Impaired Nef function is associated with early control of HIV-1 viremia

Xiaomei T. Kuang, Xiaoguang Li, Gursev Anmole, Philip Mwimanzi, Aniqa Shahid, Anh Q. Le, Louise Chong, Hua Qian, Toshiyuki Miura, Tristan Markle, Bemuluyigza Baraki, Elizabeth Connick, Eric S. Daar, Heiko Jessen, Anthony D. Kelleher, Susan Little, Martin Markowitz, Florencia Pereyra, Eric S. Rosenberg, Bruce D. WalkerTakamasa Ueno, Zabrina L. Brumme, Mark A. Brockman

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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=-0.85, P=0.004) and positively with baseline plasma viral load (Spearman's R=0.81, P=0.007) in acute controllers but not in acute progressors. Nef polymorphisms associated with functional changes over time were identified in follow-up samples from six controllers. For one such individual, mutational analyses indicated that four polymorphisms selected by HLA-A⋆31 and B⋆37 acted in combination to reduce Nef steady-state protein levels and HLA class I downregulation activity. Our results demonstrate that relative control of initial HIV-1 viremia is associated with Nef clones that display reduced function, which in turn may influence the course of HIV-1 infection. Transmission of impaired Nef sequences likely contributed in part to this observation; however, accumulation of HLA-associated polymorphisms in Nef that impair function also suggests that CD8+ T-cell pressures play a role in this phenomenon.

Original languageEnglish (US)
Pages (from-to)10200-10213
Number of pages14
JournalJournal of virology
Volume88
Issue number17
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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