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Editorial Review

Residual HIV-1 infection during antiretroviral therapy: the challenge of viral persistence

Pomerantz, Roger J.

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Introduction

HIV-1 replicates in most untreated infected individuals at high levels throughout the infection, including the clinical quiescent phase. Levels of this active viral replication directly correlate with disease progression and survival [1–4]. Combination therapeutics for HIV-1, or highly active antiretroviral therapy (HAART), has led recently to dramatic decreases in viral replication in vivo to below the clinical limits of detection (i.e. usually plasma HIV-1 RNA levels below 50–400 copies/ml, depending on the assay system utilized) and reductions in morbidity/mortality, at least in the developed world [5–7]. These therapeutic modalities have completely altered the epidemic in many regions. The era of HAART now allows both clearer investigations of classical questions in human retrovirology, as well as the generation of new clinical problems. Mechanisms of viral latency and hidden or ‘cryptic’ viral replication can also now be addressed without the ‘noise’ of active virally producing cells and high levels of cell-free virions [8], as virally suppressive HAART ‘unveils’ viral persistence. Furthermore, approaches towards possible viral eradication or at least long-term remission can be rationally studied. Nonetheless, it is critical to note that true viral eradication may be extremely difficult for many reasons (see below), including the finding that cells other than those in the immune system (e.g. kidney, heart, etc.) also appear to be infected at low levels with HIV-1 in vivo[1,9,10].

This review will discuss the mechanisms of HIV-1 persistence in vivo during the treatment of infected individuals with virally suppressive HAART. Both HIV-1 latency and low-level residual viral replication will be discussed in immune-based cells and other potential cellular reservoirs. These viral parameters will be correlated with the problems associated with maintaining long-term control of HIV-1 infections.

HIV-1 latency and persistence

Interest in retroviral latency or, more generally, persistence preceded the AIDS epidemic. Although retroviral latency was initially studied in avian retroviruses, the understanding of these processes in vivo has significantly increased in recent years, utilizing HIV-1 as a model [1]. It is critical, at the outset, to delineate the concepts of cellular latency and persistent replication for retroviruses in vivo. Viral latency is a general property of many viruses, including herpesviruses. Retroviral latency is defined as integrated provirus with no active transcription. Low-level chronic yet productive viral expression best characterizes persistent or cryptic replication. In the case of HAART, virus replication from previously infected cells is not fully ablated. Viral persistence takes place after initially successful virally suppressive therapy or effective antiviral immune responses in the infected host. Such cryptic viral replication may also continue in immunologically privileged sites, such as the brain and testes. Transcriptionally active but non-productive viral infections (i.e. certain viral messenger RNA are expressed but not intact virions) may also occur (see below).

The HIV-1 replicative cycle contains many possible stages for latency and persistence via both pre- and post-integration into the human cell genome [1]. Initially HIV-1 binds to cellular receptors and co-receptors (i.e. CD4 cell receptor and chemokine co-receptors, CCR5 and CXCR4), with subsequent viral core internalization and reverse transcription of the viral RNA template into a double-stranded DNA intermediate. The viral DNA is then integrated into the host cell genome as proviral DNA. Transcriptional activation of the integrated provirus is controlled by a complex series of interactions between HIV-1 regulatory proteins (e.g. Tat and Rev) and cellular transcription factors, controlled by the state of activation of the host cell. The activated provirus produces various viral mRNA species and, in some cases, new virions [1].

Many studies have demonstrated that ‘clinical’ HIV-1 latency, when defined as no viral expression in an entire untreated infected-individual, does not exist at the host level in any stage of disease [11–13]. In the great majority of HIV-1-infected individuals, some cultivable virus may be recovered at all stages of disease [11–13]. Nevertheless, data demonstrate that in the HIV-1-infected individual, some cells contain proviral DNA but express little or no viral RNA and produce few or no virions [11,14,15]. In addition to post-integration latency, various states of pre-integration HIV-1 latency have been described both in vitro and in vivo[16–20]. As such, latency at a cellular level exists in vivo, and the number of latently infected cells may vary based on the stage of disease. As HIV-1 infects, in vivo, both CD4 T cells, monocyte/macrophages, and other non-immune-based cells [10,21,22], the virus may maintain cellular latency by different mechanisms in differing cell types. This possibility presents important research opportunities in further elucidating the mechanisms of HIV-1 latency in vivo.

HIV-1 replicates at a rapid rate in infected individuals, with a virion half-life in plasma of hours [23]. The vast majority of this viral replication (over 99%) occurs in activated and productively infected CD4 T cells in the peripheral blood and lymphoid tissue. Analysis of plasma viral decay characteristics in patients initially treated with potent combinations of antiretroviral drugs demonstrates a rapid first phase decay of productively infected cells, a second phase decay of long-lived cells (possibly from tissue-bound macrophages), and then a third phase decay of persistently infected cells (e.g. resting CD4 T cells) [23] (Fig. 1). Effective HAART blocks the virus from infecting healthy CD4 T cells, and the initial drop in HIV-1 levels in the peripheral blood reflects the life-spans of cells that were infected before treatment was initiated. On the basis of these complex viral and cellular kinetics with slow decay of viral infected cells in several phases, most HIV-1-infected individuals would require complete suppression of viral replication for years if one is even going to consider viral eradication. However, this goal is hindered by several factors, including less than optimal treatment, HIV-1 infection in immunologically privileged sites, and partial drug sanctuary compartments in vivo (see below). This virus–cell kinetics model (Fig. 1) has been challenged in some of its aspects on empirical grounds, in the context of ‘spikes’ or ‘blips’ of plasma viremia occurring in certain patients on virally suppressive HAART, and potential on-going, de novo cellular infections, secondary to local bursts of viral replication [24].

