is the level of replicating virus and the numbers of virus-infected cells that are critical for the development of immunodeficiency and the progression of disease. Constant viral replication can be viewed as the engine that drives the disease process, regardless of the ultimate mechanisms of disease progression.

The mechanism by which efficient viral replication occurs in the face of what appears to be a strong host immune response is probably the most important unanswered question for the pathogenesis of HIV-1 and the other lentiviruses. A number of possibilities exist that are not mutually exclusive:

1.

The virus mutates rapidly and is tolerant of mutations. The resulting viral mutants can escape neutralizing antibody and cytotoxic T lymphocyte (CTL) responses. This possibility is discussed below (Immune Responses to HIV and SIV).

2.

At least a portion of the virus replicates in immunologically privileged sites. In this regard, it has been proposed for visna virus that the macrophage may serve as a “Trojan horse” limiting viral expression while effectively disseminating it (Haase 1986).

3.

The virus has special adaptations that make it relatively invisible to the immune system. The very large number of glycosylation sites on the Env proteins suggests that the virus uses carbohydrates to provide a shield against the host's immune response (Botarelli et al. 1991; Benjouad et al. 1992). Other structural features of Env proteins may be involved (Moore and Ho 1993). Although mutations (in gag and pol) that allow the virus to escape from the cellular immune response have been clearly documented, the coexistence of CTLs reactive against a specific viral sequence and of virus expressing the same sequence in an infected individual implies that a CTL response, although present, is not completely effective at controlling infection. The reason for this is not yet clear; however, the lack of adequate CD4+ T-helper-cell function may contribute to the defect. In addition, the complex replication cycle of the lentiviruses could help to avoid a CTL response by allowing an infected cell to shift rapidly from an antigen-negative state to one of high-level viral production, releasing a “burst” of virus before being detected as foreign.

4.

Early damage to the immune system may preclude a completely protective immune response.

Clinically Apparent Disease

After months to years of a continuous, yet variable, decline in the number of CD4+ T cells, the level of these cells drops from a normal range of 600–1200 to below 500 cells/μl (Fig. 5). As shown in Table 1, a number of the conditions that define AIDS as a disease are associated with the level of CD4+ T cells. At about 500 cells/ml, the first symptoms appear in the HIV-infected patient. Once the CD4+ T-cell count falls below 200 cells/μl, the patient is susceptible to AIDS-defining opportunistic infections and neoplasms. The decline in the level of CD4+ T cells typically continues until virtually all such cells are lost.

The combination of a long and variable period of disease progression in HIV infection and the genetic heterogeneity of HIV has led researchers to ask whether disease progression is the result of the evolution of pathogenic HIV variants. It has been found that HIV isolates from patients in the early, asymptomatic stages of HIV infection differ from those isolated from AIDS patients (Cheng-Mayer et al. 1988; Tersmette et al. 1989). About half the time, virus from individuals with progressive disease is T-tropic and has an SI phenotype. These differences are also seen when virus is isolated from the same individual over time (for review, see Levy 1993; Fauci and Rosenberg 1994). The emergence of SI variants correlates with increasing viral burden and increasing rate of CD4+ T-cell decline (Connor et al. 1993). The available experiments do not discriminate between cause and effect. It is not clear whether disease progression is a direct result of the emergence of the more cytopathic variants or whether declining immune competence permits the growth of variants with increased replicative capacity, nor is it clear whether cytopathicity in vitro equates with virulence in vivo.

Kaposi's sarcoma (and other opportunistic neoplasms) are discussed below in the context of tissue-specific diseases and organ system involvement.

Viral Load and Progression to Disease

Disease progression is not an inevitable outcome of lentiviral infections. African green monkeys and sooty mangabey monkeys can be persistently infected with SIV, apparently for life, but they do not appear to develop any disease. SIVs from these species are certainly capable of causing disease in a different host. Although most chimpanzees infected with wild-type HIV-1 and macaques infected with mutants of SIV usually remain persistently infected but asymptomatic (Eichberg et al. 1987; Kestler et al. 1991; Johnson et al. 1993), disease has recently been reported in an HIV-infected chimpanzee (Novembre et al. 1997). The immune systems of these species appear to control (but not eliminate) these lentiviral infections; however, other as yet unidentified factors may contribute to the lack of disease. In general, it seems that in the natural host, the virus and the host are well adapted to each other. Such adaptations must lead to features that maintain a constant low virus load, transmissibility of the virus, and prevent evolution of more virulent variants.

Although there is considerable variation in response, a typical pattern of CD4+ T-cell loss in HIV-infected individuals begins with a relatively steep decline immediately after the initial infection, followed by an average yearly loss of approximately 60 CD4+ T cells/μl (Lang et al. 1989). The steep decline in the numbers of CD4+ T cells after primary infection can be seen only in those individuals who seek medical attention for the acute syndrome following primary infection (Tindall and Cooper 1991). It may thus be limited to individuals who support a more vigorous early viral replication than occurs in individuals who do not experience acute symptoms after primary infection. The initial pattern of CD4+ T-cell decline in individuals in which the primary infection was asymptomatic is still unknown. Studies of HIV-infected cohorts identified early in the AIDS epidemic showed that over a period of approximately 10 years, there is evidence of disease progression in 80% of HIV-infected individuals; of this group, 50% developed AIDS (Rutherford et al. 1990).

