Maintenance of Nef-mediated modulation of major histocompatibility complex class I and CD4 after sexual transmission of human immunodeficiency virus type 1.

TitleMaintenance of Nef-mediated modulation of major histocompatibility complex class I and CD4 after sexual transmission of human immunodeficiency virus type 1.
Publication TypeJournal Article
Year of Publication2007
AuthorsNoviello CM, Pond SLKosakovs, Lewis MJ, Richman DD, Pillai SK, Yang OO, Little SJ, Smith DM, Guatelli JC
JournalJ Virol
Volume81
Issue9
Pagination4776-86
Date Published2007 May
ISSN0022-538X
KeywordsAmino Acid Sequence, Antigens, CD4, Base Sequence, Blotting, Western, Evolution, Molecular, Flow Cytometry, Gene Expression Regulation, Viral, Gene Products, nef, Genes, MHC Class I, Genetic Variation, HIV Infections, HIV-1, Humans, Likelihood Functions, Models, Genetic, Molecular Sequence Data, nef Gene Products, Human Immunodeficiency Virus, Phylogeny, Selection, Genetic, Sequence Alignment, Sequence Analysis, DNA, T-Lymphocytes, Cytotoxic
Abstract

Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.

DOI10.1128/JVI.01793-06
Alternate JournalJ. Virol.
PubMed ID17329339
PubMed Central IDPMC1900175
Grant ListAI 047745 / AI / NIAID NIH HHS / United States
AI 051970 / AI / NIAID NIH HHS / United States
AI 27670 / AI / NIAID NIH HHS / United States
AI 29164 / AI / NIAID NIH HHS / United States
AI 36214 / AI / NIAID NIH HHS / United States
AI 38201 / AI / NIAID NIH HHS / United States
AI 38858 / AI / NIAID NIH HHS / United States
AI 57167 / AI / NIAID NIH HHS / United States
K23 AI 055276 / AI / NIAID NIH HHS / United States