Fig. 1.
Fig. 1.:
The in-vivo dynamics and cellular reservoirs for HIV-1. This figure illustrates the different cell types infected with HIV-i in vivo and the possible sites for long-lived infected cell populations and latently infected cells (adapted with permission from R. Pomerantz, HIV-1 in semen and other reservoirs. In: HIV: advances in research and therapy, Vol. 9. Darien, CT: Cliggott Publishing Co.; 1999). Red, Viral genomic RNA; Green, integrated or unintegrated viral DNA; Blue, host cell chromosome. Upper left, productively infected cell; Upper right, pre-integration latently infected; Lower left, integrated latently infected; Lower middle, long-lived cell populations; Lower right, cells with defective proviruses.

Residual HIV-1 provirus in vivo during highly active antiretroviral therapy

Persistently infected, non-activated CD4 T cells have been demonstrated in the peripheral blood of HIV-1-infected individuals after treatment effectively suppresses most productive viral infection [25]. Replication-competent viruses can be recovered from these proviral-positive cells after CD8 T cell depletion in vitro[26–28]. The vast majority of these viruses are CCR5 tropic [29]. In addition, this cell reservoir is established soon after primary HIV-1 infection [30], and can be activated by proinflammatory cytokines in vitro, and potentially in vivo[31]. Suppressive HAART initiated before primary HIV-1 seroconversion and during perinatal HIV-1 infection was also shown to be unable to halt the development of this replication-competent virus reservoir in CD4 T cells [30,32,33].

In a noteworthy recent study [29], latent replication-competent HIV-1 provirus was demonstrated in mainly resting memory (CD45RO) CD4 T cells, but low levels of virus were also found in resting naive (CD45RA) CD4 T cells in patients on virally suppressive HAART. It was suggested that naive CD4 T cells are rarely directly infected but that the provirally harboring naive CD4 T cells are generated via reversion from a memory phenotype [29]. In addition, the direct infection of thymocytes may also lead to the infection of naive T cells [34].

Most viruses isolated from resting CD4 T cells from the peripheral blood of patients with undetectable levels of viral RNA in plasma have few mutations that confer antiretroviral drug resistance [26]. As resistance mutations in the reverse transcriptase and protease genes of HIV-1 are correlated with on-going viral replication despite treatment [35], this finding suggests that these viral strains may represent ‘archival’ species from a time before treatment. Of note is the fact that a recent study has shown that in some patients on virally suppressive HAART, with transient spikes of virus above 50 copies/ml in plasma, resistance mutations may develop [36]. Data from the above studies demonstrated that although defective proviruses accumulate in CD4 T cells in vivo (i.e. ‘viral graveyard sequences') [37], replication-competent provirus still exists in resting CD4 T cells, which may hinder attempts to reduce the viral reservoir and re-seed the body with virus if HAART is discontinued. These possibilities, therefore, confound our attempts at pharmacologically mediated viral eradication. In addition, a recent study [38] demonstrated replication-competent HIV-1 in the peripheral blood monocytes of patients on virally suppressive HAART.

Tissues that maintain blood–tissue barriers, secondary to microvascular endothelial cell fight junctions, may limit the penetration of certain antiretroviral agents and act as partial ‘drug sanctuaries'. These compartments would potentially include the central nervous system, the retina, and the testes [1,8,39]. Although a recent article suggests this may not be likely in most patients (39a). A plasma membrane localized drug transporter, the P-glycoprotein, has been shown to decrease the penetration of protease inhibitors across certain blood–tissue barriers. As such, substances that block this drug transporter will increase protease inhibitor concentrations across the blood–tissue barriers. This finding may represent a new pharmacological approach to target relative viral sanctuary sites with higher levels of antiretroviral agents [40]. Nevertheless, most analyses do show the parallel decay of HIV-1 in tissues, compared with peripheral blood, in patients on virally suppressive HAART [41]. In addition, free-drug levels, rather than protein-bound drug concentrations, have rarely been analysed in body sites outside the peripheral blood.

Active replication of HIV-1 during highly active antiretroviral therapy

Cell-associated virus

Persistently infected CD4 T cells containing non-defective but quiescent HIV-1 proviral DNA and low levels of viral replication could account for the replication-competent virus within the peripheral blood CD4 T cells and seminal cells of infected individuals on HAART [8]. Viral replication could occur at such low levels that the virus would not be detectable in peripheral body fluids using standard clinical assays. Low-level productively infected cells might infect small numbers of target cells in the surrounding cellular microenvironment. One study [42] demonstrated that, in a minority of patients on suppressive HAART, a modest evolution of viral envelope sequences occurred over time. Other studies [43,44] demonstrated that during what appears to be full suppression of HIV-1 in the plasma, as determined by clinical RNA assays, there is ongoing viral replication in a majority of patients in some cohorts, as shown by the evolution of viral sequences in cellular reservoirs. These ‘archival’ viruses did not demonstrate antiretroviral resistance mutations, even in those strains that could undergo low-level replication. Nonetheless, some selection bias of the viral genetic variants may confound analyses in such studies.

In studies by Furtado et al.[45] recently confirmed by another group [46], sensitive measures of the ‘footprints’ of persistent viral replication were used to evaluate HIV-1 mRNA species and HIV-1 long terminal repeat (LTR) DNA circles, which are formed by self-ligation of proviral DNA by cellular nuclear ligases after transport of the viral pre-integration complex to the nucleus. LTR-DNA circles were demonstrated in the CD4 T cells of most patients on suppressive HAART. The LTR circles, along with quasi-steady-state levels of HIV-1 mRNA, demonstrate the existence of low-level viral replication at some time in the recent past. Although a short in-vivo half-life for HIV-1 2-LTR DNA circles has been suggested [46], this is now controversial and further studies are necessary to confirm this finding.

