There is evidence to suggest that HIV-1 latency varies by sex; women have been reported to have fewer CD4 T cells containing HIV-1 provirus, lower levels of residual viral activity in resting CD4 T cells (rCD4), and lower T cell activation. Immunologic characteristics that correlate with latent reservoir size have been used to inform cure strategies, but these studies have been performed in predominantly male cohorts. We sought to determine if immune correlates of reservoir size differed by biological sex.
Blood samples were collected from HIV-1+, ART-suppressed (<40 copies/ml for >1 year) adults living in Rakai, Uganda (n=42 females, n=20 males). The frequency of rCD4 containing replication competent provirus was estimated by quantitative viral outgrowth assay (QVOA). 14 soluble immune biomarkers were measured in plasma using custom multiplexed immunosorbent assays (MesoScale Discovery) and T cell memory subsets, activation and exhaustion markers, and effector T cell function were quantified by flow cytometry. Regression analysis was used to identify immune characteristics associated with reservoir size according to biological sex.
Women and men were similar in terms of age, HIV-1 subtype distribution (A, D and recombinants), nadir CD4, pre-ART viral load and duration of viral suppression on ART. Compared to men, women had significantly higher serum concentration of D-dimer (272.8 vs. 130.1 ng/ml, p<0.01) and there was a trend (p<0.1) towards a lower proportion of IL2+ CD8 T cells (1.85 vs. 4.31%) and effector memory CD4 T cells (1.88 vs. 3.44%). Consistent with prior reports, among men reservoir size correlated positively with PD-1 expression on CD4 T cells (r = 0.04, p<0.05). However, this association was not observed in women. Among women, reservoir size correlated positively with CD8 and CD4 T cell effector function (IL2 and TNFa production, all p<0.05).
These data identify distinct immunologic correlates of the replication competent HIV-1 reservoir in men and women. Whether these measures are biomarkers or imply differential immune control/response to the reservoir is unknown. This is important to consider as interventions target immune checkpoint molecules, such as PD-1, for latency reversal and immune stimulation. Globally, females make up more than half of all individuals infected with HIV-1, and cure studies must be adequately powered to examine efficacy in both sexes.