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Human immunodeficiency virus (HIV) infection remains a significant public health burden globally. The role of viral co-infection in the rate of progression of HIV infection has been suggested but not empirically tested, particularly among children. We extracted and classified 42 viral species from whole-exome sequencing (WES) data of 813 HIV-infected children in Botswana and Uganda categorised as either long-term non-progressors (LTNPs) or rapid progressors (RPs). The Ugandan participants had a higher viral community diversity index compared to Batswana ( p  = 4.6 × 10 −13 ), and viral sequences were more frequently detected among LTNPs than RPs (24% vs 16%;  p  = 0.008; OR, 1.9; 95% CI, 1.6–2.3), with  Anelloviridae  showing strong association with LTNP status ( p  = 3 × 10 −4 ;  q  = 0.004, OR, 3.99; 95% CI, 1.74–10.25). This trend was still evident when stratified by country, sex, and sequencing platform, and after a logistic regression analysis adjusting for age, sex, country, and the sequencing platform ( p  = 0.02;  q  = 0.03; OR, 7.3; 95% CI, 1.6–40.5). Torque teno virus (TTV), which made up 95% of the  Anelloviridae  reads, has been associated with reduced immune activation. We identify an association between viral co-infection and prolonged AIDs-free survival status that may have utility as a biomarker of LTNP and could provide mechanistic insights to HIV progression in children, demonstrating the added value of interrogating off-target WES reads in cohort studies.

Unmapped exome reads implicate a role for Anelloviridae in childhood HIV-1 long-term non-progression