Our laboratories have recently demonstrated that levels of in-vivo cryptic HIV-1 replication differ in specific patients on virally suppressive HAART, and can be used to stratify these groups of patients with residual retroviral disease [47].

In one study [45], a further complexity towards characterizing HIV-1 persistence during HAART was also demonstrated, as certain patients had cells with multiply spliced RNA out of proportion to unspliced viral RNA, in agreement with in-vitro models [48–50]. As multiply spliced viral RNA encodes regulatory proteins, whereas unspliced RNA encodes structural proteins, this pattern suggests transcriptionally active but non-productive infection. These patterns of viral RNA species expression may be based on the state of host cell activation. Several forms of cryptic replication might thus ‘reset the virological clock’ by infecting previously uninfected cells in localized microenvironments.

Recent data have demonstrated that certain unstimulated, HLA-DR-negative CD4 T cells in lymphoid tissue sampled from HIV-1-infected individuals treated with virally suppressive HAART were positive for low levels of viral RNA [51]. HIV-1 replication was demonstrated previously to occur in activated memory CD4 T cells in both peripheral blood and lymphoid tissues [1,41]. These data suggest that there may actually be a spectrum of cell-types in a relatively inactive state that can still express low levels of viral RNA, a finding supported by others [52].

Most [53,54], but possibly not all [55], patients rebound rapidly with high levels of plasma viral RNA when standard suppressive HAART is discontinued, even when less than 50 copies/ml of plasma viral RNA has been demonstrated for significant time-periods. This observation suggests not only the presence of persistently infected cells but also on-going viral replication. One study [56] showed that rebounding virus in certain patients, after the discontinuation of HAART, did not appear to be from an outgrowth of latent provirus in resting peripheral blood CD4 T cells, but the cellular reservoir that produces the rebound virus remained unclear. Nevertheless, another recent study [57] demonstrated that rebound virus in some cases can arise from the latent virus in resting CD4 T cells.

Cell-free virus

Using a laboratory-based reverse transcriptase–polymerase chain reaction assay that can quantify at least 5 copies/ml of plasma viral RNA [58], low but detectable levels of virus were demonstrated in all HIV-1-infected patients studied with clinically undetectable levels of plasma HIV-1 RNA (i.e. less than 50 copies/ml) [59]. Of importance was the fact that this ongoing viral replication may infect cells in local sites, as well as cells at a distance within the body. Of note, however, the quantities of defective virions [37] in residual plasma HIV-1 are still unknown and remain important for understanding the possible viral spread within an infected host.

The viral decay characteristics in cells are different from viral decay characteristics in plasma [2]. In peripheral blood mononuclear cells the first phase represents the decay of productively infected and long-lived cells, whereas the second phase is the decay of cell-associated viral DNA and mRNA. Viral reservoir decay characteristics in one analysis [60] have suggested that 60 years will be necessary for patients treated with suppressive HAART to continue therapy for potential viral eradication. Unfortunately, even this estimate may not represent a best-case scenario for patients, as this analysis did not fully take into account low-level viral replication in tissues apart from the lymphoid organs.

Some patients with less than 50 copies/ml of blood plasma viral RNA on HAART still have low-level bursts of viral replication leading to more than 50 copies/ml in transient ‘spikes’[61], which carry risks of viral resistance evolution [36]. The mean decay half-life of latent replication-competent proviral reservoirs is longer in patients with transient plasma viral RNA spikes, compared with those patients who consistently maintain plasma HIV-1 RNA levels below 50 copies/ml [61]. A recent small study [62] suggested that low-level spikes of plasma HIV-1 RNA in patients on previously suppressive HAART did not appear to associate with higher rates of viral rebound, at least in the short term. Other preliminary studies [63,64], however, showed lower CD4 T cell counts in patients with plasma HIV-1 RNA spikes. It will be important to determine whether these viral spikes are caused by insufficient plasma drug levels or depressed drug penetration into unique reservoir sites, or just continued HIV-1 replication in the lymphoidal tissues, as well as the peripheral blood cells.

The findings that 60 years of suppressive HAART would be necessary possibly to allow latent reservoir eradication were suggested to be caused more by the slow decay of a truly latent proviral state rather than by ongoing viral replication [60]. The other study mentioned above [61] might lead to some optimism, as a mean half-life of approximately 6 months of the latent viral reservoir in patients who have no spikes above 50 copies/ml of plasma viral RNA on HAART may allow viral eradication in this very select group of patients in a shorter time-period. Nonetheless, once again this possibility assumes that even in these patients there exists no other viral reservoir(s) in peripheral blood, lymphoid tissue, or other solid organs [10], and that sub-clinical viral replication did not occur.

Follicular dendritic cells

Mathematical modeling to evaluate the dissociation of HIV-1 virions from follicular dendritic cells (FDC) in lymph nodes during suppressive HAART suggests that HIV-1 virions bound to FDC decrease after HAART, and that this process may take up to 30 months [41]. A recent model extends these data and suggests that a biphasic decrease in virions occurs, with the second phase being quite long, thus it may take up to several years for complete ablation of FDC-bound virions on suppressive HAART. This model is predicated upon the complete suppression of viral replication [65,66]. Virions bound to FDC could thus also be important in negatively affecting attempts at HIV-1 eradication. This virion binding may be based on the recently described DC-SIGN receptor on FDC [67]. See Table 1 and Fig. 2 for virus–cell interactions during virally suppressive HAART in vivo.

