Suppression of HIV-1 plasma viral load below detection preserves IL-17 producing T cells in HIV-1 infection

Abstract

IL-17 is proinflammatory cytokine secreted by a unique CD4+ T (Th 17 ) cell subset and proposed to play a role in host defense. We hypothesized that Th 17 cells are lost in HIV-1 infection. HIV-1-infected children with plasma viremia below 50 copies/ml had IL-17 production, whereas those with detectable viremia had minimal secretion. These results imply viral-mediated destruction or impairment of Th 17 cells and argue for complete suppression of viremia for reconstitution of Th 17 cells.IL-17 is a proinflammatory cytokine [1], unique in that it is produced by a distinct subset of human CD4+ (Th 17 ) cells [2]. Recent studies [3][4][5][6][7][8][9] highlight the influence of IL-17 as a mediator of tissue inflammation in several autoimmune disorders and host defense. IL-17 may have a direct role in Candida or Mycobacterial infections, and a loss of Th 17 cells could potentially lead to vulnerability to opportunistic infections [10][11][12][13]. In this study, we assessed the impact of HIV-1 infection on Th 17 cells in a cohort of HIV-1-infected children [14]. First, we stimulated peripheral blood mononuclear cells (PBMCs) from healthy subjects with various monoclonal antibodies (mAb) and mitogenic stimuli for detection of IL-17 production in vitro. We observed that stimulation with anti-CD3/anti-CD28 mAbs induced IL-17 secretion, primarily by CD4+ T cells (data not shown). In response to anti-CD3/anti-CD28 stimulation, the majority of the Th 17 cells did not coexpress IFN-γ. In contrast, stimulation with phorbol myristate acetate/ionomycin induced IL-17 secretion from both CD4+ and CD8+ T cells, as well as dual secreting IL-17/IFN-γ T cell subsets (data not shown). These results suggest that anti-CD3/anti-CD28 stimulation is an effective method to We next tested for the frequency of Th 17 cells in PBMCs using an anti-CD3/anti-CD28 stimulation IL-17 enzyme-linked immunosorbent spot assay in 12 HIV-1-infected children with differing levels of plasma viremia and compared this to a group of HIV-1-uninfected subjects who served as controls. The median number of IL-17-specific spot forming units (SFU) in healthy pediatric and adult subjects was 300 SFU/10 6 (range: 85-970 SFU/10 6 ; n = 12) and 760 SFU/10 6 (range: 110-1370 SFU/10 6 ; n = 7), respectively (Fig. 1a). A marked reduction in Th 17 cells was observed in the HIV-1-infected children (median: 62 SFU/10 6 ; range: 10-270 SFU/10 6 ; n = 12). Strikingly, the infected children with HIV-1 plasma viral loads exceeding 50 copies/ml had minimal numbers of Th 17 cells (median: 35 SFU/10 6 ; range: 10-95 SFU/10 6 ; n = 7), whereas those with suppressed viral loads had higher levels of Th 17 cells (median: 170 SFU/10 6 ; range: 75-270 SFU/10 6 ; n = 5). Interestingly, all groups had robust IFN-γ secretion (Fig. 1b). Flow cytometry assessment confirmed that CD4+ T cells were the primary source of IL-17 following anti-CD3/anti-CD28 mAb stimulation (data not shown). We carried out a univariate logistic regression analysis to test for an association between HIV-1 plasm...

The Th1/Th2/Th17 cytokine profile of HIV-infected individuals: A multivariate cytokinomics approach

“…When patients progressing to AIDS were included, IL-17A levels were lowered. Literature documenting an inverse correlation between viral load, the number of Th17 cells and therefore IL-17A exists [5]. In these articles IL-17A was measured following the isolation and in vitro stimulation of cells.…”

“…A newly defined subset of CD4 cells [4] called Th 17 cells produce, amongst others, the pro-inflammatory IL-17A [5]. Th17 cells and cytokines are associated with protection against bacterial, fungal and viral infections [4,6] and are important for maintaining a healthy mucosa.…”

“…Th17 cells and cytokines are associated with protection against bacterial, fungal and viral infections [4,6] and are important for maintaining a healthy mucosa. Because HIV primarily infects CD4 cells (including the Th17 subset), infection could potentially lead to a decrease in IL-17A production [5 and reviewed in 7] leaving the affected host susceptible to opportunistic infections [5,8]. The role of Th17 cells and cytokines in the context of HIV infection is not entirely resolved but their possible involvement as prognostic indicators, contributors to disease progression and/or as antiviral agents has been reported.…”

Impact of HIV Infection and HAART Therapy on CD4 T Helper Cell Subset Expression and Function

“…The first report that associated HIV with IL-17 showed an increase of IL-17 production by CD4 T cells in peripheral blood of HIV patients both in cells left untreated or stimulated with PMA/ionomycin (Maek, Buranapraditkun et al, 2007). It was later shown that HIV-1 infected children with a plasma viral load of below 50 copies/ml (undetectable HIV) had enhanced IL-17 production in contrast to those with detectable HIV, which had no observable IL-17 production (Ndhlovu, Chapman et al, 2008). This suggested a possible impairment of Th17 cells in patients with detectable HIV levels and decreased IL-17 levels, and that restoration of Th17 cells could be possible through suppression of viremia.…”

The comparison of Th1, Th2, Th9, Th17 and Th22 cytokine profiles in acute and chronic HIV-1 infection

“…In untreated HIV-infected individuals, depletion of Th17 cells can be observed in the gut mucosa and is linked to the loss of integrity of gut mucosal barrier [22]. In HIVinfected children, Ndhlovu et al found a positive correlation between viremia and decrease in Th17 cell count [23]. Th22 cells synthesize IL-22, a cytokine responsible for the maintenance of epithelial barrier integrity.…”