title: 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=-0.85, 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.
  
  
  OBJECTIVE
  Rare individuals can spontaneously control HIV-1 viremia in the absence of antiretroviral treatment. Understanding the host and viral factors that contribute to the controller phenotype may identify new strategies to design effective vaccines or therapeutics. The HIV-1 Nef protein enhances viral pathogenesis through multiple mechanisms. We examined the function of plasma HIV-1 RNA-derived Nef clones isolated from 10 recently infected individuals who subsequently controlled HIV viremia compared to the function of those from 50 individuals who failed to control viremia. Our results demonstrate that early Nef clones from HIV controllers displayed lower HLA class I and CD4 downregulation activity, as well as a reduced ability to enhance virion infectivity. The accumulation of HLA-associated polymorphisms in Nef during the first year postinfection was associated with impaired protein function in some controllers. This report highlights the potential for host immune responses to modulate HIV pathogenicity and disease outcome by targeting cytotoxic T lymphocyte (CTL) epitopes in Nef.
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
authors: Xiaomei T
authors: XT
authors: Kuang
authors: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors: Xiaoguang
authors: X
authors: Li
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
authors: Gursev
authors: G
authors: Anmole
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Philip
authors: P
authors: Mwimanzi
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Aniqa
authors: A
authors: Shahid
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Anh Q
authors: AQ
authors: Le
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
authors: Louise
authors: L
authors: Chong
authors: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors: Hua
authors: H
authors: Qian
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Toshiyuki
authors: T
authors: Miura
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
authors: Tristan
authors: T
authors: Markle
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Bemuluyigza
authors: B
authors: Baraki
authors: Department of Medicine, University of Colorado-Denver, Denver, Colorado, USA.
authors: Elizabeth
authors: E
authors: Connick
authors: David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, USA.
authors: Eric S
authors: ES
authors: Daar
authors: Jessen-Jessen Praxis, Berlin, Germany.
authors: Heiko
authors: H
authors: Jessen
authors: Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, Australia.
authors: Anthony D
authors: AD
authors: Kelleher
authors: Division of Infectious Diseases, University of California, San Diego, San Diego, USA.
authors: Susan
authors: S
authors: Little
authors: Aaron Diamond AIDS Research Center, New York, New York, USA.
authors: Martin
authors: M
authors: Markowitz
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Florencia
authors: F
authors: Pereyra
authors: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Eric S
authors: ES
authors: Rosenberg
authors: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors: Bruce D
authors: BD
authors: Walker
authors: Center for AIDS Research, Kumamoto University, Kumamoto, Japan International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
authors: Takamasa
authors: T
authors: Ueno
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors: Zabrina L
authors: ZL
authors: Brumme
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada mark_brockman@sfu.ca.
authors: Mark A
authors: MA
authors: Brockman
mesh_terms: D015704:CD4 Antigens / Q000032:analysis; D015536:Down-Regulation; D005838:Genotype; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D008969:Molecular Sequence Data; D010949:Plasma / Q000821:virology; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D017422:Sequence Analysis, DNA; D019562:Viral Load; D014766:Viremia / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000172:deficiency* / Q000235:genetics
chemical_list: D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1