Abstract
HIV-associated inflammation has been implicated in the premature aging and increased risk of age-associated comorbidities in cART-treated individuals. However, the immune mechanisms underlying the chronic inflammatory state of cART-suppressed HIV infection remain unclear. Here, we investigated the role of γδT cells, a group of innate IL-17 producing T lymphocytes, in the development of systemic inflammation and leaky gut phenotype during cART-suppressed SIV infection of macaques. Plasma levels of inflammatory mediators, intestinal epithelial barrier disruption (IEBD) and microbial translocation (MT) biomarkers, and Th1/Th17-type cytokine functions were longitudinally assessed in blood and gut mucosa of SIV-infected, cART-suppressed macaques. Among the various gut mucosal IL-17/IL-22-producing T lymphocyte subsets including Th17, γδT, CD161+ CD8+ T, and MAIT cells, a specific decline in the Vδ2 subset of γδT cells and impaired IL-17/IL-22 production in γδT cells significantly correlated with the subsequent increase in plasma IEBD/MT markers (IFABP, LPS-binding protein, and sCD14) and pro-inflammatory cytokines (IL-6, IL-1β, IP10, etc.) despite continued viral suppression during long-term cART. Further, the plasma inflammatory cytokine signature during long-term cART was distinct from acute SIV infection and resembled the inflammatory cytokine profile of uninfected aging (inflammaging) macaques. Overall, our data suggest that during cART-suppressed chronic SIV infection, dysregulation of IL-17/IL-22 cytokine effector functions and decline of Vδ2 γδT cell subsets may contribute to gut epithelial barrier disruption and development of a distinct plasma inflammatory signature characteristic of inflammaging. Our results advance the current understanding of the impact of chronic HIV/SIV infection on γδT cell functions and demonstrate that in the setting of long-term cART, the loss of epithelial barrier-protective functions of Vδ2 T cells and ensuing IEBD/MT occurs before the hallmark expansion of Vδ1 subsets and skewed Vδ2/Vδ1 ratio. Thus, our work suggests that novel therapeutic approaches toward restoring IL-17/IL-22 cytokine functions of intestinal Vδ2 T cells may be beneficial in preserving gut epithelial barrier function and reducing chronic inflammation in HIV-infected individuals.
Highlights
The discovery of efficient, well-tolerated combinational antiretroviral therapy regimens has remarkably reduced the rates of HIV-associated mortality and transformed it into a chronic, manageable disease that requires life-long treatment
Gut barrier breakdown and persistent inflammation are hallmarks of chronic HIV infection despite long-term treatment with antiretroviral drugs, and people living with HIV (PLWH) have an immune aging/ inflammaging phenotype. gdT cells are a subset of innate Th17type T cells that are key players in gut barrier function and immune activation [48], yet their role in inflammaging during the course of treated HIV infection is not understood
To investigate the role of gdT cell functions in the onset of inflammaging phenotype during combinational antiretroviral therapy (cART) suppressed SIV infection, this longitudinal study comprehensively examined the kinetics of plasma inflammatory and intestinal epithelial barrier damage (IEBD)/microbial translocation (MT) markers through the course of treated SIV infection and evaluated gdT cell frequencies and cytokine effector functions in blood and gut mucosa
Summary
The discovery of efficient, well-tolerated combinational antiretroviral therapy (cART) regimens has remarkably reduced the rates of HIV-associated mortality and transformed it into a chronic, manageable disease that requires life-long treatment. Aberrant immune activation and chronic inflammation during HIV/SIV infection is strongly associated with loss of Th17-type mucosal immune functions and intestinal epithelial barrier damage (IEBD) resulting in intestinal permeability (leaky gut) and microbial translocation (MT) [6,7,8,9]. This leaky gut-associated chronic inflammation persists even with long-term effective cART and predicts mortality and incidence of age-related co-morbidities (e.g. neurocognitive, metabolic, cardiovascular disorders) [10,11,12]. The dynamic role of gut mucosal gd T cells in IEBD, MT and persistent inflammation through the course of treated HIV infection remains unclear
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