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. 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.

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

“…We have found that HIV-specific CD8 ϩ T cell responses in some HICs enrolled in the ANRS CO21 cohort wane over time, yet the plasma viral load remains undetectable (unpublished observations). Similar observations have been made in macaques spontaneously controlling simian immunodeficiency virus (SIV) SIVmac251 infection (10). In HICs, highly responsive CD8 ϩ T cells tend to have an effector phenotype (4,8,11), whereas weakly responsive CD8 ϩ T cells tend to have a resting memory phenotype (8,9).…”

Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV

“…2 and data not shown), suggesting that the specificity of T cells in the periphery did not determine whether animals were able to prevent the replication of viruses with full-length nef sequences after intrarectal, but not intravenous, challenge. Together, these observations are consistent with data from previous studies suggesting that control of SIV replication may be independent of the CD8 T cell response, especially among animals that do not have protective MHC alleles (19,20). It is alternately possible that persistent replication of the m3KO⌬nef virus in some animals offered the maintenance of effective host immune responses, but this hypothesis is difficult to test in the small cohort of animals in this study.…”

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

“…Comparison of CD4:CD8 ratios in BAL of humans and macaques was confounded by the observation that DP T expressing both CD4 and CD8 were observed in BAL of macaques, but not of humans. DP T populations have been reported in multiple animal models (39)(40)(41) and in previous human studies (42)(43)(44). In humans, DP T have been described in the peripheral blood as differentiated antigen-specific cells developed in response to viral pathogens (44) and in the affected tissues of suspected autoimmune diseases (reviewed in Reference 39); DP T were also identified in BAL of HIV-infected patients with chronic obstructive pulmonary disease but not in HIV infection or chronic obstructive pulmonary disease alone (45).…”