Chronic HIV-1 infection is characterized by T-cell dysregulation that is only partly restored by antiretroviral therapy. Here, we demonstrate a protective role for autophagy in HIV-1 disease pathogenesis. Targeted analysis of genetic variation in core autophagy gene ATG16L1 revealed a previously unidentified polymorphism, which correlated functionally with enhanced autophagy and clinically with improved survival of untreated HIV-1-infected individuals. Intrinsically-enhanced autophagy in homozygous minor T-cells resulted in superior antiviral immunity, evidenced by increased proliferation, revamped immune responsiveness, and suppressed exhaustion/immunosenescence features. In-depth flow-cytometric and transcriptional T-helper-profiling revealed signatures unique to minor genotyped individuals with enriched regulation of pro-inflammatory networks and skewing towards immunoregulatory T-cell-phenotype. Treatment with autophagy-enhancing pharmaceuticals reprogrammed T-cells to exhibit the protective traits observed in homozygous minor donors. These data underscore the in vivo relevance of autophagy for longer-lasting T-cell-mediated HIV-1 control, with implications towards development of host-directed therapeutics targeting autophagy to restore immune function in chronic HIV-1 infection.