Fig. 2.
Fig. 2.:
Residual HIV-1 infection during suppressive highly active antiretroviral therapy. This schematic illustrates known and potential sites for HIV-1 residual disease during virally suppressive highly active antiretroviral therapy (HAART). These include low-level productively infected CD4 T cells, transcriptionally active but non-productive CD4 T cells expressing mainly multiply spliced viral RNA, and latently infected resting CD4 T cells. Other potential sites include follicular dendritic cells to which virions are bound and may exist in this form for significant time periods in vivo. Potential sanctuaries for both cryptically replicating and latently infected cells are demonstrated behind various blood–tissue barriers. Macrophages that may be latently infected or cryptically replicating are also illustrated, and other potential diverse cell types for HIV-1 residual disease are listed on the left of this figure. I, Cells infected with HIV-1.
Table 1
Table 1:
 Factors in the persistence of HIV-1 infection.

Treatment of residual HIV-1 disease

Stimulatory therapy

The treatment options for attempting to rid the body of cells infected with HIV-1, which can produce replication-competent virus in patients on effective HAART, are now beginning to be explored (Table 2). On the basis of our understanding of molecular lentiviral pathogenesis, approaches can be developed to activate persistently infected cells, which might lead to virus-induced cell death and purging of the viral reservoir. In theory, activation approaches for eliminating persistently infected cells would not lead to increases in newly infected cells, virus spread would be prevented by HAART. This approach was attempted recently utilizing solely IL-2 [68], but it might also include infusions of anti-CD3 antibodies and even IFN-γ for activating monocyte/macrophage scavenger cells. An initial study [69] using anti-CD3 monoclonal antibodies plus IL-2 was unsuccessful in trying to eliminate HIV-1 in patients on suppressive HAART. Patients had increased viral replication and experienced serious side-effects from the high doses of drugs. No intensification therapy (i.e. additional antiretroviral drugs) was added in this clinical trial, in attempts to halt low-level viral replication [59]. Therefore, persistently infected cells were stimulated, but the on-going cryptic viral replication was probably not affected in a substantial manner.

Table 2
Table 2:
Potential therapeutic options for HIV-1-infected individuals or virally suppressed highly active antiretroviral therapy.

Some patients on suppressive HAART treated with intermittent IL-2 had decreased or undetectable levels of resting CD4 T cells containing replication-competent virus [68]. When treatment was interrupted in two patients in whom replication-competent virus could not be found in resting CD4 T cells, virus was readily isolated in vitro and high levels of viral RNA in plasma were observed within weeks of stopping therapy [70]. Another larger group of 18 patients with undetectable levels of virus for more than one year had therapy interrupted [71]. All patients relapsed to relatively high levels of plasma HIV-1 RNA in 2–3 weeks after stopping HAART. Neither relatively long-term suppressive HAART alone nor this treatment combined with IL-2 led to the elimination of HIV-1 infection. Such studies suggested that ‘rebound’ viremia after stopping HAART with IL-2 may be produced from yet unidentified reservoir sites.

Intensification therapy

Hydroxyurea has been used in several HAART regimens, especially combined with didanosine, with which it has synergistic effects in inhibiting HIV-1 replication [72]. Hydroxyurea selectively inhibits cellular ribonucleotide reductase, a scavenger for tyrosyl-free radicals, which is essential for enzyme activity. This effect leads to a dramatic decrease in intracellular deoxyribonucleoside triphosphate (dNTP) pools. As such, hydroxyurea inhibits HIV-1 replication, notably in non-activated CD4 T cells, by indirectly blocking reverse transcriptase, which is dependent on intracellular dNTP as substrates [72]. Mycophenolic acid, by affecting dNTP concentrations combined with the reverse transcriptase inhibitor, abacavir, may also have an effect on residual HIV-1 replication similar to didanosine and hydroxyurea [73,74].

At least one patient had a dramatically low proviral reservoir in the peripheral blood, when treated with a didanosine and hydroxyurea-containing regimen, and maintained undetectable plasma viral RNA after HAART was discontinued [55]. In addition, a small cohort of patients on didanosine and hydroxyurea did not manifest viral rebound when the antiretroviral therapy was discontinued [75]. Unfortunately, another study [76] showed that a quick and profound rebound of plasma HIV-1 developed after treatment with HAART, plus or minus hydroxyurea therapy during primary HIV-1 infection. One patient in the study remained with less than 50 copies/ml of plasma HIV-1 RNA off HAART for 46 weeks [76]. However, this was an anecdotal case, and there remained a lack of compelling data from randomized, controlled studies, and certain safety issues exist, regarding the use of hydroxyurea in inducing ‘remissions’ in HIV-1 infection. Cytoreduction therapy may also be useful in removing both persistently infected cells and available uninfected target cells. Whether cyclophosphamide, as a low-level cytotoxic agent, or even hydroxyurea at high levels at which it is cytotoxic [77], could be utilized in this manner will require further study. This approach may be based on the ‘predator and prey’ relationship of HIV-1 with CD4 T cells [78,79]. Targeting specific immunotoxins to deplete the HIV-1 proviral reservoir, after stimulation of viral transcription from the proviruses, and potentially ongoing viral replication should now also be re-addressed in the era of HAART [80].

As low levels of ongoing viral replication occur in many HIV-1-infected individuals on effective HAART, ‘intensification’ therapeutics must be added to initial combination therapy to ablate this viral replication if eradication is a goal. Utilizing approaches to purge only the latent viral reservoirs will probably not be successful. In addition, further studies on the penetration of different pharmacological agents across blood–tissue barriers (e.g. blood–brain and blood–testes) will be of importance in attacking potential sanctuary sites, which may contain both cryptically replicating as well as latently infected cells (Fig. 2). Certainly, combinations of each of these approaches listed above may also be required for the elimination of the HIV-1 reservoirs in vivo. As such, one might now begin to think of the treatment of HIV-1 in somewhat of an ‘oncological’ paradigm. This would include effective HAART as ‘induction’ therapy and then further approaches against HIV-1 latency, cryptic replication, and sanctuary sites for the removal of ‘residual disease'. This approach is not induction followed by ‘maintenance’ therapy, but induction followed by aggressive therapies to approach residual viral disease, with the induction HAART continued unaltered. In any case, HAART alone decreases mortality and morbidity in the vast majority of patients maintaining a low viral load, despite residual HIV-1 infection, even in subjects with virological ‘failure’ and drug resistance [81].

