Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

Abstract

Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P < 0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R ‫؍‬ ؊0.

Consequences of HLA-B*13-Associated Escape Mutations on HIV-1 Replication and Nef Function

“…Naturally occurring sequence variation in Nef can modulate its CD4 and HLA class I downregulation activities (33)(34)(35)(36)58). We therefore investigated the impact of B*13-associated polymorphisms on Nef function.…”

“…In other words, this naturally occurring mutant combination, selected in vivo under B*13-mediated CTL pressure, conferred a functional cost to Nef's immune evasion activity. Although attenuation of Nef's HLA class I downregulation function as a consequence of CTL escape has been described previously (35,36), the mutations required to confer these effects are rare in vivo. The HLA-B*35-driven Nef-R75T and -Y85F escape mutations, when present together, reduced Nef's HLA class I downregulation activity nearly 2-fold, but this combination occurs in Ͻ0.2% of natural HIV-1 sequences (35).…”

“…Western blotting was performed as described previously (36). GXR-A*02 cells were infected with control or mutant viruses.…”

“…In addition, naturally occurring sequence variation in Nef (32)(33)(34), including HLA-driven escape mutations (35,36), can modulate this protein's major functions, including cell surface CD4 (37) and HLA class I (38) downregulation. However, the functional costs of B*13-driven immune escape mutations outside Gag and their possible contributions to B*13-mediated protective effects have not been investigated.…”

Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection

“…Other host responses, including the subject's more dominant T cell responses which exhibited consistent oligofunctionality, could have contributed to the virus control observed; particularly as this subject expressed the HLA B*81 allele which is overrepresented in viremic controllers [37]. Other viremic factors, variation in Nef-mediated immune evasion [38,39] or Gag-Protease replicative capacity [40] could have resulted in emergence of less fit and or less pathogenic viruses resulting in the lower setpoint. Given the number of variables in this, a single patient study, we cannot draw firm conclusions regarding the HIV-1 control observed.…”