Functional variability of Nef in antagonizing SERINC5 during acute to chronic HIV-1 infection

The ability of HIV-1 Nef to counteract the host restriction factor SERINC5 and enhance virion infectivity has been well established. However, the impact of long-term within-host Nef evolution on this antagonistic capability remains unclear.

Analysis of longitudinal activity of Nef in antagonizing SERINC5.

We investigated the downregulation activity of Nef against SERINC5 at different stages of infection by analyzing the cognate transmitted/founder, set point, and/or chronic Nef isolates from a cohort of 19 people with either subtype B or C HIV-1.

The Nef isolates from different stages exhibited varying abilities to antagonize SERINC5. Long-term evolution resulted in mutations accumulated in Nef and a decline of Nef-mediated SERINC5 downregulation function in subtype B, but not in subtype C viruses, leading to a rapid reduction in viral load from peak viremia. Furthermore, we identified four polymorphisms of both subtype B and C Nef that are associated with variations in the SERINC5 antagonistic function and viral infectivity. HIV-1 NL4-3 variants encoding Nef E63G, A83G, R105K, or D108E mutants exhibited reduced replication capacity through a SERINC5-dependent mechanism. However, among different subjects, only a small part of naturally occurring mutations at these sites were selected by host T-cell responses, suggesting a limited impact of host T-cell responses on influencing Nef's ability to antagonize SERINC5.

These results highlight the potential contribution of functional variation in Nef to differences in HIV-1 pathogenesis and provide significant implications for understanding the evolutionary interaction between Nef and SERINC5 in vivo .