Immune-based approaches and structured treatment interruptions

As the potential for viral eradication remains an unproved concept and a difficult goal, studies aimed at disease remission have been developed. Gradual improvements in the immune system with effective HAART are tied to increased thymic and possibly extra-thymic output of cells [82,83]. Increased anti-HIV-1-specific immune responses were detected in certain patients who were treated with virally suppressive HAART and then had it discontinued after various periods of time. There is a report of two patients who maintained undetectable levels of plasma viral RNA by clinical assays (below 50 copies/ml) [84]. It is now being tested whether some patients may be placed into clinical ‘remission’ and can be maintained off HAART for significant periods of time (see below). HIV-1-specific CD8 cytotoxic T lymphocytes (CTL), which usually become undetectable with fully suppressive HAART, do increase when a significant level of viral RNA in plasma re-develops again off HAART, in patients who have been virologically suppressed previously [85]. In addition, HIV-1-specific CD4 T lymphocyte proliferation, which is usually not found in patients first treated with suppressive HAART months to years after primary infection, remained detectable in infected individuals who were treated at the time of primary infection with fully suppressive HAART [86]. In one study, known early but chronic infection treated with HAART did demonstrate preserved anti-HIV-1 CD4 T lymphocyte responses [87]. These studies suggest that residual, antigen-specific CD8 T lymphocytes may expand during cyclical periods of starting and stopping HAART. Nevertheless, these findings require further controlled studies to validate the clinical relevance of the alterations of specific anti-HIV-1 immunological parameters.

Structured cyclic antiretroviral therapy interruptions have begun to be studied in attempts to augment anti-HIV-1 immune responses. A few patients do show a substantial decrease in plasma HIV-1 RNA ‘set-points’ after structured therapy interruptions. Although the augmentation of select immune parameters may occur, there are many cases in these initial studies in which little or no virological effects were demonstrated [88–104]. Diverse antiretroviral immune responses do seem to be well preserved if suppressive HAART is initiated soon after primary HIV-1 infection in vivo[86,105]. A recent study [106] showed exciting new data on ‘remissions’ induced in a small group of patients treated with HAART during primary HIV-1 seroconversion, with subsequent treatment interruptions. Although HIV-1 was not eradicated in these patients, low plasma viral RNA levels resulted and were maintained off all antiretroviral therapy. Further studies and long-term follow-up of these patients will be required to determine the durability of this effect, and whether any patients initially treated with HAART during chronic HIV-1 infection will benefit from this approach. Unfortunately, structured treatment interruptions in chronically HIV-1-infected individuals treated after primary seroconversion, unlike structured treatment interruptions in patients treated during primary infection, have not been very effective [107]. Selected therapeutic immunization should also be utilized in future studies. Recent data in SIV-infected macaques demonstrated viral control (i.e. with low plasma viral ‘set-points'), when specific immunization with viral proteins was combined with structured treatment interruptions [108].

The potential use of selected immunotoxins, in synergy with the augmentation of antiretroviral immune responses, towards maintaining HIV-1 ‘remission', has also been proposed and awaits evaluation [80]. Exploring the hypothesis that the immune system may keep the virus ‘in check’ (i.e. remission) and induce long-term non-progression without leading to full viral eradication is an intriguing idea that clearly merits further clinical analyses. Converting HIV-1 infections into a manageable long-term disease may also possibly be based on selection of less fit (i.e. lower replicative capacity) or less virulent (i.e. lower CD4 T cell depletion) viral variants.

HAART has led to dramatic and positive changes in the treatment of HIV-1 infection. Nonetheless, in its present form, HAART is unlikely to lead to virus elimination in the majority of HIV-1-infected individuals within clinically reasonable time periods. Nonetheless, the progress obtained with therapy against HIV-1 within the past decade suggests cautious optimism regarding approaches for the continued suppression of residual HIV-1 infection.

Acknowledgements

The author wishes to thank Drs Hui Zhang, Robert Siliciano, Ian Frank, and Edward Berger for helpful discussions, and Ms Rita M. Victor and Ms Brenda O. Gordon for excellent secretarial assistance. This work was supported, in part, by USPHS grant AI4628940 to R.J.P.

