Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques

Abstract

Loss of CD4 + T cells in the gut is necessary but not sufficient to cause AIDS in animal models, raising the possibility that a differential loss of CD4 + T-cell subtypes may be important. We found that CD4 + T cells that produce interleukin (IL)-17, a recently identified lineage of effector CD4 + T-helper cells, are infected by SIV mac251 in vitro and in vivo, and are found at lower frequency at mucosal and systemic sites within a few weeks from infection. In highly viremic animals, Th1 cells predominates over Th17 T cells and the frequency of Th17 cells at mucosal sites is negatively correlated with plasma virus level. Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, our finding may explain the chronic enteropathy in human immunodeficiency virus (HIV) infection. Thus, therapeutic approaches that reconstitute an adequate balance between Th1 and Th17 may be beneficial in the treatment of HIV infection.

Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection

“…Th1 cells are the dominant subset in the gut mucosa during chronic infection, and the loss of Th1 cells in HIV/SIV infection impairs their responses to bacterial pathogens in gut mucosal tissues. 16,30 The decline of gut-homing Th1 cells during acute infection in our data (Figure 5b and 5c) indicates that a lack of Th1 cell recruitment from blood to the gut mucosa may occur during persistent HIV-1 infection and contribute to AIDS progression.…”

“…[15][16][17] Therefore, we determined the ratios of Th1:Treg, Treg:Th17, and Th1:Th17 of gut-homing CD4 1 T cells in AHIs. Acute HIV-1 infection led to a loss of guthoming Th1:Treg compared to HCs (Figure 6b), and the Treg:Th17 ratio increased in the gut-homing CD4 1 T-cell subset with statistical significance (Figure 6c).…”

“…[10][11][12][13][14] Alterations in Th17:Th1 and Th17:Treg balance also contribute to disease progression in HIV/SIV infection. [15][16][17] The gut-homing receptor integrin a4b7 mediates lymphocyte migration from the circulation to the intestine through interaction with MAdCAM-1 on endothelial cells of gut tissues. 18,19 The binding of integrin a4b7 and HIV-1 gp120 facilitates selective infection and replication in a4b7 CD4 1 T cells, which results in HIV-1 cell-to-cell spreading.…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…First and foremost, it is possible that a different "quality" of CD4 ϩ T-cell depletion in natural versus nonnatural SIV hosts at the intestinal mucosal level plays a major role. Indeed, both SIV-infected RM and HIV-infected persons experience a significant and preferential reduction of the IL-17-producing CD4 ϩ (Th17) and CD8 ϩ (Tc17) T-cell subsets throughout the gastrointestinal tract (81)(82)(83)(84). Similarly, the depletion of IL-17-producing innate lymphocytes in the GI tracts of SIV-infected Asian macaques has been demonstrated (85,86).…”

“…In a longitudinal study aimed at assessing the composition of microbial products translocating in peripheral blood prior to and during ART, we reported that patients with a poor immunological response to therapy exhibited a translocating bacterial microflora enriched in Enterobacteriaceae, with no evidence of probiotic Lactobacillus spp. (40), which are known to possess immunomodulatory and anti-inflammatory properties (106), including the suppression of proinflammatory cytokine production from E. coli LPS-activated monocytes (83). This change in the composition of the gut microbiome might result in a disproportionate antigenic challenge that is not contained by counterregulatory bacterially derived factors, overall exacerbating immune activation in this population of HIV-infected individuals.…”