Emergence of cytotoxic T lymphocyte escape mutants following antiretroviral treatment suspension in rhesus macaques infected with SIVmac251

Janos Nacsa, Jennifer Stanton, Kevin J. Kunstman, Wen Po Tsai, David Watkins, Steven M. Wolinsky, Genoveffa Franchini

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Structured treatment interruption (STI) of antiretroviral drugs has been proposed as an alternative approach for managing patients infected with HIV-1. While STI is thought to spare drug-related side effects and enhance the HIV-1-specific immune response, the long-lasting clinical benefit of this approach remains uncertain, particularly in patients with long-standing HIV-1 infection. Here, we investigated the basis of unabated virological replication following different STI regimens in rhesus macaques that expressed the MHC class I Mamu-A*01 molecule treated during acute and long-standing infection with SIVmac251. An amino acid change at the anchor residue within the immunodominant Mamu-A*01-restricted Gag181-189 CM9 epitope (T → A) in one of six macaques with acute SIVmac251 infection and in three of four macaques with long-standing SIVmac251 infection (T → A; T → S; S → C) was found in the majority of plasma virus. These amino acid changes have been shown to severely decrease binding of the corresponding peptides to the Mamu-A*01 molecule and, in the case of the T → A change, escape from CTL. In one macaque with long-standing SIVmac251 infection, a mutation emerged that conferred resistance to one of the antiretroviral drugs (PMPA) as well. These results provide insights into the mechanism underlying the limited capacity of repeated interruption of antiretroviral therapy as an approach to restrain viral replication. In addition, these data also suggest that interruption of therapy may be less effective in chronic infection because of preexisting immune escape and that immune escape is a risk of interruption of therapy.

Original languageEnglish
Pages (from-to)210-218
Number of pages9
JournalVirology
Volume305
Issue number1
DOIs
StatePublished - Jan 18 2003
Externally publishedYes

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Cytotoxic T-Lymphocytes
Macaca mulatta
Suspensions
Macaca
HIV-1
Infection
Therapeutics
Amino Acids
Drug-Related Side Effects and Adverse Reactions
Pharmaceutical Preparations
HIV Infections
Epitopes
Viruses
Peptides
Mutation

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Emergence of cytotoxic T lymphocyte escape mutants following antiretroviral treatment suspension in rhesus macaques infected with SIVmac251. / Nacsa, Janos; Stanton, Jennifer; Kunstman, Kevin J.; Tsai, Wen Po; Watkins, David; Wolinsky, Steven M.; Franchini, Genoveffa.

In: Virology, Vol. 305, No. 1, 18.01.2003, p. 210-218.

Research output: Contribution to journalArticle

Nacsa, Janos ; Stanton, Jennifer ; Kunstman, Kevin J. ; Tsai, Wen Po ; Watkins, David ; Wolinsky, Steven M. ; Franchini, Genoveffa. / Emergence of cytotoxic T lymphocyte escape mutants following antiretroviral treatment suspension in rhesus macaques infected with SIVmac251. In: Virology. 2003 ; Vol. 305, No. 1. pp. 210-218.
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