References

1. O'Brien W, Pomerantz RJ. AIDS and other diseases due to HIV infection. In:Viral pathogenesis. Nathanson N (editor). New York, NY: Raven Press; 1997. pp. 813–837.
2. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373: 123–126.
3. Mellors J, Rinaldo C, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV infection predicted by the quantity of virus in plasma. Science 1996, 272: 1167–1170.
4. Piatak M, Saag MS, Yang LC. et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993, 259: 1749–1754.
5. Gulick RM, Mellors JW, Havlir D. et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997, 337: 734–739.
6. Palella FJ Jr, Delaney KM, Moorman AC. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.HIV Outpatient Study Investigators. N Engl J Med 1998, 338: 853–860.
7. Hammer SM, Squires KE, Hughes MD. et al. A controlled trial of two nucleoside analogous plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less.AIDS Clinical Trial Group 320 Study Team. N Engl J Med 1997, 337: 725–733.
8. Zhang H, Dornadula G, Beumont M. et al. HIV-1 in the semen of men receiving highly active anti-retroviral therapy. N Engl J Med 1998, 339: i803–i809.
9. Bruggeman LA, Rose MD, Tanji N, et al.The kidney is a previously unrecognized reservoir for HIV-1 replication.7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February 2000 [Abstract 16].
10. Levy JA. HIV-1 and the pathogenesis of AIDS. Washington, DC: ASM Press; 1998.
11. Embretson J, Zupancic M, Ribas JL. et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993, 362: 357–362.
12. Pantaleo G, Graziosi C, Dernarest JF. et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993, 362: 355–358.
13. Piatak M, Saag M, Yang L. et al. High levels of HIV-1 in plasma during all stages of infection by competitive PCR. Science 1993, 259: 1749–1754.
14. Patterson B, Till M, Otto P. et al. Detection of HIV-1 DNA and RNA in individual cells by PCR-driven in situ hybridization and flow cytometry. Science 1993, 260: 976–979.
15. Peng H, Reinhart TA, Retzel EF, Staskus K, Zupancic M, Haase AT. Single cell transcript analysis of human immunodeficiency virus gene expression in the transition from latent to production infection. Virology 1995, 206: 16–27.
16. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen ISY. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 1990, 61: 213–222.
17. Zack JA, Haislip AM, Krogstad P, Chen ISY. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life-cycle. J Virol 1992, 66: 1717–1725.
18. Bukrinsky NU, Stanwick TL, Dempsey MP, Stevenson M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 1991, 254: 423–427.
19. Stevenson M, Stanwick U, Dempsey NW, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J 1990, 9: 1551–1560.
20. Spina CA, Guateffi JC, Richman DD. Establishment of a stable, inducible form of human immunodeficiency virus type 1 DNA in quiescent CD4 lymphocytes in vitro. J Virol 1995, 69: 2972–2988.
21. Schnittman SM, Psallidopoulos MC, Lane HC. et al. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science 1989, 245: 305–308.
22. Koenig S, Gendelman HE, Orenstein JM. et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients. Science 1986, 233: 1089–1093.
23. Perelson AS, Essunger P, Cao Y. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997, 387: 188.188.
24. Grossman A, Polis M, Feinberg MB. et al. Ongoing HIV dissemination during HAART. Nat Med 1999, 5: 1099–1104.
25. Chun TWL, Carruth D, Finzi D. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997, 387: 183–188.
26. Wong JK, Hezareh M, Gunthard HF. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997, 278: 1291–1295.
27. Finzi D, Hermankova M, Pierson T. et al. Identification of a reservoir for HIV-1 in patients on highly active anti-retroviral therapy. Science 1997, 278: 1295–1300.
28. Chun TW, Stuyver L, Mizell SB. et al. Presence of an inducible HIV-1 latent reservoir during highly active anti-retroviral therapy. Proc Natl Acad Sci U S A 1997, 94: 13193–13197.
29. Pierson T, Hoffman TL, Blankson J. et al. Characterization of chemokine receptor utilization of viruses in the latent reservoir for human immunodeficiency virus type 1. J Virol 2000, 74: 7824–7833.
30. Chun TW, Engle D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A 1998, 95: 8869–8873.
31. Chun T-W, Engel D, Mizeh SB, Ehler LA, Fauci AS. Induction of HIV-1 replication in latently infected CD4+ T-cells using a combination of cytokines. J Exp Med 1998, 188: 83–91.
32. Persaud D, Pierson T, Ruff C. et al. A stable latent reservoir for HIV-1 in resting CD4+ T-lymphocytes in infected children. J Clin Invest 2000, 105: 995–1003.
33. Poggi C, Profizi N, Djediouane A, Chollet L, Hittinger G, Lafeuillade A. Long-term evaluation of triple nucleoside therapy administered from primary HIV-1 infection. AIDS 1999, 13: 1213–1990.
34. Brooks DG, Kitchen SG, Kitchen KMR, Scripture-Adams DD, Zack JA. Generation of HIV latency during thympoiesis. Nat Med 2001, 7: 459–464.
35. Gunthard HT, Wong JK, Ignacio CC. et al. Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent anti-retroviral therapy. J Virol 1998, 72: 2422–2428.
36. Martinez-Picado J, DePasquale MP, Kartsonis N. et al. Antiretroviral resistance during successful therapy of HIV type 1 infection. Proc Natl Acad Sci U S A 2000, 97: 10948–10953.
37. Sanchez G, Xu X, Chermann JC, Hirsch I. Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol 1997, 71: 2233–2240.
38. Sonza S, Mutimer HP, Oelrichs R. et al. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS 2001, 15: 17–22.
39. Pomerantz RJ, Kuritzkes DR, de la Monte SM, Hirsch MS. Infection of the retina by human immunodeficiency virus type 1. N Engl J Med 1987, 317: 1643–1647.
39a. Gunthard HF, Havlir DV, Fiscus S. et al. Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis 2001, 183: 1318–1327.
40. Huisman MT, Smit JW, Schinkel AH. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 2000, 14: 237–242.
41. Cavert W, Notermans DW, Staskus K. et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 1997, 276: 960–964.
42. Zhang L, Ramratnam B, Tenner-Racz K. et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999, 340: 1605–1613.
