HIV - specific CD 8 + T cells and HIV eradication

Introduction HIV is an infection of the immune system that, despite induction of both humoral and cellular immune responses, is not eliminated. Animal models show that a stable reservoir of quiescent CD4+ T cells containing integrated provirus is created within days following transmission (1). Despite the induction of vigorous, HIV-specific CD8+ T cell responses that would be expected to eliminate infected cells (2–4), the immune system appears incapable of clearing this reservoir. This is at least partially attributable to the greatly reduced or absent viral antigen expression that occurs in these quiescent “latently” infected cells. Additionally, virus escape from CD8+ T cell recognition, CD8+ T cell dysfunction, and compartmentalization of both CD8+ T cells and viral reservoirs limit the efficacy of the naturally induced immune response to clear infection. Indeed, 35 years into the epidemic, there are no documented cases of immune-mediated clearance of established infection. In the absence of effective CD8+ T cell–mediated viral clearance, combination antiretroviral therapy (cART) can effectively contain viral replication; however, like the adaptive immune response, cART does not eliminate infected quiescent cells, because the viral enzyme targets of the antiviral therapies are not required once the provirus has been integrated into the host genome. The latent reservoir appears to have been eliminated and a cure achieved (5–7) in one bone marrow transplant recipient, in whom donor cells were homozygous for a 32-bp deletion in the HIV coreceptor CCR5, rendering the repopulating cells resistant to infection. The combination of conditioning regimen and graft-versus-host disease (GVHD) may have also contributed to the elimination of the reservoir and apparent cure. This case has mobilized intense efforts toward HIV eradication, ideally with less toxic interventions. Foremost are attempts to pharmacologically reactivate virus from latently infected cells using a variety of latency-reversing agents (LRAs). However, emerging data indicate that LRA-treated cells do not die by viral cytopathic effects, suggesting that eliminating them through engagement of HIV-specific CD8+ T cells will be required if this approach is to succeed (8, 9). For clearance to occur, the CD8+ T cell response will have to be more effective than it is in natural infection. Here, we discuss the prospects for the contribution of HIV-specific CD8+ T cells to elimination of the viral reservoir in the context of longterm cART. Short of viral eradication, we discuss the prospects for harnessing HIV-specific CD8+ T cells to contain rather than eradicate virus replication, effecting a functional cure as defined by sustained remission of viremia after cessation of therapy.