Role of Viral Reservoirs in the Pathogenesis of HIV Disease

National Institute Of Allergy And Infectious Diseases

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Linked publications & trials

Abstract

Well over a decade ago, we demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all HIV-infected individuals receiving clinically effective ART. In addition, we demonstrated that HIV continually replicates at low levels in some chronically infected individuals who are consistently aviremic during prolonged periods of receiving ART. Based on the above findings and similar observations from other groups, the persistent viral reservoir has become a major impediment to the eradication of HIV in infected individuals receiving ART. Consequently, a major emphasis of HIV therapeutic research is the development of strategies to eliminate HIV reservoirs and to achieve ART-free virologic remission in infected individuals. Considering that complete eradication of HIV is not currently feasible in the majority of infected individuals, even under the best of circumstances involving early initiation of ART, new approaches aimed at containing viral replication are being considered. The goal is not necessarily to achieve complete eradication of the virus, but rather to boost HIV-specific immune responses (using therapeutic agents) in order to keep plasma viremia suppressed after discontinuation of ART. The ultimate evaluation of the efficacy of a therapeutic agent in achieving sustained virologic suppression would require discontinuation of ART given the vast majority of HIV-infected individuals experience plasma viral rebound upon cessation of therapy. However, it has not been clear what impact ATI and subsequent reinitiation of ART have on immunologic and virologic parameters of HIV-infected individuals who initiated antiretroviral drugs during the acute/early phase of infection. Accordingly, we used longitudinal specimens collected from study subjects who had participated in the therapeutic vaccine trial to investigate the impact of ATI and reinitiation of ART on immunologic and virologic parameters. Twenty-two study subjects in whom ART was initiated during the acute/early phase of infection were studied at three time points (prior to ATI, during ATI, and following initiation of ART). The median duration of ATI was 124 days and the geometric mean of peak plasma viremia was 28,702 copies/ml during the treatment interruption period. The median duration on ART following reinitiation of antiretroviral drugs was 702 days. No significant change in the size of HIV reservoir, determined by the level of CD4+ T cells carrying HIV proviral DNA, cell-associated HIV RNA, or replication-competent virus, was observed between baseline and following reinitiation of ART. In addition, no significant change in a number of immunologic parameters, such as frequencies of CD4+ and CD8+ T, B, and natural killer cells, was observed between pre-ATI and following reinitiation of ART. These findings suggest that ATI does not permanently expand the size of HIV reservoirs nor induce irreparable immunologic damage to cells in the peripheral blood and, collectively, they provide strong support for the inclusion of ATI, irrespective of stage of infection when ART was initiated, in clinical trials examining the efficacy of therapeutic interventions in infected individuals. In an effort to explore a promising therapeutic option for the treatment of HIV infection, we launched a clinical trial to investigate the effect of anti-a4b7 antibody (vedolizumab) in infected individuals undergoing ATI. The concept for this trial was based on previous observations that HIV preferentially binds and infects a4b7hi CD4+ T cells in vitro and that administration of anti-a4b7 antibody prevents and/or delays transmission of SIV in rhesus macaques. Furthermore, it has been shown that anti-a4b7 antibody suppressed plasma viremia for extended periods following discontinuation of ART in SIV-infected rhesus macaques, suggesting that sustained virologic remission may be achieved via direct targeting of a4b7 integrin. Based on these animal data, we conducted a clinical trial to investigate the effect of vedolizumab on plasma viral rebound following ATI in HIV-infected individuals who had suppressed viral replication while receiving ART. Vedolizumab infusions were well-tolerated without any infusion-related safety issues. However, a majority of the study subjects (72%) experienced plasma viral rebound within 11 weeks following ATI that necessitated reinitiation of ART per protocol. Of note, a non-statistically significant subset of study subjects (28%) reached the study endpoint without having met criteria to restart ART, suggesting vedolizumab may have had some impact on plasma viral rebound. Since this was an open-label study, it is unclear whether these latter patients would have been any different from the other study participants. Further studies are needed to reconcile the apparent discrepancies between the animal and the human studies and to delineate the mechanisms by which a subset of study subjects achieved a degree of virologic suppression (spontaneous as opposed to intervention-induced) following discontinuation of ART.