The Antiviral Efficacy of Simian Immunodeficiency Virus-Specific CD8
            <sup>+</sup>
            T Cells Is Unrelated to Epitope Specificity and Is Abrogated by Viral Escape

103

CD8؉ cytotoxic T lymphocytes (CTL) are strong mediators of human immunodeficiency virus type 1 (HIV-1) control, yet HIV-1 frequently mutates to escape CTL recognition. In an analysis of sequences in the Los Alamos HIV-1 database, we show that emerging CTL escape mutations were more often present at lower frequencies than the amino acid(s) that they replaced. Furthermore, epitopes that underwent escape contained amino acid sites of high variability, whereas epitopes persisting at high frequencies lacked highly variable sites. We therefore infer that escape mutations are likely to be associated with weak functional constraints on the viral protein. This was supported by an extensive analysis of one subject for whom all escape mutations within defined CTL epitopes were studied and by an analysis of all reported escape mutations of defined CTL epitopes in the HIV Immunology Database. In one of these defined epitopes, escape mutations involving the substitution of amino acids with lower database frequencies occurred, and the epitope soon reverted back to the sensitive form. We further show that this escape mutation substantially diminished viral fitness in in vitro competition assays. Coincident with the reversion in vivo, we observed the fixation of a mutation 3 amino acids C terminal to the epitope, coincident with the ablation of the corresponding CTL response. The C-terminal mutation did not restore replication fitness reduced by the escape mutation in the epitope and by itself had little effect on replication fitness. Therefore, this C-terminal mutation presumably impaired the processing and presentation of the epitope. Finally, for one persistent epitope, CTL cross-reactivity to a mutant form may have suppressed the mutant to undetected levels, whereas for two other persistent epitopes, each of two mutants showed poor cross-reactivity and appeared in the subject at later time points. Thus, a viral dynamic exists between the advantage of immune escape, peptide cross-reactivity, and the disadvantage of lost replication fitness, with the balance playing an important role in determining whether a CTL epitope will persist or decline during infection.

Section: Discussionmentioning

confidence: 99%

Evolution of Human Immunodeficiency Virus Type 1 Cytotoxic T-Lymphocyte Epitopes: Fitness-Balanced Escape

Liu

McNevin

Zhao³

et al. 2007

103

“…The antiviral activity of AIDS virus-specific CD8 ϩ T cells is well documented in both in vivo (1,4,21) and in vitro (8,24,29) studies. Accordingly, human immunodeficiency virus (HIV) vaccine modalities that focus on engendering antiviral CD8 ϩ T cells are being developed (13,26,28).…”

mentioning

confidence: 94%

Simian Immunodeficiency Virus-Specific CD8⁺T Cells Recognize Vpr- and Rev-Derived Epitopes Early after Infection

Sacha

Buechler

Newman

et al. 2010

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The kinetics of CD8؉ T cell epitope presentation contribute to the antiviral efficacy of these cells yet remain poorly defined. Here, we demonstrate presentation of virion-derived Vpr peptide epitopes early after viral penetration and prior to presentation of Vif-derived epitopes, which required de novo Vif synthesis. Two Rev epitopes exhibited differential presentation kinetics, with one Rev epitope presented within 1 h of infection. We also demonstrate that cytolytic activity mirrors the recognition kinetics of infected cells. These studies show for the first time that Vpr-and Rev-specific CD8 ؉ T cells recognize and kill simian immunodeficiency virus (SIV)-infected CD4 ؉ T cells early after SIV infection.

“…We performed in vitro viral-suppression assays (VSAs) as previously described (24). Briefly, CD8-depleted, phytohemagglutinin-stimulated lymphocytes were infected with SIVmac239 at an MOI of 5 ϫ 10 Ϫ5 and incubated with SIV-specific CD8 ϩ T-cell clones for 7 days.…”

Section: Animalsmentioning

confidence: 99%

Pol-Specific CD8 ⁺ T Cells Recognize Simian Immunodeficiency Virus-Infected Cells Prior to Nef-Mediated Major Histocompatibility Complex Class I Downregulation

Sacha

Chung²,

Reed³

et al. 2007

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