Understanding formation and dynamics of the SIV reservoir.

ABSTRACT The suppression of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy (ART). Major advances have been made towards this end with the advent of ART regimens. However, despite the sustained suppression of viremia below detectable limits in infected patients for many years on ART regimens, intact replication-competent virus can still be recovered from a variety of hidden subterfuges within the host, and most notably from long-lived quiescent memory CD4+ T lymphocytes. This viral reservoir represents the final impediment to the eradication and clearance of HIV infection or to a sustained virologic remission in the absence of ART. Currently, our understanding of HIV reservoirs in patients living with HIV (PLWH) is incomplete. Knowledge of early reservoir formation and dynamics in the setting of early ART initiation is limited, particularly in anatomic tissues. My laboratory has shown that persistent viral reservoirs are established very early- within the first few days after SIV infection (Whitney et al., Nature 2014). While early ART can limit the seeding and expansion of cellular reservoirs of HIV, conventional understanding is that latent HIV-1 persists primarily in memory CD4+ T cells. However, studies from my laboratory (Whitney et al., Nat Commun., 2018) suggest that the contribution of long-lived naïve T cell populations to the intact were among the first to viral reservoir is greatly underestimated, particularly in early seeding and reservoir formation. Similarly, recent work from other groups have shown that naïve CD4+ T cells contribute to the maintenance of viral reservoir by harboring inducible proviruses. Thus, infected naïve CD4+ T cells harboring intact virus serve as an important “proto”-reservoir with an extended half-life, high proliferative capacity and intrinsic resistance to CTL killing. These observations underscore the potential of this cell population to renew and maintain the intact reservoir. Combined, these studies suggest that naïve CD4+ T cells harbor an important and functionally distinct reservoir that is needful of further investigation for its role in reservoir establishment, persistence and rebound after cessation of ART.