Overall, the most important correlate of progression to AIDS is the steady-state viral load—or setpoint—seen at the end of the primary phase of infection. Prospective studies on a large cohort of men at high risk for HIV infection have shown that individuals with viral loads in the highest quartile have about a threefold shorter time of progression to disease than individuals whose viral load lies within the lowest quartile (Fig. 8) (Mellors et al. 1996, 1997).

It is important to point out the difference between long-term nonprogression of HIV disease and long-term survival. Long-term survivors are patients who although infected for 10 or more years are still alive, but whose HIV disease may or may not have progressed with regard to deterioration of their immune systems. Long-term nonprogressors are those HIV-infected individuals who not only have survived 10–15 years of HIV infection, but are also free of symptoms and have CD4+ T cell counts that have remained stable and reasonably normal. Five percent or less of HIV-infected individuals fall into this category, displaying no evidence of disease progression despite 10–15 years of documented HIV infection (for review, see Cao et al. 1995; Kirchhoff et al. 1995; Pantaleo et al. 1995). Although viral titers are quite low in these patients (Cao et al. 1995; Pantaleo et al. 1995), persistent low-level viremia can be demonstrated in most of them (Pantaleo et al. 1995). Although no consistent viral defect can be demonstrated in most patients, in at least some cases, genetic defects in the infecting virus may play a part in long-term nonprogression. One patient was found to have a defect in nef (Kirchhoff et al. 1995); in addition, seven blood or blood product recipients were infected by virus from a donor that had sustained deletions in the nef gene. Six of these seven recipients remained free of HIV-related disease and had stable and normal CD4+ T-cell counts 10–14 years after infection. Virus obtained from these recipients had nef gene deletions similar to those in the infecting virus (Deacon et al. 1995).

The possibility that, at least in some cases, alterations of nef might be responsible for long-term nonprogression is consistent with observations made with SIV. Adult rhesus monkeys infected with cloned virus in which the nef gene was partially deleted become persistently infected, but they have only low levels of viremia and, analogous to human long-term nonprogressors, do not progress to disease (Kestler et al. 1991; Daniel et al. 1992). This suggests that nef is not necessary to establish or maintain infection, but it is required for high viral load and disease. The mechanisms that underlie this effect are not understood. nef might increase cell division and expand the numbers of cells available for productive infection (Luo and Garcia 1996; Wiskerchen and Chang-Mayer 1996); the highly virulent SIVsmmPBj14 (Fultz 1991) derives its pathogenicity from a point mutation in nef that may increase its interaction with cellular kinases (Du et al. 1995). Monkeys infected with nef-minus virus are also protected from infection by wild-type virus, raising the possibility that nef-deleted HIV strains might be useful vaccines (Daniel et al. 1992; Wyand et al. 1996; see Chapter 12.

CD8+ T-cell counts remain high in long-term survivors but decline during disease progression (Lifson et al. 1991). Nonprogressors who maintain high levels of CD8+ T-cell responses carry relatively noncytopathic variants of HIV; such variants have a restricted cell tropism and grow to low titer in cells in vitro (Cheng-Mayer et al. 1988; Mackewicz and Levy 1992). The low titer may reflect selection for viral variants with greater resistance to the immune response. Relatively low levels of free infectious virus and infected CD4+ T cells are seen in the peripheral blood of these individuals; neutralizing antibodies are present and enhancing antibodies (to be discussed later) are absent (Homsy et al. 1990). Although it has been proposed that the presence of a strong CD8+ T-cell response is responsible for the suppression of HIV replication (Levy 1993) (see below, Immune Responses to HIV and SIV), it is not clear to what extent humoral and cellular immunity contribute to this effect.

Variation in rate of disease progression may also reflect genetic variation in the host. Consistent with this idea, it has been reported that HIV-infected individuals who are heterozygous for a 32-base deletion in the CCR5 gene (which renders homozygotes resistant to infection) have a somewhat slower rate of progression to AIDS (Dean et al. 1996; Huang et al. 1996). Other epidemiologic studies did not show this effect, so the point awaits resolution.

With models for HIV pathogenesis that relate progression to disease and genetic variation, it might be expected that the virus population in slow or nonprogressors would display less diversity than that in rapid progressors. However, several studies have reported the opposite effect: Genetic diversity in the variable regions of env is noticeably less in rapid progressors (Wang et al. 1996; Wolinsky et al. 1996). This might mean that a less virulent virus variant is also less fit and therefore that there are more mutations that confer a positive selective benefit.

Taken together, the available data suggest that HIV-infected long-term nonprogressing individuals are a heterogeneous group. Further studies of long-term healthy survivors of HIV infection, both those who maintain normal and stable CD4+ T-cell counts and those whose counts decline markedly but still remain healthy, are important for a better understanding of the pathogenesis of HIV infection and for the design of appropriate therapeutic and preventive strategies.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
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