Broadly increased sensitivity to cytotoxic T lymphocytes resulting from Nef epitope escape mutations.
Nef is an HIV-1 protein that is absent in most retroviruses, yet its reading frame is highly maintained despite frequent targeting by CD8(+) CTL in vivo. Because Nef is not necessarily required for viral replication, this consistent maintenance suggests that Nef plays an important role(s) and substantial fitness constraints prevent its loss in vivo. The ability of Nef to down-regulate cell surface MHC class I (MHC-I) molecules and render infected cells resistant to CTL in general is likely to be an important contributing function. We demonstrate that mutational escape of HIV-1 from Nef-specific CTL in vitro leads to progeny virions that are increased in their susceptibility to CTL of specificities for proteins other than Nef. The escape mutants contain multiple nef mutations that impair the ability of the virus to down-regulate MHC-I through disruption of its reading frame as well as epitope point mutations. Given the rarity of nef frameshifts in vivo, these data support the concept that the ability to down-regulate MHC-I could be a key constraint for preservation of Nef in vivo.
Ali
Ayub
A
Department of Medicine and AIDS Institute, Center for Health Sciences, University of California, Los Angeles, CA 90095, USA.
Pillai
Satish
S
Ng
Hwee
H
Lubong
Rachel
R
Richman
Douglas D
DD
Jamieson
Beth D
BD
Ding
Yan
Y
McElrath
M Juliana
MJ
Guatelli
John C
JC
Yang
Otto O
OO
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000502:physiology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000502:physiology; D017353:Gene Deletion; D015693:Gene Products, nef / Q000235:genetics* / Q000502:physiology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008969:Molecular Sequence Data; D017354:Point Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D014771:Virion / Q000235:genetics / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D018984:Epitopes, T-Lymphocyte; D015693:Gene Products, nef; D015789:HLA-A2 Antigen; D054311:nef Gene Products, Human Immunodeficiency Virus