Natural Immunity to HIV is associated with Low BLyS/BAFF levels and low frequencies of innate marginal zone like CD1c+ B-cells in the genital tract

Abstract

BLyS/BAFF is recognized for its role in B-cell ontogenesis, as well as cell fate decision towards the first-line/innate marginal zone (MZ) B-cell pool. Excess BLyS/BAFF is associated with hyperglobulinemia and increased frequencies of activated precursor-like MZ B-cells. Herein, we show that HIV highly-exposed seronegative (HESN) commercial sex workers (CSWs) had lower soluble BLyS/BAFF levels and relative frequencies of BLyS/BAFF expressing cells in their genital mucosa when compared to those from HIV-infected CSWs and HIV-uninfected non-CSWs. Furthermore, we identified genital innate and/or marginal zone (MZ)-like CD1c + B-cells that naturally bind to fully glycosylated gp120, which frequencies were lower in HESNs when compared to HIV-infected CSWs and HIV-uninfected non-CSWs. Although genital levels of total IgA were similar between groups, HESNs had lower levels of total IgG1 and IgG3. Interestingly, HIV-gp41 reactive IgG1 were found in some HESNs. Low genital levels of BLyS/BAFF observed in HESNs may allow for controlled first-line responses, contributing to natural immunity to HIV.

Natural killer cell phenotype is altered in HIV-exposed seronegative women

“…In the female genital tract, the presence of antibodies that are capable of mediating ADCC against HIV gp120 is associated with reduced cervical viral load [59], suggesting that ADCC may act as a mechanism of defense against HIV in this setting. Our finding that NK cells from HESN women have a trend of increased ADCC activity may be particularly relevant as HIV gp41-reactive IgG1 antibodies have been found in CVL samples from women in this cohort [34]. Although no difference in ADCC-mediating antibodies have been observed in this cohort between HESN and healthy women [60], differences in ADCC activity at the level of effector cells could contribute to protection.…”

“…Prior studies of immune correlates of HIV protection in Beninese HESN women revealed a low inflammatory immune profile in the blood and genital tract. In fact, low levels of soluble B lymphocyte stimulator (BLyS)/BAFF were detected in the blood and cervicovaginal lavages (CVL) [34,35] and low levels of pro-inflammatory cytokines in the CVL of these HESN women [36,37]. This raised the possibility that HIV resistance in these women may be the result of a balance between strong innate immune responses and low inflammatory conditions and fewer HIV target cells at the exposure site [38].…”

Ex vivo rectal explant model reveals potential opposing roles of Natural Killer cells and Marginal Zone-like B cells in HIV-1 infection

“…MZB cells are emerging as a cell type of interest in HIV-1 transmission and pathogenesis. Recent studies have reported decreased numbers of MZB in the blood and within the female reproductive tract of HIV-exposed but uninfected commercial sex workers 22,23 . This suggests that MZB cells could be contributing to HIV transmission within the female genital tract, although mucosal B cells at this site are relatively rare 29 .…”

“…Although macrophages and DCs are more commonly associated with trans infection, there are higher proportions of MZB than macrophages, mDC, or pDC in RM, and it has been shown previously that peripheral B cells mediate trans infection as efficiently as other APC subsets 14 . Although traditional HIV-binding receptors such as CD21 and DC-SIGN were not quantified here, studies have reported MZB cells are capable of binding directly to HIV gp120 23 . When combined with unique intrinsic features of the rectal mucosa ex vivo HIV challenge model (i.e.…”

“…This process could be highly relevant during mucosal transmission, where APC have been implicated as actors in the first stages of intravaginal infection 16,17 . Interestingly, a unique subset of B cells that are considered 'innate-like' , Marginal Zone-like B cells (MZB), are also found within mucosal and epithelial barriers in humans, including the RM, and have been recently associated with HIV transmission and pathogenesis in humans [18][19][20][21][22][23] .…”