title: Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination.
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.
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA. rbm19@pitt.edu
authors.forename: Robbie B
authors.initials: RB
authors.lastname: Mailliard
authors.forename: Kellie N
authors.initials: KN
authors.lastname: Smith
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Fecek
authors.forename: Giovanna
authors.initials: G
authors.lastname: Rappocciolo
authors.forename: Eduardo J M
authors.initials: EJ
authors.lastname: Nascimento
authors.forename: Ernesto T
authors.initials: ET
authors.lastname: Marques
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rinaldo
mesh_terms: D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008855:Microscopy, Electron, Scanning; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology
chemical_list: D018984:Epitopes, T-Lymphocyte
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