Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire

Spyros A. Kalams*, R. Paul Johnson, Alicja K. Trocha, Mark J. Dynan, H. Steve Ngo, Richard T. D'Aquila, James T. Kurnick, Bruce D. Walker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

202 Scopus citations

Abstract

Human immunodeficiency virus 1 (HIV-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using freshly isolated peripheral blood mononuclear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-1-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCR) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-1-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using Vα and Vβ family-specific primers was performed on each clone, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized Vα14 and Vβ4 genes. Sequence analysis of the TCR revealed the first nine clones isolated to also be identical at the nucleotide level. The TCR-α junctional region sequence of the tenth clone was identical to the junctional region sequences of the other nine, but this clone utilized distinct Dβ and Jβ gene segments. This study provides evidence that the observed high degree of HIV-1-specific CTL activity may be due to monoclonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.

Original languageEnglish (US)
Pages (from-to)1261-1271
Number of pages11
JournalJournal of Experimental Medicine
Volume179
Issue number4
DOIs
StatePublished - Apr 1 1994

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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