Long-term control of simian immunodeficiency virus (SIV) in cynomolgus macaques not associated with efficient SIV-specific CD8⁺ T-cell responses

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.