HIV infection is typically characterized by a prolonged asymptomatic phase prior to the development of AIDS. New insights into the nature of this deceptively quiet phase in the natural history of HIV infection, primarily revealed by the alterations in viral and cellular dynamics that occur with the initiation of highly active antiretroviral therapy (HAART), may hold the key to designing the next generation of HIV therapies. With the advent of HAART and quantitative plasma viral RNA assays, it became clear that this 'clinically latent' stage of disease represents a dynamic steady state of active infection and death of replication active cells [1,2]. In individuals who are not receiving therapy, the years following initial infection are characterized by a viremia 'set point' that is relatively constant over time within each individual but widely variable between individuals, and by progressive loss of CD4 T cells. The set point of viremia is reflective of the magnitude of viral replication and is directly related to the rate of disease progression . Although HAART has resulted in a dramatic decline in the progression of HIV disease (AIDS-related opportunistic infections and death) [4-6], administering these combination regimens to patients long-term is difficult. HAART regimens often require many pills in carefully timed doses that limit patient adherence; they are expensive, and there are a growing number of potential adverse effects and complex drug interactions to consider [7-9]. The initial optimism that continual suppression of viral replication could lead to complete eradication after several years  has faded with the identification of a stable form of latent HIV infection in resting CD4 T cells [11-15]. Furthermore, an increasing number of reports demonstrate that a reservoir of infectious virus persists despite prolonged effective viral load suppression [16-20].
The steady state of viral replication in untreated individuals is highly dynamic and the specific viral load level at steady state is probably determined by a combination of factors. While the frequency of activated T cells is a contributing factor to the level of viral replication [21-26], there is a rapidly growing body of evidence that the dominant control mechanism is an HIV-specific cellular immune response. A distinct goal for the long-term therapy of HIV infection has recently emerged that focuses on inducing efficient immune control over viral replication, rather than the more daunting objective of complete viral eradication. The rationale for this therapeutic approach is based on the following hypotheses. (i) An HIV-specific cellular immune response is the primary mechanism that controls viral replication - this response brings the acute infection syndrome to an end and ultimately determines the steady-state 'set point' during chronic infection. (ii) HAART administration results in a significant reduction in this antigen-driven immune response, which may allow persistence of a low level of viable virus. (iii) Although deletion of relevant HIV-specific CD4 T cells may occur during acute infection, deletion is not complete and anergy mediated by HIV products may serve to render the steady-state level of immune response inefficient during chronic disease. (iv) Therapeutic immunization of patients with adequate inhibition of viral replication with HIV antigens may allow reversal of this anergic state and the establishment of efficient immune control characteristic of long-term nonprogressor patients.
Rapidly evolving experimental assays
Assessing the impact of HIV-specific cellular immune responses on HIV disease progression has been challenging, in part because the complex cellular interactions involved lead to dilemmas about which components are pertinent to measure. In addition, the results of HIV-specific in vitro assays have an uncertain relationship to actual immune function in vivo or to clinical outcomes. The standard assay for antigen-specific T helper cell responses involves measurement of cellular proliferation in culture following stimulation with soluble protein antigens. In general, lymphoproliferative assays (LPA) for HIV-specific responses are lost very early on in the course of acute HIV infection and are extremely low or nonexistent among patients with chronic HIV infection . There is re-assuring evidence that LPA to several opportunistic pathogens (cytomegalovirus, mycobacterial infections) improve following HAART, but there is limited or no improvement in LPA responses to HIV antigens among patients with well-established HIV disease or AIDS [28-30]. Although proliferation after 6-day cell culture is dependent on CD4 T-cell function, the magnitude of this response may not always be directly related to the frequency of antigen-specific CD4 T cells or to the 'help' delivered to CD8 T cells. An alternative approach utilizes direct measurement of the frequency of CD4 T cells producing specific cytokines after antigen activation (usually interferon [IFN]-γ and/or tumor necrosis factor [TNF]-α have been measured). This approach confirms that CD4+ lymphocyte responses to other pathogens (like cytomegalovirus) may be recovered following HAART , and additionally reveals that there may be a degree of HIV-specific CD4 cell responsiveness in some chronically infected patients not reliably detected using standard LPA .
