Functional adaptation of Nef to the immune milieu of HIV-1 infection in vivo.
Nef-mediated down-regulation of MHC class I (MHC-I) molecules on HIV-1-infected cells has been proposed to enhance viral persistence through evasion of host CTLs. This conclusion is based largely on demonstrations that Nef from laboratory HIV-1 strains reduces the susceptibility of infected cells to CTL killing in vitro. However, the function and role of Nef-mediated MHC-I down-regulation in vivo have not been well described. To approach this issue, nef quasispecies from chronically HIV-1-infected individuals were cloned into recombinant reporter viruses and tested for their ability to down-regulate MHC-I molecules from the surface of infected cells. The level of function varied widely between individuals, and although comparison to the immunologic parameters of blood CD4(+) T lymphocyte count and breadth of the HIV-1-specific CTL response showed positive correlations, no significant correlation was found in comparison to plasma viremia. The ability of in vivo-derived Nef to down-regulate MHC-I predicted the resistance of HIV-1 to suppression by CTL. Taken together, these data demonstrate the functionality of Nef to down-regulate MHC-I in vivo during stable chronic infection, and suggest that this function is maintained by the need of HIV-1 to cope with the antiviral CTL response.
Lewis
Martha J
MJ
Geffen School of Medicine, University of California, Department of Medicine, Division of Infectious Diseases, Los Angeles, CA 90095, USA. malewis@mednet.ucla.edu
Balamurugan
Arumugam
A
Ohno
Ayako
A
Kilpatrick
Stephanie
S
Ng
Hwee L
HL
Yang
Otto O
OO
D000222:Adaptation, Physiological / Q000276:immunology*; D000328:Adult; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D011237:Predictive Value of Tests; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000097:blood / Q000502:physiology*
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1