CD8 T-cells play a pivotal role in clearance of HIV-infected cells, such that CD8 exhaustion contributes to their dysfunction and consequently, viral persistence. Mesenteric lymph nodes (MLNs), which drain the large and small intestine, are critical sites for the induction and maintenance of gut mucosal immunity. However, the dynamics of CD8 T-cells in MLNs is less known due to the lack of accessibility to these tissues in human. Thus, we assessed CD8 T-cell dynamics in MLNs vs blood in SIV-infected rhesus macaques (RMs) following early antiretroviral therapy (ART) initiation.
32 female Chinese RMs were enrolled including 25 intravenously SIVmac251-infected animals. Nine monkeys were treated at day 4 post-infection with a cocktail of antiretroviral drugs. Furthermore, 5 RMs after ART interruption (8 weeks post-ART initiation) and 4 untreated chronically infected were also studied. Peripheral blood and mechanically isolated cells from MLNs were analyzed by flow cytometry.
Acute SIV infection was associated with decreased CD4/CD8 ratio and increased memory CD8 T-cell immune-activation (CD39/HLA-DR), exhaustion (PD1) and immunosuppressive CTLA-4 expression in both blood and MLNs which were all normalized by early ART initiation. Notably, MLN CD8 T-cells had consistently higher levels of immunosuppressive CTLA-4 and CD39 expression compared to matched blood samples in acute phase. Furthermore, acute SIV infection resulted in the expansion of FoxP3+ CD8 Tregs in both blood and MLNs, while early ART decreased CD8 Tregs only in blood. Helios+ thymic CD8 Tregs were also increased in both tissues in acute infection which were normalized by ART. Analyzing the trafficking of CD8 T-cells by assessing the expression of chemokine receptors, we found that the acute SIV infection results in decreased of CCR6+ but not CXCR3-expressing CD8 T-cells in both MLNs and blood, which was recovered following early ART. ART interruption was associated with increased HLA-DR+ CD8 T-cells and decreased CCR6+ CD8 T-cells within MLNs.
Early ART initiation during acute infection normalized CD8 frequencies and their markers of immune activation and function in both MLNs and blood, but elevated levels of suppressive CD8 Tregs persists despite early ART in MLNs. This could be of great importance regarding immune surveillance of SIV persistence despite ART.