Assays for HIV-specific CD8 T-cell function are generally further along in development than those targeting CD4 function, but which (if any) of these assays directly reflect the in vivo ability to block HIV replication remains unclear. One standard approach is to measure the lysis of 51Cr-labeled target cells expressing relevant major histocompatibility complex (MHC) class I/peptide epitopes in the presence of patient peripheral blood mononuclear cells. Bulk assays are typically carried out using different ratios of effector to target cells. Such direct lysis assays can be performed in several formats that have different levels of sensitivity. If active cytotoxic T lymphocytes (CTLs) are present at a relatively high frequency, a direct lysis assay using effector cells directly from a patient's blood sample can be performed [33,34]. Alternatively, cells can be stimulated in vitro for several weeks in the presence of interleukin (IL)-2 and then determination of lytic activity can be carried out . Direct lysis has been demonstrated during the acute HIV infection syndrome [36,37], but this assay generally does not detect CTL activity in peripheral blood mononuclear cells from chronically infected patients. Assays based on bulk stimulation and expansion in vitro, on the contrary, are capable of detecting the level of CTL precursors in selected specimens derived from patients with established, chronic HIV infection [33,38]. The frequency of precursor cells capable of generating multiple active daughter cells can also be measured in a limiting dilution format, with the actual 51Cr release assay as the method to score positive wells. Antigen-specific activation of CD8 T cells not only activates the lytic program, but also activates cytokine gene expression, particularly IFN-γ and TNF-α . Cytokine expression can be assessed in several different assay formats including detection of soluble protein by enzyme-linked immunosorbent assay, the ELISPOT assay [38,40,41], or by intracellular cytokine staining with flow cytometry analysis [42-44].
Our understanding of the in vivo dynamics of CD8 T cells has also been dramatically improved using MHC-peptide tetramers capable of recognizing HIV antigen-specific cells . In different immununological situations, including the response to HIV infection , the frequency of tetramer-positive cells is greater than the number of precursor cells detected by limiting dilution analysis. In some dramatic circumstances, for example during acute viral infections, CTLs that respond to a specific antigen may comprise a substantial fraction of all the CD8 T cells present. This analytical technique is limited by the requirement to construct a tetramer reagent for each distinct MHC class I/peptide specificity, but many of these reagents have been produced and preliminary results suggest the ability to quantitate cellular immune responses to HIV longitudinally in some cases . There is also proof-of-concept that tetramer constructs can be developed to assay for class II, CD4+ pathogen-specific, cellular immune responses [48,49].
There is an emerging consensus that effective immune responses to HIV antigens can be evoked, at least under certain clinical situations, and that the steady-state 'set point' of plasma viral load is predominately controlled by an active CD8 T-cell-mediated immune response. Although many investigators initially concluded that a normal host immune response was incapable of controlling HIV infection, recent data indicate the existence of HIV exposed but uninfected individuals with evidence of active HIV-specific CD8 T-cell responses [41,50-52], suggesting that some individuals can mount an immune response capable of clearing initial infection. For those individuals who do become infected, development of active CTL is temporally related to the control of viral replication and the resolution of the acute retroviral syndrome [37,53-55]. In addition, HIV-specific CTL activity is detectable during chronic infection in untreated subjects using either the chromium release or tetramer methodologies [46,56,57]. Furthermore, there is evidence from viral sequence evolution studies that viral persistence and disease progression may be associated with the selection of specific CTL escape mutants [58-62]. Thus, ideal cellular immune responses that occur very quickly may conceivably eliminate infection altogether, and chronic infection is associated with consistently detectable CTL responses and ongoing selective pressure on viral growth. Although initially considered paradoxical, there are now substantial data that potent ARV suppression also leads to a significant decline in the activity of HIV-specific CTL responses [38,46,56,63,64]. Not only do CTL responses fall when ARV therapy inhibits viral replication, but the viral rebound that occurs when therapy is stopped is followed by re-emergence of the CTL response in several reports [65-67].
Further evidence for the key role of CD8 T cells in the control of viral load comes from the strong association between particular class I MHC (but not class II) alleles and the degree of viral replication [68,69]. Since the function of MHC class I antigens is to present peptide epitopes to CD8 T cells, allelic variation in these molecules gives rise to a variation in the magnitude of CD8 T-cell immune responses. The correlation of the viral load 'set point' with the genetic elements that control CD8 T-cell immune responses further supports the central role of this immune response in steady-state infection. In addition, the added benefit of heterozygosity at MHC class I loci in lowering the viral load  suggests that the more diverse CD8 repertoire possible with more MHC restriction molecules is also a contributor to lower viral load at steady state.
