Background
Non-HIV chronic/latent Viruses (NHV) such as CMV, EBV, HHV-8, HSV-1, HSV-2, HCV, and HBV are associated with markers of aging and/or age-related diseases and play a role in the accelerated cellular aging in people living with HIV (PLWH). We investigated association(s) between sex, HIV status, and NHVs, and selected markers of immune aging, in a cohort of PLWH and controls.
Methods
CARMA cohort participants (2-76y), balanced for sex, HIV status, and age were analyzed (Table 1). Seropositivity for the NHV were ELISA-based or self-reported (HIV, HCV, HBV). The CD4:CD8, CD8 proliferation competent:senescent (CD8+,CD28+:CD28–) and the naïve:effector CD4 and CD8 T cell ratios were determined via flow cytometry. Associations between number of NHV (0-1, 2-3, 4-6), HIV status, sex, and age were assessed using Mann-Whitney, Kruskal-Wallis, and Spearman’s tests. Multivariable linear regression determined independent associations (β= effect size) between the markers of aging, NHV, and sex, controlling for age and other potential confounders.
Results
Among 350 study participants, despite similar ages, females and PLWH had more NHV than males and controls, respectively (Table 1). By univariate analysis, a lower CD4:CD8 ratio was associated with male sex, HIV+ status, and having 2-3 or 4-6 vs. 0-1 NHV. The CD8+,CD28+:CD28– ratio decreased with increasing number NHV, and was lower among PLWH. For both CD4 and CD8 T cells the naive:effector ratio decreased with increasing number of NHV. Living with HIV, being male, and having CMV were all independently associated with a decreased CD4:CD8 ratio when controlling for age, ethnicity, smoking, and the six other NHVs (all β >0.22, p<0.001) . In a similar model for the CD8+,CD28+:CD28– ratio, HIV, CMV and HSV2 were independently associated with a decreased ratio (all β >0.21, p<0.01), but male sex was not (p=0.055). Finally, male sex and CMV were independently associated with lower naive:effector ratio in CD4 and CD8 T cells. In contrast, HSV1 was associated to a decrease in naive CD4 T cells, while HSV2 was associated with a decrease in naive CD8 T cells (all β >0.11, p<0.01).
Conclusions
Our findings suggest that NHV, including those that are typically asymptomatic such as CMV, HSV1 and HSV2, likely contribute to immune aging. Paradoxically, despite harbouring more NHV, female participants showed healthier immune cell profiles for all markers studied, a sex effect similar in size to that seen for HIV or CMV.