Longitudinal Analysis of Peripheral and Colonic CD161+ CD4+ T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation

Abstract

CD161 expression on CD4+ T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161+ CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161+ CD4+ T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161+ CD4+ T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161+ CD4+ T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161+ CD4+ T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161+ CD4+ T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161+ CD4+ T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161+ CD4+ T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161+ CD4+ T cell population that could not be completely prevented by the initiation of ART.

Enhanced IL-17 Producing and Maintained Cytolytic Effector Functions of Gut Mucosal CD161+CD8+ T Cells in SIV-Infected Rhesus Macaques

“…The chronic SIV infection period ranged from 18–26 weeks post-SIV inoculation, which is equivalent to early chronic HIV infection in humans without antiretroviral therapy. In concordance with earlier studies in HIV/SIV infected cohorts [ 17 , 18 , 28 ], lower frequencies of peripheral blood CD161 + T cells were most significant in chronic SIV-infected group of macaques for the CD4 + subsets ( p < 0.0001), in comparison to the SIV-naïve group ( Figure 2 ). Interestingly, however, there was no significant difference in CD161 + CD8 + T cell frequencies between SIV-naïve and SIV-infected macaques ( Figure 2 ).…”

“…Our results concur with previous studies demonstrating depletion of CD161-expressing CD4 T cells from blood during HIV and SIV infections [ 10 , 17 , 18 ], primarily due to viral infection and redistribution to mucosal tissues [ 10 ]. This was further supported by higher levels of CCR5 expression on CD161 + CD4 + T cells in our cohort of SIV-infected macaques.…”

“…Previous studies have shown that CD4 T cells expressing CD161 are depleted from blood during HIV and SIV infections [ 10 , 17 , 18 ] because of viral infection and redistribution to mucosal tissues along with significant loss of IL-17 functions [ 10 ]. However, the impact of HIV/SIV infection on tissue-resident CD161 + CD8 + T cells remain unclear.…”

“…Corresponding with the decline of Th17 cells, the IL-17/IL-22-producing subset of innate lymphoid cells, ILC3, has been observed to lose IL-17 cytokine functions and increase production of TNF-α, IFN-γ, and MIP-1β in SIV-infected animals [ 14 , 15 , 16 ]. While the impairment of the immune system and the reduction of Th17 cells in response to the loss of mucosal CD4 + T cells is well-documented in HIV/SIV infections [ 10 , 17 , 18 ], the impact on mucosal immune functions of other IL-17-producing T cell subsets remains partially understood [ 19 ].…”