Patterns of immune recovery in people living with HIV who initiated antiretroviral therapy as late presenters.

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-025-11318-2.