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Background Some people living with HIV-1 (PWH) do not reconstitute their CD4 + T cell counts despite complete inhibition of HIV-1 replication on antiretroviral therapy (AR); these are known as immunological nonresponders (INR). This is a retrospective analysis to estimate the prevalence of INR in a hospital-based cohort of PWH who initiated ART with severe immunodeficiency and/or opportunistic infections. We also explored mechanisms of poor immune recovery, with emphasis on the gut microbiome. Methods All PWH included in this study achieved virologic suppression (plasma viral load < 200 copies of HIV-1/mL) six months after ART initiation and remained virally suppressed thereafter. INR and immunological responders (IR) were defined according to the CD4 + T cell counts after 24-months on ART initiation (< 350 or ≥ 350 cells/µL, respectively). Both INR ( n  = 15) and IR ( n  = 15) were matched for nadir CD4 (< 200 cells/µL). Uninfected individuals at high-risk of HIV infection were also included ( n  = 40). We assessed indirect markers linked to HIV disease progression (markers of innate immune activation and enterocyte damage) and gut dysbiosis using cryopreserved plasma and stool samples using Enzyme-Linked immunosorbent Assay and 16S ribosomal DNA sequencing. Results The estimated prevalence of INR after 24-months on ART was 50%. Microbial translocation, gut epithelial damage and gut dysbiosis persisted in PWH on ART, yet were not different between INR and IR. After adjusting for multiple comparisons, we found that INR had lower alpha diversity (Shannon) and higher levels of sCD163 compared with PWoH ( p  = 0.013 and p  = 0.017, respectively). No differentially-abundant genera were identified; differences in the gut microbiome were primarily driven by a Prevotella and Bacteroides gradient, which is linked to sexual practices (men who have sex with men, MSM). Indeed, in our cohort, most INR were non-MSM, while PWoH were all MSM. Conclusions In the Instituto Nacional de Enfermedades Respiratorias, a tertiary reference centre, a disproportionate number of individuals are diagnosed with HIV-1 with severe immunodeficiency and/or opportunistic infections; they represent a high-risk population for the INR phenotype. Our data on possible mechanisms of the INR phenotype linked to the gut microbiome yielded modest results, precluding any decisive conclusions. Interventions to boost the immune function in this at-risk population are warranted and deserving of further studies.

Background Unwanted weight gain is often reported in people living with HIV (PWH) who start on or switch to integrase strand transfer inhibitors (INSTI). Mechanisms are incompletely understood. An unintended off-target of INSTI might be the gut microbiota. Methods We explored the fecal microbiota of treated aviremic PWH ( n  = 70) who switched from efavirenz (EFV)- to a bictegravir (BIC)-based regimen. 16S rRNA sequencing, and enzyme-linked immunosorbent assays were used to characterize the fecal microbiota and quantify markers of HIV disease progression. A cohort of high-risk HIV-negative individuals ( n  = 18) was included to address differential effects of antiretroviral therapy (ART) on the fecal microbiota. Results This real-life cohort was predominantly male ( n  = 63) and mostly men who have sex with men ( n  = 40). All PWH were on the same antiretroviral regimen for at least 1 year; the mean time on ART was 10.83 ± 5.530 years and all had undetectable plasma viral loads (< 40 HIV-1 RNA copies/mL). PWH gained a median weight of 3.375 kg and the mean percent weight change relative to baseline was 4.32%. Seven (10%) PWH gained significant weight (> 10% relative to baseline). Switching to a BIC-based regimen had contrasting effects. PWH on BIC/FTC/TAF showed decreased microbial translocation (soluble CD14, sCD14), decreased enterocyte damage (intestinal fatty-acid binding protein, I-FABP), and increased alpha diversity (richness and shannon); all indicative of a better restoration of the gut mucosa and microbiota. Conversely, increases in sCD163, monocyte chemoattractant protein 1 (MCP-1) and decreases in adiponectin, markers linked to cardiovascular disease, insulin resistance and adiposity, were unfavorable. Conclusion Our data suggest that INSTI have a less detrimental effect on the gut microbiota compared to EFV-based regimen. The link between weight gain on INSTI and the gut microbiota was not readily apparent.

Cervical ectopy is a benign condition of the lower genital tract that is frequently detected in women of reproductive age. Although cervical ectopy is regarded as a physiological condition, some women experience symptoms such as leucorrhoea, persistent bleeding and recurrent vaginal infections that require medical intervention. Cervical ectopy has not been linked to cervical cancer, but it is thought to facilitate the acquisition of sexually transmitted diseases (STDs), like Human Papillomavirus (HPV) infection, as it provides a favorable microenvironment for virus infection and dissemination. We and others have described the presence of oncogenic HPV types in women with symptomatic cervical ectopy. The relevance of this finding and the impact of symptomatic cervical ectopy on the cervicovaginal microenvironment (vaginal microbiota, immune and inflammatory responses) are currently unknown. To shed some light into the interplay between HPV, the vaginal microbiota and mucosal immune and inflammatory responses in the context of this condition, we enrolled 156 women with symptomatic cervical ectopy and determined the presence of HPV using a type-specific multiplex genotyping assay. Overall, HPV was detected in 54.48% women, oncogenic HPV types were found in more than 90% of HPV-positive cases. The most prevalent HPV types were HPV16 (29.4%), HPV31 (21.17%) and HPV18 (15.29%). Next, we evaluated the vaginal microbial composition and diversity by 16S rDNA sequencing, and quantified levels of cytokines and chemokines by flow cytometry using bead-based multiplex assays in a sub-cohort of 63 women. IL-21 and CXCL9 were significantly upregulated in HPV-positive women ( p =0.0002 and p =0.013, respectively). Women with symptomatic cervical ectopy and HPV infection had increased diversity ( p <0.001), and their vaginal microbiota was enriched in bacterial vaginosis-associated anaerobes ( Sneathia , Shuttleworthia , Prevotella , and Atopobium ) and depleted in Lactobacillus spp. Furthermore, the vaginal microbiota of women with symptomatic cervical ectopy and HPV infection correlated with vaginal inflammation (IL-1β, rho=0.56, p =0.0004) and increased mucosal homeostatic response (IL-22, rho=0.60, p =0.0001). Taken together, our results suggest that HPV infection and dysbiotic vaginal communities could favor a vaginal microenvironment that might delay the recovery of the cervical epithelium in women with symptomatic cervical ectopy and favor STDs acquisition.