Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+ T-Cell Responses

ABSTRACT The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+ T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+ T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+ T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+ T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+ T cells that lacked efficient SIV suppression capacity ex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+ T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+ cell depletion and inducible SIV replication from its CD4+ T cells in vitro. Altogether, our results suggest that CD8+ T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control. IMPORTANCE Spontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+ T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+ T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+ cells induced a rise in the viral load. However, viremia was correlated with CD4+ T-cell activation subsequent to CD8+ cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+ T cells. Our results suggest that CD8+ T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.