Abstract
ABSTRACTSexual transmission of HIV requires exposure to the virus and infection of activated mucosal immune cells, specifically CD4+ T cells or dendritic cells. The foreskin is a major site of viral entry in heterosexual transmission of HIV. Although the probability of acquiring HIV from a sexual encounter is low, the risk varies even after adjusting for known HIV risk factors. The genital microbiome may account for some of the variability in risk by interacting with the host immune system to trigger inflammatory responses that mediate the infection of mucosal immune cells. We conducted a case-control study of uncircumcised participants nested within a randomized-controlled trial of male circumcision in Rakai, Uganda. Using penile (coronal sulcus) swabs collected by study personnel at trial enrollment, we characterized the penile microbiome by sequencing and real-time PCR and cytokine levels by electrochemiluminescence assays. The absolute abundances of penile anaerobes at enrollment were associated with later risk of HIV seroconversion, with a 10-fold increase in Prevotella, Dialister, Finegoldia, and Peptoniphilus increasing the odds of HIV acquisition by 54 to 63%, after controlling for other known HIV risk factors. Increased abundances of anaerobic bacteria were also correlated with increased cytokines, including interleukin-8, which can trigger an inflammatory response that recruits susceptible immune cells, suggesting a mechanism underlying the increased risk. These same anaerobic genera can be shared between heterosexual partners and are associated with increased HIV acquisition in women, pointing to anaerobic dysbiosis in the genital microbiome and an accompanying inflammatory response as a novel, independent, and transmissible risk factor for HIV infection.
Highlights
Sexual transmission of HIV requires exposure to the virus and infection of activated mucosal immune cells, CD4ϩ T cells or dendritic cells
The foreskin is the major site of HIV exposure and viral entry in uncircumcised heterosexual men [2,3,4], and the interplay between the immune responses and genital microbiome at this site could be an important determinant of host HIV susceptibility
Increased levels of chemoattractant cytokines interleukin-8 (IL-8) and monokine induced by interferon gamma (MIG) in the penile coronal sulcus have been linked to increased density of highly HIV-susceptible CD4ϩ T cells in the underlying foreskin tissue, with consequent increased HIV risk [8]
Summary
Sexual transmission of HIV requires exposure to the virus and infection of activated mucosal immune cells, CD4ϩ T cells or dendritic cells. Increased abundances of anaerobic bacteria were correlated with increased cytokines, including interleukin-8, which can trigger an inflammatory response that recruits susceptible immune cells, suggesting a mechanism underlying the increased risk These same anaerobic genera can be shared between heterosexual partners and are associated with increased HIV acquisition in women, pointing to anaerobic dysbiosis in the genital microbiome and an accompanying inflammatory response as a novel, independent, and transmissible risk factor for HIV infection. We found that having higher levels of penile anaerobes was associated with higher production of immune factors that recruit HIV target cells to the foreskin, suggesting that anaerobes may modify HIV risk by triggering inflammation These anaerobes are known to be shared by heterosexual partners and are associated with HIV risk in women. Changes in the genital microbiome that provoke inflammation could facilitate infection by pathogens, such as HIV; this may explain how a vaginal ecological imbalance could increase HIV risk [15, 16], or how reducing penile anaerobes could decrease HIV risk [17]
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