43. Gunthard HF, Frost SDW, Leigh-Brown J. et al. Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy. J Virol 1999, 73: 9404–9412.
44. Martinez MA, Cababa M, Ibanez A, Clotet B, Arno A, Ruiz L. Human immunodeficiency virus type 1 genetic evolution in patients with prolonged depression of plasma viremia. Virology 1999, 256: 180–187.
45. Furtado MR, Callaway DS, Phair JP. et al. Persistence of HIV-1 transcription in peripheral blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999, 340: 1614–1622.
46. Sharkey ME, Teo I, Greenough T. et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active antiretroviral therapy. Nat Med 1999, 6: 76–81.
47. Dornadula G, Nunnari G, Vanella M, et al.Human immunodeficiency virus type 1-infected persons with residual disease and viral reservoirs on suppressive highly active antiretroviral therapy can be stratified into relevant virologic and immunologic subgroups.J Infect Dis 2001, in press.
48. Pomerantz RJ, Trono D, Feinberg MB, Baltimore D. Cells non-productively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell 1990, 61: 1271–1276.
49. Butera ST, Roberts BD, Lam L, Hodge T, Folks TM. Human immunodeficiency virus type 1 RNA expression by four chronically infected cell lines indicates multiple mechanisms of latency. J Virol 1994, 68: 2726–2730.
50. Michael NL, Morrow F, Mosca J, Vahey M, Burke DS, Redfield RR. Induction of human immunodeficiency virus type 1 expression in chronically infected cells is associated primarily with a shift in RNA splicing patterns. J Virol 1991, 65: 1291–1303.
51. Zhang Z-Q, Schuler T, Zupancic M. et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 1999, 286: 1353–1357.
52. Derdeyn CA, Kilby JM, Diego Miralles G. et al. Evaluation of distinct blood lymphocyte populations in human immunodeficiency virus type 1 infected subjects in the absence or presence of effective therapy. J Infect Dis 1999, 180: 1851–1862.
53. Harrigan PR, Whaley M, Montaner JSG. Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy. AIDS 1999, 13: F59–F62.
54. Montaner JSG, Harris M, Mo T, Harrigan RP. Rebound of plasma HIV viral load following prolonged suppression with combination therapy. AIDS 1998, 12: 1398–1399.
55. Lisziewicz J, Rosenberg E, Lieberman J. et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999, 340: 1683.1683.
56. Chun T-W, Davey RT, Ostrowsi M. et al. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat Med 2000, 6: 757–761.
57. Zhang L, Chung C, Hu B-S. et al. Genetic characterization of rebounding HIV-1 after cessation of highly active anti-retroviral therapy. J Clin Invest 2000, 106: 839–845.
58. Zhang H, Dornadula G, Wu Y, Havlir D, Richman DD, Pomerantz RJ. Kinetic analysis of intravirion reverse transcription in the blood plasma of human immunodeficiency virus type 1-infected individuals: direct assessment of resistance to reverse transcriptase inhibitors in vivo. J Virol 1996, 70: 628–634.
59. Dornadula G, Zhang H, Van Uitert B. et al. Residual HIV-1 RNA in the blood plasma of patients on suppressive highly active anti-retroviral therapy (HAART). JAMA 1999, 282: 1627–1632.
60. Finzi D, Blankson J, Siliciano JS. et al. Latent infection of CD4+ T-cells provides a mechanism for lifelong persistence of HIV-1 even in patients on effective combination therapy. Nat Med 1999, 5: 512–517.
61. Ramratnam B, Mittler JE, Zhang L. et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med 1999, 6: 82–85.
62. Havlir D, Hirsch MS, Richman DD, et al.Prevalence and predictive value of intermittent viremia in patients with viral suppression.XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract TuPeB3195].
63. Ward D, Sklar P. The significance of low-level viremia in patients with previously ‘undetectable’ HIV-1 RNA levels.XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract MoPpB1O19].
64. Easterbrook P, Ives N, Peters B, Gazzard B. The natural history and clinical significance of intermittent virological ‘blips’ in patients who attain an initially undetectable viral load (VL) on HAART.XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract WeOrB6lO].
65. Hlavacek WS, Wofsy C, Perelson AS. Dissociation of HIV-1 from follicular dendritic cells during HAART: mathematical analysis. Proc Natl Acad Sci U S A 1999, 96: 14681–14686.
66. Hlavacek WS, Stilianakis NI, Notermans SA. et al. Influence of follicular dendritic cells on decay of HIV during antiretroviral therapy. Proc Natl Acad Sci U S A 2000, 97: 10872–10966.
67. Geijtenbeek TB, Kwon DS, Torensma R. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000, 100: 587–597.
68. Chun T-W, Engel D, Mizell SB. et al. Effect of interleukin-2 on the pool of latently infected resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med 1999, 5: 651–655.
69. Prins JM, Jurrianns S, van Praag RME. et al. Immunoactivation with anti-CD3 and recombinant human IL-2 and HIV-1- infected patients on potent antiretroviral therapy. AIDS 1999, 13: 2405–2410.
70. Chun T-W, Davey RT Jr, Engel D, Lane HC, Fauci AS. Re-emergence of HIV after stopping therapy. Nature 1999, 401: 874–875.
71. Davey RT Jr, Bhat N, Yoder C. et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A 1999, 96: 15109–15114.
72. Lori F, Malykh A, Cara A. et al. Hydroxyurea as an inhibitor of human immunodeficiency virus type 1 replication. Science 1994, 266: 801–804.
73. Margolis D, Heredia A, Gaywee J. et al. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenese, have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr 1999, 21: 362–370.
74. Chapuis AG, Rizzardi GP, D'Agostino C. et al. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med 2000, 6: 762–768.
75. Vila J, Nugier F, Bargues G. et al. Absence of viral rebound after treatment of HIV-infected patients with didanosine and hydroxycarbamide. Lancet 1997, 2: 88–89.
76. Zala C, Salomon H, Gun A, et al.Viral load rebound upon discontinuation of d4T + ddI and NVP with or without hydroxyurea (HU) during primary HIV infection (PHI).7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February, 2000 [Abstract 558].
77. DeBoer RJ, Boucher CAB, Perelson AS. Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine. AIDS 1998, 12: 1567–1570.
78. Smith C, Lilly S, Nfiralles GD. Treatment of HIV infection with cytoreductive agents. AIDS Res Hum Retroviruses 1998, 14: 1305–1313.
