Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination

Robbie B. Mailliard, Kellie Smith, Ronald J. Fecek, Giovanna Rappocciolo, Eduardo J M Nascimento, Ernesto T. Marques, Simon C. Watkins, James I. Mullins, Charles R. Rinaldo

Research output: Contribution to journalArticle

Abstract

The ability of HIV-1 to rapidly accumulate mutations provides the virus with an effective means of escaping CD8+ CTL responses. In this study, we describe how subtle alterations in CTL epitopes expressed by naturally occurring HIV-1 variants can result in an incomplete escape from CTL recognition, providing the virus with a selective advantage. Rather than paralyzing the CTL response, these epitope modifications selectively induce the CTL to produce proinflammatory cytokines in the absence of target killing. Importantly, instead of dampening the immune response through CTL elimination of variant Ag-expressing immature dendritic cells (DC), a positive CTL-to-DC immune feedback loop dominates whereby the immature DC differentiate into mature proinflammatory DC. Moreover, these CTL-programmed DC exhibit a superior capacity to mediate HIV-1 trans-infection of T cells. This discordant induction of CTL helper activity in the absence of killing most likely contributes to the chronic immune activation associated with HIV-1 infection, and can be used by HIV-1 to promote viral dissemination and persistence. Our findings highlight the need to address the detrimental potential of eliciting dysfunctional cross-reactive memory CTL responses when designing and implementing anti-HIV-1 immunotherapies.

Original languageEnglish (US)
Pages (from-to)2570-2580
Number of pages11
JournalJournal of Immunology
Volume191
Issue number5
DOIs
StatePublished - Sep 1 2013
Externally publishedYes

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Dendritic Cells
HIV-1
Epitopes
Viruses
Immunotherapy
HIV Infections
Cytokines
T-Lymphocytes
Mutation
Infection

ASJC Scopus subject areas

  • Immunology

Cite this

Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination. / Mailliard, Robbie B.; Smith, Kellie; Fecek, Ronald J.; Rappocciolo, Giovanna; Nascimento, Eduardo J M; Marques, Ernesto T.; Watkins, Simon C.; Mullins, James I.; Rinaldo, Charles R.

In: Journal of Immunology, Vol. 191, No. 5, 01.09.2013, p. 2570-2580.

Research output: Contribution to journalArticle

Mailliard, RB, Smith, K, Fecek, RJ, Rappocciolo, G, Nascimento, EJM, Marques, ET, Watkins, SC, Mullins, JI & Rinaldo, CR 2013, 'Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination', Journal of Immunology, vol. 191, no. 5, pp. 2570-2580. https://doi.org/10.4049/jimmunol.1300373
Mailliard, Robbie B. ; Smith, Kellie ; Fecek, Ronald J. ; Rappocciolo, Giovanna ; Nascimento, Eduardo J M ; Marques, Ernesto T. ; Watkins, Simon C. ; Mullins, James I. ; Rinaldo, Charles R. / Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination. In: Journal of Immunology. 2013 ; Vol. 191, No. 5. pp. 2570-2580.
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