Antiretroviral treatment is less effective at reducing gut microbiome-associated inflammation and T cell activation in people living with HIV in rural than urban Zimbabwe
The widespread availability of antiretroviral therapy (ART) for people living with HIV (PLWH) has dramatically reduced mortality and improved life expectancy. But 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 Africa have differences in many environmental factors such as water source or diet that may impact gut microbiome composition, which have also been associated with inflammation in treated HIV infection. However, differences in immune phenotype and gut microbiome composition response to ART between PLWH living in rural versus urban areas of sub-Saharan Africa have not been explored. Here, we measured immune phenotypes and assessed fecal microbiome composition in PLWH and healthy participants recruited in an urban hospital in Harare, Zimbabwe and a hospital that services rural areas nearby. 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 significant only 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 ART, 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 important role for the gut microbiome in disease progression in uncontrolled infection. Further work is needed to understand why PLWH in rural areas of sub-Saharan Africa experience muted improvements in T cell activation and exhaustion levels with effective ART.