79. Bartlett JA, Silberman M, Miralles GD, et al.Antiretroviral therapy (ART) plus cyclophosphamide (CTX) to diminish HIV DNA in lymphoid tissue.8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February 2001 [Abstract 16].
80. Berger EA, Moss B, Pastan I. Reconsidering targeted toxins to eliminate HIV infection: you gotta have HAART. Proc Natl Acad Sci U S A 1998, 95: 11511–11513.
81. Deeks SG, Barbour ID, Martin IN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure to protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000, 181: 946–953.
82. McCune JM, Loftus R, Schmidt DK. et al. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J Clin Invest 1998, 101: 2301–2308.
83. Douek DC, McFarland RD, Keiser PH. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998, 396: 690–695.
84. Ortiz GM, Nixon DF, Trkola A. et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 1999, 104: R13–R18.
85. Kalams SA, Goulder PJ, Shea AK. et al. Levels of human immunodeficiency virus type I specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol 1999, 73: 6721–6728.
86. Rosenberg ES, Billingsley JM, Calieno AM. et al. Vigorous HIV-1-specific CD4+ T-cell responses associated with control of viremia. Science 1997, 278: 1447–1450.
87. Al-Haarthi L, Siegel J, Spritzler L, Pottage L, Agnoh M, Landay A. Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease. AIDS 2000, 14: 761–770.
88. Ruiz L, Martinez-Picado J, Romeu J. et al. Structured treatment interruption in chronically HIV-1-infected patients after long-term viral suppression. AIDS 2000, 14: 397–403.
89. Deeks SG, Wrin T, Hoh R, et al.Virologic and immunologic evaluation of structured treatment interruptions (STI) in patients experiencing long-term virologic failure.7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February, 2000 [Abstract LB10].
90. Garcia F, Plana M, Ortiz GM, et al.Structured cyclic antiretroviral therapy interruption (STI) in chronic infection may induce immune responses against HIV-1 antigen associated with spontaneous drop in viral load.7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February, 2000 [Abstract LB11].
91. Kilby JM, Saag MS, Goeppert PA, Hockeft RD, Saha BK, Bucy RP. Significant delay in plasma vRNA rebound during a scheduled treatment interruption in HIV-1 chronically infected patients previously on effective therapy.7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February, 2000 [Abstract 359].
92. Ionnidis JPA, Havlir DV, Tebas P, Hirsch NIS, Collier AC, Richman DD. Dynamics of HIV-l viral load rebound among patients with previous suppression of viral replication.7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February, 2000 [Abstract 360].
93. Carcelain G, Tubiana R, Mollet L, et al.Intermittent interruptions of antiretroviral therapy in chronically HIV-1 infected patients do not induce immune control of HIV.7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 30 January–2 February, 2000 [Abstract 356].
94. Hirschel B, Fagad C, Lebraz M, et al.The Swiss–Spanish intermittent trial (SSITT). XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract ThOrB747].
95. Capobianchi MIR, Abbate I, Dianzani F, et al.Host cell-derived differentiation, activation and costimulatory/adhesion molecules acquired by circulating HIV-1: longitudinal analysis in patients undergoing controlled therapy interruption.XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract ThOrB749].
96. Dybul M, Yoder C, Belson M, et al.Short cycle intermittent HAART: a pilot study.XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract LBOr12].
97. Wellons M, Jacobson AJ, Van Loon K, et al.A controlled trial of treatment interruption in chronically HIV-infected subjects.XIIIth International Conference on AIDS. Durban, South Africa, 9–14 July, 2000 [Abstract WePeB4208].
98. Phillips A, Youle M, Tyrer M, et al.CD4 count changes in people interrupting HAART therapy after a CD4 count increase.8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February 2001 [Abstract 361].
99. Fagard C, Lebraz M, Guthard HJ, et al.SSITT: a prospective trial of strategic treatment interruptions in 128 patients.8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February 2001 [Abstract 357].
100. Garcia F, Plana M, Ortiz GM, et al.Outcome after 1 year of HAART, 3 cycles of STI and 12 months off therapy vs natural evolution without ART in early chronic HIV-1 infection (CHI). A case control study.8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February 2001 [Abstract 289].
101. Hermans P, Kabeya K, Van Wanzelle F, Verhofstede C, Clumeck N. Successful interruption of antiretroviral therapy (ARVT) in patients with primary HIV infection (PHI).8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February, 2001 [Abstract 290].
102. Ruiz L, Carcelain G, Martinez-Picado J, et al.HIV dynamics and HIV-specific CD8+ T cells response after three structured treatment interruptions (STI) of antiretroviral treatment (ART) in chronic HIV-infected patients.8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February 2001 [Abstract 291].
103. Bonhoeffer S, Rembiszewski M, Ortiz GM, Nixon DF. Risks and benefits of structured antiretroviral drug therapy interruptions in HIV-1 infection.AIDS14:2313–2322.
104. Markowitz M, Jin X, Ramratnam B, et al.Prolonged HAART initiated within 120 days of primary HIV-1 infection does not result in sustained control of HIV-1 after cessation of therapy.8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 4–8 February 2001 [Abstract 288].
105. Markowitz M, Vesanen M, Tenner-Racz K. et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type I infection on viral replication and antiviral immune responses. J Infect Dis 1999, 179: 525–537.
106. Rosenberg ES, Altfeld M, Poon SH. et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000, 407: 523–526.
107. Carcelam G, Tubiana R. et al. Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection. J Virol 2001, 75: 234–241.
108. Hel Z, Venzon D, Poudyal M. et al. Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques. Nat Med 2000, 6: 1140–1146.
Keywords:

eradication; HAART; HIV-1; reservoirs; residual disease

© 2001 Lippincott Williams & Wilkins, Inc.