Abstract
Men who have sex with men (MSM) have differences in immune activation and gut microbiome composition compared with men who have sex with women (MSW), even in the absence of HIV infection. Gut microbiome differences associated with HIV itself when controlling for MSM, as assessed by 16S rRNA sequencing, are relatively subtle. Understanding whether gut microbiome composition impacts immune activation in HIV-negative and HIV-positive MSM has important implications since immune activation has been associated with HIV acquisition risk and disease progression. To investigate the effects of MSM and HIV-associated gut microbiota on immune activation, we transplanted feces from HIV-negative MSW, HIV-negative MSM, and HIV-positive untreated MSM to gnotobiotic mice. Following transplant, 16S rRNA gene sequencing determined that the microbiomes of MSM and MSW maintained distinct compositions in mice and that specific microbial differences between MSM and MSW were replicated. Immunologically, HIV-negative MSM donors had higher frequencies of blood CD38+ HLADR+ and CD103+ T cells and their fecal recipients had higher frequencies of gut CD69+ and CD103+ T cells, compared with HIV-negative MSW donors and recipients, respectively. Significant microbiome differences were not detected between HIV-negative and HIV-positive MSM in this small donor cohort, and immune differences between their recipients were trending but not statistically significant. A larger donor cohort may therefore be needed to detect immune-modulating microbes associated with HIV. To investigate whether our findings in mice could have implications for HIV replication, we infected primary human lamina propria cells stimulated with isolated fecal microbiota, and found that microbiota from MSM stimulated higher frequencies of HIV-infected cells than microbiota from MSW. Finally, we identified several microbes that correlated with immune readouts in both fecal recipients and donors, and with in vitro HIV infection, which suggests a role for gut microbiota in immune activation and potentially HIV acquisition in MSM.
Highlights
Men who have sex with men (MSM) comprise over half of all people living with HIV in the United States and accounted for 67% of new U.S infections in 2016 [1]
Recent studies have reported a distinct gut microbiome composition in men who have sex with men (MSM) exhibiting HIV-risk behaviors when compared with low-risk men who have sex with women (MSW), regardless of their HIV infection status
Whether these gut microbiome differences in high-risk MSM directly impact immune activation is important to understand since increased T cell activation is associated with increased HIV transmission risk and more severe disease
Summary
Men who have sex with men (MSM) comprise over half of all people living with HIV in the United States and accounted for 67% of new U.S infections in 2016 [1]. Recent studies have found that a distinct gut microbiome composition is found in MSM when compared with heterosexual men (men who have sex with women, MSW) even in the absence of HIV infection [2,3,4]. Several studies have shown that high-risk HIVnegative MSM exhibit immune differences, such as higher blood T cell activation [5], increased endotoxemia [6], and increased T cell pro-inflammatory cytokine production in colon mucosa [3], when compared with HIV-negative MSW. Establishing a direct impact of the gut microbiome on immune activation in HIV-negative and HIV-positive MSM may have important implications for transmission and disease, since vaginal immune activation in women has been associated with HIV acquisition risk [9,10,11,12] and T cell activation is well known to be a correlate of disease progression in HIV-positive individuals [13]. Whether the gut microbiome may be a risk factor for HIV transmission in MSM has not been investigated
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