Differential effects of antiretroviral treatment on immunity and gut microbiome composition in people living with HIV in rural versus urban Zimbabwe

The widespread availability of antiretroviral therapy (ART) for people living with HIV (PLWH) has dramatically reduced mortality and improved life expectancy. However, even with suppression of HIV-1 replication, chronic immune activation and elevated inflammation persist. Chronic immune activation has been linked to a pro-inflammatory gut microbiome composition, exacerbated by compromised intestinal barrier integrity that occurs after HIV infection. Individuals living in urban versus rural areas of sub-Saharan Africa have differences in environmental factors that may impact gut microbiome composition, yet immune phenotype and gut microbiome composition response to ART in PLWH living in rural versus urban areas of sub-Saharan Africa have not been compared. Here, we measured immune phenotypes and fecal microbiome composition in PLWH and healthy participants recruited from the urban Mabvuku polyclinic in the city of Harare, Zimbabwe and the Mutoko District hospital located in a district 146 km from Harare that services surrounding rural villages. PLWH were either ART naïve at baseline and sampled again after 24 weeks of treatment with efavirenz/lamivudine/tenofovir disoproxil fumarate (EFV/3TC/TDF) and the prophylactic antibiotic cotrimoxazole or were ART experienced at both timepoints. Although expected reductions in the inflammatory marker IL-6, T-cell activation, and exhaustion were observed in individuals who had suppressed HIV-1 with treatment, these changes were much more pronounced when considering individuals in the urban and not the rural area. Gut microbiome composition showed more marked differences from healthy controls in the ART experienced compared to ART naïve cohort, and consistent longitudinal changes were also observed in ART naïve PLWH after 24 weeks of treatment, including a reduction in alpha diversity and altered composition. However, gut microbiome composition showed a more pronounced relationship with chronic immune activation and exhaustion phenotypes in the ART naïve compared to ART experienced PLWH, suggesting a particularly significant role for the gut microbiome in disease progression in uncontrolled infection.