HIV-specific cytotoxic T lymphocytes (CTL) are preferentially primed for apoptosis, and this may represent a viral escape mechanism. We hypothesized that HIV-infected individuals that control virus to undetectable levels without antiretroviral therapy (ART) (elite controllers [EC]) have the capacity to upregulate survival factors that allow them to resist apoptosis. To address this, we performed cross-sectional and longitudinal analysis of proapoptotic (cleaved caspase-3) and antiapoptotic (Bcl-2) markers of cytomegalovirus (CMV) and HIV-specific CD8 T cells in a cohort of HIV-infected subjects with various degrees of viral control on and off ART. We demonstrated that HIV-specific CTL from EC are more resistant to apoptosis than those with pharmacologic control (successfully treated patients [ST], despite similar in vivo conditions. Longitudinal analysis of chronically infected persons starting ART revealed that the frequency of HIV-specific T cells prone to death decreased, suggesting that this phenotype is artially reversible even though it never achieves the levels present in EC. Elucidating the apoptotic factors contributing to the survival of CTL in EC is paramount to our development of effective HIV-1 vaccines. Furthermore, a better understanding of cellular markers that can be utilized to predict response durability in disease- or vaccine-elicited responses will advance the field. © 2013, American Society for Microbiology.