The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. and blood T cell subsets were characterized by flow cytometry and immunohistochemistry (IHC). Th17 and Th1 cells from both the blood and foreskin expressed higher levels of CCR5 and were more activated than other CD4 T cell subsets. contamination was associated with an increased frequency of highly HIV-susceptible Th1, Th17 and Th22 cell subsets in the blood, but these T cell immune differences did not extend to the foreskin. induced changes in T cell immunology mediated through the common mucosal immune system are not likely to increase HIV susceptibility in the foreskin. Author Summary Fishing Rubusoside communities in East Africa have a very high prevalence of HIV, and also high rates of other endemic infections such as malaria and the fluke contamination in the gut mucosa might increase recruitment and activation of Rubusoside HIV target cells Rubusoside at other mucosal sites, and thereby contribute to high HIV rates in fishing communities. We enrolled men from a fishing community in Uganda and examined the frequency of highly HIV-susceptible cell types in their blood and foreskin tissue (a main site of HIV acquisition in heterosexual men). We found that men with contamination had a greater frequency of HIV target cells in their blood, but not their foreskin tissue, perhaps because foreskin cells did not express mucosal homing markers. It is possible that HIV target cells observed in the blood of contamination increases risk at these sites should be explored. Introduction HIV continues to be a public health crisis, with 2.3 million new infections and 1.6 million HIV-related deaths in 2013. Most new infections (70%) occurred in sub-Saharan Africa (SSA), where the predominant mode of transmission is usually heterosexual sex . Despite the high number of new cases of HIV, the likelihood of transmission during a single sexual exposure is usually low, and is almost always established by a single virus quasispecies out of multiple distinct strains in the transmitting partner . This suggests that the genital mucosa presents a significant barrier to contamination. The substantial heterogeneity in susceptibility between individuals [3, 4] may reflect differences in the availability of target cells in the genital mucosa [5, 6], and increased levels of genital immune activation may account for the much higher per-contact risk of acquisition after exposure in SSA [7, 8]. CD4 T cells expressing the chemokine receptor CCR5 are the predominant targets of HIV during initial contamination [2, 9, 10], and specific CD4+ T helper (Th) subsets are particularly susceptible to HIV. Activated Notch1 Th cells are more susceptible to contamination [11C13], as are Th17 cells (defined by the production of IL-17 ), Th1 cells (produce IFN ) and Th22 cells (produce IL-22 in the absence of IL-17 or IFN [16C18]). Not only are these subsets more susceptible to HIV contamination [19C22], but they are also selectively depleted early in HIV contamination [21, 23C25], and are less frequent in HIV-exposed seronegative (HESN) men . Th17 cells have the capacity to not only produce IL-17, but also other pro-inflammatory cytokines, including IL-22 and IFN [27, 28]. Polyfunctional Th17 cells are more susceptible to HIV contamination than either Th1 cells or Th17 cells that produce IL-17 alone [20C22], and are rapidly depleted in early HIV contamination . The mucosal availability of these highly susceptible CD4 T cells may determine whether exposure to HIV results in contamination . In keeping with the role of these mucosal cell subsets in HIV susceptibility, their numbers are increased in the genital mucosa by sexually-transmitted infections (STIs) that enhance HIV risk, such as Herpes simplex virus type 2 (HSV-2) [29C34], even in the absence of clinically apparent ulceration . Recent studies show that nongenital infections common to SSA, such as helminthic infections, promote systemic inflammation and CCR5 expression [36C40]. Whether immune activation from infections of the gastrointestinal mucosa, such as helminthic infections, would translate into genital immune alterations is not known, but immune stimulus at one mucosal surface often leads to T cell activation and recruitment at Rubusoside distal mucosal sites through the expression of common mucosal homing markers . This may explain why Kenyan women without STIs nonetheless have an increased frequency of activated CD4 T cells in their cervical mucosa compared to their peers from the United States . While helminthic infections were not tested for in this study, their high regional prevalence suggests a potential role in the mucosal immune activation observed in.