Background.  The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whether and how these alleles influence the immune distribution of the HIV reservoirs.

Methods.  Cell-associated HIV-DNA levels were quantified in blood sorted resting CD4 T-cell subsets from 8 LTNPs with and 10 without HLA-B*27 or HLA-B*57 alleles (HLA-B27/B57).

Results.  A remarkably lower infection level of central memory CD4 T cells (T_CM) was an exclusive feature that distinguished the HLA-B27/B57 HIV reservoirs from the other ones. In LTNPs, T_CM protection was correlated with preservation of T_CM counts, which correlated positively with the magnitude of HIV Gag-specific CD8 T cells. In HLA-B27/B57 LTNPs, a lower activation level of their memory CD4 T cells was associated with lower amounts of cell HIV-DNA in each resting memory CD4 subset and were also associated with higher ratios of HIV Gag-specific CD8 T cells per infected resting CD4 T cell (effector/target [E/T]). As a result, HLA-B27/B57 E/T ratios were negatively correlated with the contribution of memory CD4 T-cell subsets to the total HIV reservoirs.

Conclusions.  The potent antiviral immunity governed by the protective HLA-B27/B57 alleles, by limiting T_CM infection and pool exhaustion, are associated with a reduced T_CM contribution to the HIV reservoir.