Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation

AI Summary

This study investigated how genetic differences in a viral protein called Nef affect its ability to counteract a human protein called SERINC3, which normally reduces how well HIV can infect new cells. Nef helps HIV become more infectious by removing SERINC3 from the surface of infected cells, but the specific viral genetic changes that influence this process, especially in HIV‑1 subtype C (common in Southern Africa), were not well understood. The researchers tested 107 naturally occurring Nef variants from people with early subtype C infection to see how well each version could reduce SERINC3 on cells in the lab. They found that while the ability to remove SERINC3 did not predict how quickly a person’s virus levels rose or their immune cells declined, it did contribute to the overall strength and “fitness” of the Nef protein’s functions. They identified about 30 specific amino acid positions in Nef that were linked to differences in SERINC3‑removal ability, with many changes located in the front part of the protein. These findings show that variation in the Nef gene influences one of its key activities and suggest that understanding these genetic determinants could help in designing therapies or vaccines that target important parts of Nef. By mapping how natural variation affects Nef activity, the work adds insight into how HIV adapts to host defenses and may inform future approaches to weaken the virus’s ability to spread.