Further support for the critical role of effective cellular immunity in controlling retrovirus infection comes from studies of the SIV infection model in rhesus macaques. First, as in human infection with HIV, strong CTL responses are associated with the control of initial viremia in SIV infection [71-75]. Second, infection with a live attenuated SIV strain is associated with the induction of a vigorous immune response  and protection from subsequent infection with a virulent strain . Furthermore, vaccination of rhesus macaques with a gp120 subunit preparation that primarily stimulates CD4 T cells results in a lower viral load set point after infection, compared with nonimmunized controls . Finally, and perhaps most persuasively, two groups have independently shown that depletion of CD8 T cells with a cytotoxic anti-CD8 monoclonal antibody in SIV-infected rhesus macaques results in rapid increases in plasma viral load [79,80]. Even in SIV-infected animals with undetectable plasma HIV RNA , depletion of CD8 T cells (without an appreciable change in the number of target CD4 T cells) results in a 2-4 log rise in viral load within several days. Thus, the presence of CD8 T cells, presumably continuously activated by viral antigen, is required to maintain the steady-state level of viral replication.
Multiple lines of evidence thus lead to the conclusion that an active antigen-driven immune response occurs in HIV-1 infection, but this response is not efficient enough to maintain viral replication below levels that result in long-term damage to the immune system. In mathematical formulations of the dynamics between virus growth and immune response [82,83], the nonintuitive result finding is that efficiency or responsiveness of each individual determines the steady-state viral load, rather than the magnitude of the response at a particular instant. The hypothesis that steady-state viral replication is maintained by an antigen-driven immune clearance of replication active cells in competition with growth rate of the virus (which is the source of viral antigen) predicts the relatively uniform rapid rate of decline of viremia with HAART initiation . Furthermore, this concept leads to a natural explanation of the rapid generation of latent infection early in disease, but subsequent stability of this pool of cells and a potential explanation for the persistence of active infection on HAART [83-85].
HIV-Specific CD4+ cell responsiveness
There is thus substantial evidence to support the view that an antigen-driven active CTL response is the dominant host mechanism controlling the extent of viral replication. The problem in most chronically HIV-infected individuals, however, is that this response is not adequately efficient. The relative inefficiency of the CD8 T-cell response may be due to the lack of an effective HIV-specific CD4 T-cell response in chronic HIV disease. The maintenance of effective CTL responses, along with a wide spectrum of humoral and cellular immune responses, appears to depend upon the orchestration provided by CD4+ T helper cells. In experimental animal models of viral infection, the critical role of an effective CD4 T-cell response to clear chronic infection is well documented [86-90], despite the dominant effector mechanism being a CTL response. The presence of strong CD4 T-cell responses by proliferation in patients who can maintain low viral load without ARV therapy  suggests that the presence of effective CD4 T-cell responses are critical for efficient CD8 responses to HIV-1. The subsequent observations that strong LPA responses present in subjects who initiate HAART very early after primary infection  suggests that chronic infection may lead to the death of most HIV-specific CD4 T cells. Since HIV preferentially infects antigen-activated CD4 T cells and either a direct viral cytopathic effect or immune elimination quickly kills infected cells, the critical viral antigen-specific CD4 T cells may be deleted very early during infection. Another possibility is that these antigen-specific cells are rendered anergic by the persistent level of HIV antigens together with the effects of potentially immunosuppressive viral products such as viral envelope proteins [92-94] and HIV-1 tat[95-97]. This concept suggests that HIV-specific CD4 T cells could be effectively immunized and the anergic effect reversed if they were stimulated while active viral replication was substantially suppressed by HAART. The observation that HIV-responsive CD4 T cells exist since they can make some cytokines after antigenic stimulation  is consistent with this idea. Furthermore, the frequency of CD4 T cells that can respond is increased by co-stimulation with anti-CD28 or by CD40 crosslinking , suggesting an altered sensitivity and/or cytokine pattern of response rather than clonal deletion as the primary mechanism of low responses during chronic infection. It is also possible that HIV products produce materials that inhibit dendritic cell function and thereby result in aberrant activation of CD4 T cells and inefficient helper activity for CD8 T cells.
