Role of Viral Reservoirs in the Pathogenesis of HIV Disease

National Institute Of Allergy And Infectious Diseases

Investigators

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 aim 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. We conducted a clinical trial in 2015-2016 in which we investigated the feasibility of achieving sustained virologic remission in HIV-infected individuals through multiple infusions of virus-specific monoclonal antibody (mAb) VRC01 following the cessation of ART. Although all 10 subjects experienced plasma viral rebound (>40 copies/ml) following cessation of ART, in part due to the presence of pre-existing and/or emergence of VRC01-resistent HIV, this clinical trial gave us a unique opportunity to examine the effect of short-term ATI on immunologic and virologic parameters in HIV-infected individuals. We demonstrated a significant increase of HIV burden (proviral DNA and cell-associated RNA) in the CD4+T cells of infected individuals who underwent ATI with subsequent plasma viral rebound. However, the size of the HIV reservoirs as well as immune parameters (such as CD4+T cell counts and degrees of exhaustion and activation in CD8+T cells) returned to pre-ATI levels 6-12 months after the study subjects resumed ART. These data demonstrate that short-term ATI in the setting of close monitoring does not necessarily lead to expansion of the persistent HIV reservoir nor irreparable damages to the immune system, rationalizing inclusion of ATI in future clinical trials evaluating curative strategies. There is a need to develop therapeutic strategies that can either eliminate/suppress persistent viral reservoirs and/or boost host immunity to prevent rebound of virus from these reservoirs following discontinuation of ART. One approach to achieving this goal is through augmentation of virus-specific immune responses by therapeutic vaccination. We conducted a randomized, placebo-controlled trial of a therapeutic vaccine regimen in infected individuals in whom ART was initiated during the early stage of HIV infection and whose immune system was anticipated to be relatively intact to determine if the vaccine regimen was safe and could induce an immune response that would maintain suppression of plasma viremia following discontinuation of ART. The vaccinations were well-tolerated with no serious adverse events; however, the vaccine regimen produced only modest augmentation of existing HIV-specific CD4+ T cell responses with little augmentation of CD8+ T cell responses. Compared with placebo, the vaccines had no significant effect on the kinetics or magnitude of viral rebound following interruption of ART and no impact on the size of the HIV reservoir. Of note, 26% of subjects in the placebo arm exhibited sustained suppression of plasma viremia (<400 copies/ml) following ATI - a rate of spontaneous suppression higher than previously reported. Our findings regarding the degree and kinetics of plasma viral rebound following ATI have potentially important implications for the design and interpretation of future trials testing interventions aimed at achieving ART-free virologic remission. Finally, we launched a clinical trial in 2016 to investigate the effect of anti-47 mAb (vedolizumab) in HIV-infected individuals undergoing ATI. The concept for this trial was based on previous observations that HIV binds and preferentially infects 47hi CD4+ T cells and that administration of anti-47 mAb prevents and/or delays transmission of SIV in rhesus macaques. Furthermore, it has been shown that anti-47 mAb 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 47 integrin. Our human clinical trial is ongoing and is now fully enrolled. We are currently examining the effect of vedolizumab on plasma viral rebound in HIV-infected individuals following ATI and will be studying various immunologic and virologic parameters in the study subjects in the coming months.