Gastrointestinal Mucosal Disruptions During ART-Treated SIV/Plasmodium fragile Co-Infection

Background: Human immunodeficiency virus (HIV) and Plasmodium spp., which causes malaria, are co-endemic. Previously, we showed that during antiretroviral therapy (ART)-treated simian immunodeficiency virus (SIV)/Plasmodium fragile co-infection, peripheral markers of neutrophil extracellular trap (NET) formation positively correlated with peripheral markers of disease and gastrointestinal (GI) dysfunction. However, the impact of co-infection directly in the GI mucosa is unclear. We hypothesized that ART-treated SIV/P. fragile co-infection would result in peripheral and GI immune disruption associated with exacerbated clinical manifestations of SIV and P. fragile. Methods: Adult male rhesus macaques (RMs; n=6) were inoculated with SIVmac239, initiated ART at week 8 post-SIV infection (p.i.), were inoculated with P. fragile at week 12 p.i., and were followed until week 20 p.i. Plasma viral loads, peripheral parasitemia, and peripheral and GI immune cell frequencies and function were assessed longitudinally. Results: We observed significant CCR5+ CD4+ T cell decline in the periphery, colon, and duodenum following SIV infection. Neutrophil frequencies were unchanged throughout ART-treated SIV/P. fragile co-infection. Notably, duodenum NET-forming granulocyte frequencies were significantly positively associated with peripheral SIV burden following P. fragile co-infection but were unassociated with peripheral parasitemia and CD4+ T cell frequencies. Finally, although P. fragile was present in the duodenum, GI parasite burden was not associated with NET-forming granulocyte frequencies, peripheral viral loads, or CD4+ T cell frequencies. Conclusions: P. fragile co-infection during ART-treated SIV could cause mucosal disruptions that contribute to peripheral SIV replication despite ART. These data may have implications for HIV and malaria disease progression and treatment strategies.