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Novel cytotoxic T-lymphocyte escape mutation by a three-amino-acid insertion in the human immunodeficiency virus type 1 p6Pol and p6Gag late domain associated with drug resistance.

Abstract
Cytolytic T lymphocytes (CTL) play a major role in controlling human immunodeficiency virus type 1 (HIV-1) infection. To evade immune pressure, HIV-1 is selected at targeted CTL epitopes, which may consequentially alter viral replication fitness. In our longitudinal investigations of the interplay between T-cell immunity and viral evolution following acute HIV-1 infection, we observed in a treatment-naïve patient the emergence of highly avid, gamma interferon-secreting, CD8(+) CTL recognizing an HLA-Cw*0102-restricted epitope, NSPTRREL (NL8). This epitope lies in the p6(Pol) protein, located in the transframe region of the Gag-Pol polyprotein. Over the course of infection, an unusual viral escape mutation arose within the p6(Pol) epitope through insertion of a 3-amino-acid repeat, NSPT(SPT)RREL, with a concomitant insertion in the p6(Gag) late domain, PTAPP(APP). Interestingly, this p6(Pol) insertion mutation is often selected in viruses with the emergence of antiretroviral drug resistance, while the p6(Gag) late-domain PTAPP motif binds Tsg101 to permit viral budding. These results are the first to demonstrate viral evasion of immune pressure by amino acid insertions. Moreover, this escape mutation represents a novel mechanism whereby HIV-1 can alter its sequence within both the Gag and Pol proteins with potential functional consequences for viral replication and budding.
AuthorsJianhong Cao, John McNevin, Matthew McSweyn, Yi Liu, James I Mullins, M Juliana McElrath
JournalJournal of virology (J Virol) Vol. 82 Issue 1 Pg. 495-502 (Jan 2008) ISSN: 1098-5514 [Electronic] United States
PMID17942528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anti-HIV Agents
  • Epitopes, T-Lymphocyte
  • gag Gene Products, Human Immunodeficiency Virus
  • p6 gag protein, Human immunodeficiency virus 1
  • pol Gene Products, Human Immunodeficiency Virus
Topics
  • Anti-HIV Agents (pharmacology)
  • Epitopes, T-Lymphocyte (genetics, immunology)
  • HIV Infections (immunology, virology)
  • HIV-1 (drug effects, genetics, immunology)
  • Humans
  • Longitudinal Studies
  • Mutagenesis, Insertional
  • Protein Structure, Tertiary
  • T-Lymphocytes, Cytotoxic (immunology)
  • gag Gene Products, Human Immunodeficiency Virus (chemistry, genetics, immunology)
  • pol Gene Products, Human Immunodeficiency Virus (chemistry, genetics, immunology)

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