Evasion of cytotoxic T lymphocytes is a functional constraint maintaining HIV-1 Nef expression.
Nef expression is not required for HIV-1 replication and is highly targeted by CD8+ CTL, raising the question of why Nef expression is not lost in order to evade immunity in vivo. We explore whether MHC class I (MHC-I) down-regulation to evade CTL in general is a selective pressure maintaining Nef. HIV-1 with functional Nef (wild type, WT) is compared to virus containing a Nef point mutation (M20A) that selectively ablates MHC-I down-regulation. WT-infected cells are relatively resistant to cytolysis and less suppressed for viral replication by Gag- and RT-specific CTL compared to M20A. These viruses grow similarly in vitro in the absence of CTL, but the presence of Gag- or RT-specific CTL strongly favors WT overgrowth of M20A. Finally, while in vitro selection by Nef-specific CTL readily drives disruption of the nef reading frame, the addition of Gag- or RT-specific CTL markedly limits such escape. These data indicate that MHC-I down-regulation is an important function favoring Nef maintenance due to a net selective advantage in the setting of the general CTL response.
Ali
Ayub
A
AIDS Institute, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Ng
Hwee L
HL
Dagarag
Mirabelle D
MD
Yang
Otto O
OO
D000595:Amino Acid Sequence; D002460:Cell Line; D002999:Clone Cells; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D015693:Gene Products, nef / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D014779:Virus Replication / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus