Abstract Body

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals, but does not eliminate an extremely durable reservoir of latently infected cells that is established early after infection. Consequently, discontinuation of ART typically leads to rapid rebound of plasma viremia Understanding the phenotype and location of latently infected cells represents a critical challenge in designing a cure for HIV; furthermore, many HIV-infected individuals given ART exhibit residual inflammation, which is associated with non-AIDS-related morbidity and mortality and may contribute to virus persistence. In this context, there is a strong consensus that a cure for HIV infection will not be achieved through ART intensification alone, and that novel approaches aimed at limiting residual inflammation and targeting persistently infected cells are needed. This presentation will discuss state-of-the-art concepts and immune based strategies targeting HIV persistence developed over the past several years using the model of SIV infection in rhesus macaques (RMs). Collectively, these studies support a model in which among memory CD4+ T-cells, those expressing co-inhibitory receptors (Co-IRs) are enriched in latent HIV. Recent work identified PD-1+ follicular helper CD4+ T-cells as an important cellular compartment for viral persistence. We have described that CTLA-4+PD-1- memory CD4+ T-cells, which share phenotypic markers with regulatory T-cells and localize outside the B-cell follicle of the lymph nodes, are significantly enriched in SIV-DNA; contain robust levels of replication-competent virus; and significantly increase their contribution to the SIV reservoir with prolonged ART. Finally, we showed that Interleukin-21 administration in ART-treated, SIV-infected RMs reduces residual inflammation in blood and intestinal mucosa, which is in turn associated with diminished viral persistence during ART. These recent advancements highlight the complexity and diversity of the mechanisms and T-cell populations that can contribute to the residual reservoirs of virally infected cells. Understanding this complexity and developing a range of different interventions to target individual components of viral reservoirs represent both a formidable challenge and an exciting opportunity for the years to come.