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

J Virol. 2008 Jan;82(1):495-502. doi: 10.1128/JVI.01096-07. Epub 2007 Oct 17.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / pharmacology
  • Epitopes, T-Lymphocyte / genetics*
  • Epitopes, T-Lymphocyte / immunology
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Humans
  • Longitudinal Studies
  • Mutagenesis, Insertional
  • Protein Structure, Tertiary
  • T-Lymphocytes, Cytotoxic / immunology*
  • gag Gene Products, Human Immunodeficiency Virus / chemistry
  • gag Gene Products, Human Immunodeficiency Virus / genetics*
  • gag Gene Products, Human Immunodeficiency Virus / immunology
  • pol Gene Products, Human Immunodeficiency Virus / chemistry
  • pol Gene Products, Human Immunodeficiency Virus / genetics
  • pol Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • 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