Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover

Abstract

The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)–B27 patients. To understand further the nature of CD8+ T cell–mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27–restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10–specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

“…Recent studies suggest that measuring multiple phenotype parameters simultaneously may better reflect the quality of CD8 + T cells [33][34][35]55]. The addition of canarypox expressing CD40L had not only increased specific CD8 + T cell responses qualitatively but also improved the quality of CD8 + T cells as exhibited by more specific polyfunctional CD8 + T cells and potentially more long lived memory CD8 + T cells as determined by IL-7Rα staining.…”

“…2B and C). Recent studies suggest polyfunctional T cells that produce more than one cytokine, chemokine, and marker of degranulation correlate with virologic control and could be used as an immunological parameter for assessing vaccine efficacy [33][34][35]. We therefore measured the effect of vCPmCD40L and vCPmSP-D-CD40L on the induction of polyfunctional CD8 + T cells.…”

The mucosal and systemic immune responses elicited by a chitosan‐adjuvanted intranasal influenza H5N1 vaccine

“…To our knowledge, this study is the first to show that an intranasal pandemic influenza vaccine formulated with a mucosal adjuvant induces high frequencies of multifunctional CD4 + T cells in mice. Multifunctional T cells have been associated with better clinical outcomes of patients infected with human immunodeficiency virus (HIV), 51 reduced HIV replication 52 and protection elicited against smallpox by priming with vaccinia virus 53 . However, the strongest evidence to date for the importance of multifunctional CD4 + T cells in eliciting a protective immune response is in the mouse model of Leishmania major infection 48 , 54 .…”

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…Both IFN-g À IL-2 1 central memory T cells as well as the so-called multifunctional CD8 1 and CD4 1 T cells simultaneously producing IFN-g, TNF and IL-2 were shown to mediate long-term immunity to Leishmania in mice [35,36]. Recent reports, as reviewed by Makedonas and Betts [37], suggest that multifunctional CD8 1 memory T cells are crucial for disease control in HIV infection [38,39] and polyfunctional CMV-specific CD4 1 and pp65 CD8 1 T cells protect against highlevel replication after liver transplantation [40].Several studies brought new insights into complexity of the CD4 1 [41] and CD8 1 [42,43] T-cell memory, but data on the more detailed analysis of memory T-cell response to EBV are missing.In this study we performed a multiparameter flow cytometry approach to comprehensively analyze the EBV-specific T-cell response in latent infection. Using 15-mer overlapping proteinspanning peptide pools of latent EBNA-1 and lytic BZLF-1 we characterized EBV-specific memory CD4 1 and CD8 1 T cells based on cytokine-producing capability (IL-2, TNF, IFN-g), and differentiation marker expression (CCR7, CD45RA).…”

“…Both IFN-g À IL-2 1 central memory T cells as well as the so-called multifunctional CD8 1 and CD4 1 T cells simultaneously producing IFN-g, TNF and IL-2 were shown to mediate long-term immunity to Leishmania in mice [35,36]. Recent reports, as reviewed by Makedonas and Betts [37], suggest that multifunctional CD8 1 memory T cells are crucial for disease control in HIV infection [38,39] and polyfunctional CMV-specific CD4 1 and pp65 CD8 1 T cells protect against highlevel replication after liver transplantation [40].…”