Virologic control in vivo following immune-based interventions
Further evidence that the immune system can maintain control of viral replication comes from a series of tantalizing anecdotes related to interruptions of ARV therapy, which have raised hopes that a heightened immune response to HIV antigens that efficiently controls viral replication may be achievable. One of the first indications that long-term control of viral replication might be obtained is a case report of an individual (often referred to as the 'Berlin patient') who started HAART shortly after primary infection . The patient briefly discontinued HAART several times due to intercurrent illnesses, and then ultimately stopped all HAART against medical advice. Subsequently, he has remained healthy with no detectable viremia for several years. As already described, early induction of HAART shortly after primary infection has been shown to preserve substantial HIV-specific immune responses (both CD4 and CD8 T cells) [27,100]. Subsequently, several other subjects who started HAART shortly after primary infection, had several episodes of intermittent adherence, and who then discontinued therapy have been described [65,91,101,102]. Although these studies have not been conducted in a randomized fashion, several subjects have experienced delayed rebound followed by a spontaneous fall in plasma viral load to below detection without re-introduction of HAART. In some subjects who underwent several repeated therapy withdrawals, preliminary reports suggested that the rebound back to baseline was slower following each subsequent treatment interruption . Follow-up reports on several of these subjects demonstrates that the fall in viral load without ARV therapy is associated with measurable increases in CTL activity in the blood , strongly suggesting that immune control of the infection has occurred. The association between the development of improved in vitro measures of HIV-specific T-cell responses and viral control after therapy withdrawal was also documented in a recent study in which subjects with early HAART treatment underwent therapy withdrawal .
A key question is whether these observations in acutely infected patients can be duplicated in the much more common clinical scenario of chronic infection. If clonal deletion by HIV infection is the predominant mechanism that accounts for low CD4 T-cell responses in chronic infection, then attempts to boost this response may be futile. If the relative inefficiency of the CD8 T-cell response is due primarily to anergy induced by HIV viral products during high-level replication, then it may be possible to reverse this anergic phenotype and obtain efficient immune control of viral replication. Either therapeutic immunization with existing vaccine products, such as Remune that can stimulate significant LPA responses in chronically infected patients , or the canary pox vectors that have shown some success in stimulating CTL responses in HIV seronegative subjects  may be able to activate efficient responses in HIV-infected subjects. While larger studies designed to address the role of therapuetic immunization are ongoing, there are several reports of studies of chronically infected patients with serial structured treatment interruption (STI) designed to induce heighten immunity and control of viral replication. In a cohort from Barcelona, four of nine subjects experienced a transient burst of viremia followed by suppression in the absence of ARV drugs after the second STI, although all rebounded to near the previous set point on the first STI . Patients who have received HAART and IL-2 therapy may experience dramatic viral rebound off therapy, but then quickly return to lower steady-state levels of viral load without restarting HAART . On the contrary, early results from a large Swiss-Spanish cooperative study, while demonstrating that some individuals achieve lower viral load steady states after therapy interruption indicate that the majority return to their previous set point as a result of serial treatment interruptions .
Since CD8 T-cell-mediated immune responses seem to be functionally active, albeit inefficient, during chronic infection, the prospect of inducing efficient immune control in these patients most likely depends on reconstitution of the CD4 T-cell response to viral antigens. Whether this is a feasible prospect depends on the existence of viral antigen-specific CD4 T cells with the implication that actively growing virus produces materials that can anergize these cells as well as produce relevant antigen. Thus, release of ARV drug control of replication may simply result in re-establishing the scenario of CD4 T-cell anergy and the previous 'set point' level of replication determined by 'helper-independent' CD8 responses.
While there are many remaining questions to be answered, it is possible that STI may not only serve as a diagnostic strategy to detect increased efficiency of the immune response, but may also be important in the elicitation of this response. While the ability to induce efficient immune control in chronic infection remains speculative, the benefit of maintaining viral replication at extremely low levels is clear. If a therapeutic immunization regimen can achieve the very low levels of viral replication typical of long-term nonprogressors or of subjects successfully treated with HAART, the rate of disease progression will probably also be similarly low . If such heightened immunity can maintain low viral load without the need for continual ARV therapy, even if not indefinitely, the long-term prognosis of HIV infection would be considerably brighter. Furthermore, the execution of clinical trials to test HIV-specific immunization as a therapeutic strategy for chronically infected people offers the prospect of significant new insights into HIV pathogenesis and the correlates of effective immune control. This information and empirical characterization of specific HIV vaccine agents can be directly translated into vaccine regimens that may prevent initial HIV infection.
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