Blunted IL17/IL22 and Pro-Inflammatory Cytokine Responses in the Genital Tract and Blood of HIV-Exposed, Seronegative Female Sex Workers in Kenya

Abstract

BackgroundIdentifying the immune correlates of reduced susceptibility to HIV remains a key goal for the HIV vaccine field, and individuals who are HIV-exposed, seronegative (HESN) may offer important clues. Reduced systemic immune activation has been described in HESN individuals. Conversely, pro-inflammatory T cell subsets, particularly CD4+ T cells producing the cytokine IL17 (Th17 cells), may represent a highly susceptible target for HIV infection after sexual exposure. Therefore, we characterized the cellular pro-inflammatory and IL17/IL22 cytokine immune milieu in the genital mucosa and blood of HESN female sex workers (FSWs).Methods and ResultsBlinded lab personnel characterized basal and mitogen-induced gene and cytokine immune responses in the cervix and blood of HESN FSWs (n = 116) and non-FSW controls (n = 17) using qPCR and ELISA. IL17 and IL22 production was significantly reduced in both the cervix and blood of HESNs, both in resting cells and after mitogen stimulation. In addition, HESN participants demonstrated blunted production of both pro-inflammatory cytokines and β-chemokines.Discussion and ConclusionsWe conclude that HIV exposure without infection was associated with blunted IL17/IL22 and pro-inflammatory responses, both systemically and at the site of mucosal HIV exposure. It will be important for further studies to examine the causal nature of the association and to define the cell subsets responsible for these differences.

Stable CD4 Expression and Local Immune Activation in the Ectocervical Mucosa of HIV-Infected Women

“…Women included in the HIV 2 FSW group had been enrolled in the sex worker cohort for at least 3 y, and some of them thus met the criterion of being relatively HIV resistant (24). A low immune activation state can be associated with resistance to heterosexual HIV transmission in the present cohort, as previously identified in blood, cervical mononuclear cells, and cervicovaginal secretions (36)(37)(38). Thus, the relatively low CD4 cell counts and immune activation status that we observed at the genital tissue level for some of the HIV 2 FSW women may reflect and represent this rare phenotype of HIV-resistant individuals.…”

Mucosal Immune Regulation: Does it Help Thwart HIV?

“…In a recent study, cervical and peripheral cellular responses to mitogen stimulation were compared between low-risk women and CSWs active in the field for 1 to 38 years. Following mitogen stimulation, PBMC and CMC from CSWs demonstrated a reduced production of Th17/Th22-related cytokines in both compartments, but no difference in the magnitude of the immune response was observed according to duration of sex work [107]. Immunostaining of endocervical biopsies demonstrated that active sex work alters DC phenotypes at the FGT.…”

“…Decreased levels of T cell activation and host proteins required for HIV-1 replication were observed in HESN sex workers that limit available target cells for viral replication [105]. Factors that affect lymphocytes trafficking to the FGT and that regulate the inflammatory state of the genital mucosa could be key contributors to the induction of immune quiescence and, therefore, protection to HIV [106,107].…”

“…As mentioned previously, it has been reported that HESNs present a quiescent phenotype at the FGT and periphery and this low level of activation is less suitable for the establishment of HIV infection and may contribute to protection [105][106][107]125,126]. The way the mucosal immune system responds to commercial sexual activities and HIV pressure could contribute to this quiescent phenotype.…”

Association between Cellular Immune Activation, Target Cell Frequency, and Risk of Human Immunodeficiency Virus Type 1 Superinfection

“…A number of studies have examined immune activation in HIV-exposed but uninfected individuals. The majority of these studies support the idea that low levels of immune activation at the time of exposure reduce the risk of HIV-1 infection (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, one recent study indicated that condom use was associated with lower levels of immune activation, potentially confounding some of the prior results (10).…”