Mitochondrial DNA Fragment Dynamics in Acute and Chronic Human Immunodeficiency Virus: Insights From Human and Nonhuman Primate Models.

Abstract

Circulating cell-free mitochondrial DNA (ccf-mtDNA) fragments are released into the bloodstream following cell death and are associated with comorbidities seen in people with HIV-1 (PWH). However, ccf-mtDNA dynamics in acute and chronic HIV infection remain unclear. We quantified short and long ccf-mtDNA fragments in serum from 2 cohorts of PWH and people without HIV (PWoH), collected at 1, 3, and 5 years in the first cohort (N = 890) and 1 and 5 years in the second (N = 427). Mixed-effect linear regression models were used to analyze longitudinal associations of ccf-mtDNA levels with HIV status and markers (CD4-cell count, viral load). In parallel, we examined ccf-mtDNA levels in nonhuman primates (NHPs) before and after simian immunodeficiency virus (SIV) infection and following 3 and 6 months of ART. In both human cohorts, PWH had significantly lower levels of short and long ccf-mtDNA fragments compared with PWoH. Individuals with lower CD4 T-cell counts exhibited further reductions in ccf-mtDNA levels. In NHPs, short ccf-mtDNA levels increased after infection, peaking before ART initiation (P = .001), and subsequently declined, reaching levels below baseline after 6 months on ART. Long ccf-mtDNA fragments remained stable during the early post-ART phase but declined significantly by 6 months (P = .02). Chronic HIV infection and treated SIV infection are associated with reduced ccf-mtDNA levels, particularly in advanced disease stages. Further research is needed to clarify their role in immune activation, chronic inflammation, and aging-related comorbidities in PWH and their applicability as clinically relevant biomarkers of these processes.