Ovariectomy Increases CD4 + T cell Activation in Simian Immunodeficiency Virus Infection

Abstract

People living with HIV (PLWH) have a higher prevalence of alcohol use disorder (AUD), which has been associated with accelerated HIV disease progression. Older PLWH, especially postmenopausal women, are at a greater risk for alcohol-related problems. Previous studies have shown that chronic binge alcohol (CBA) administration leads to higher simian immunodeficiency virus (SIV) loads and accelerated progression towards end-stage disease in rhesus macaques. Clinical studies have shown that ovariectomy (OVX) increases T cell activation and serum TNF-alpha levels. We tested the hypothesis that CBA and ovarian hormone loss, resulting from OVX, increases T cell activation in SIV-infected female rhesus macaques. CBA or isovolumetric water was administered through an intragastric catheter for 30 minutes, 5 days a week, with peak blood alcohol concentrations reaching 50-60 mM. After three months of CBA/VEH administration, macaques were infected with SIVMac251 and 2.5 months later initiated on ART. OVX was performed one month after ART initiation, and study endpoint was ~12 months post-SIV infection. Blood samples obtained at study end point were used for flow cytometry analysis with FITC-CD38, PerCP-CD3, PE-CD45, Qdot 655-CD8, ECD-CD20, APC-Cy7-CD4, PE-Cy7-CD16, APC-CD66, Pacific Blue-CD14, and Am Cyan-Live Dead, using a BD Biosciences LSRII flow cytometer and FlowJo software (version 10.7.1). Two-way ANOVA was used to detect significant differences between groups (N = 7-8/group). At study end-point, there was a main effect of OVX to increase activated CD4+CD38+ T cells (p = 0.0171) compared to SHAM. Neither CBA nor OVX had an effect on activation of CD8+ T cells. There was a main effect of OVX (p = 0.0195) and an interaction (p = 0.05) observed for CD4 T cell numbers (cells/ml). Post-hoc analysis showed higher CD4 T cell number in the CBA/SIV/ART/OVX compared to CBA/SIV/ART/SHAM (p = 0.0174) animals. There were no significant differences between the treatment groups for CD20+, CD14+, and CD16+ cells. Our results show that OVX lead to an increase in activation of peripheral CD4+ T cells and an increase in peripheral CD4+ T cells within CBA animals, which could favor a pro-inflammatory environment and an increase in target cells in SIV-infected female macaques.