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Interleukin-2 production by polyfunctional HIV-1-specific CD8 T cells is associated with enhanced viral suppression.

ABSTRACT: BACKGROUND:Assays to measure the induction of HIV-1-specific CD8 T-cell responses often rely on measurements of indirect effector function such as chemokine and cytokine production, which may not reflect direct elimination of an invading pathogen. Assessment of the functional ability of CD8 T cells to suppress HIV-1 replication has been viewed as a surrogate marker of an effectual immune response. To further investigate this, we measured the capacity of virus-specific CD8 T cells to inhibit HIV-1 replication in an in vitro suppression assay. METHODS:We expanded 15 epitope-specific CD8 T-cell lines from peripheral blood mononuclear cells of chronically HIV--infected progressors (n = 5) and controllers (n = 4) who were not on antiretroviral therapy. Cell lines were tested for their ability to produce effector molecules (CD107a, IL-2, IFN-?, TNF-?, perforin) and suppress virus replication in autologous CD4 T cells. RESULTS:CD8 T-cell lines from both progressors and controllers had largely similar effector function profiles as determined by intracellular cytokine staining. In contrast, we observed that CD8 T-cell lines derived from controllers show enhanced virus suppression when compared with progressors. Virus suppression was mediated in an major histocompatibility complex-dependent manner and found to correlate with a polyfunctional IL-2 CD8 T-cell response. CONCLUSIONS:Using a sensitive in vitro suppression assay, we demonstrate that CD8 T-cell-mediated suppression of HIV-1 replication is a marker of HIV-1 control. Suppressive capacity was found to correlate with polyfunctional IL-2 production. Assessment of CD8 T-cell-mediated suppression may be an important tool to evaluate vaccine-induced responses.

SUBMITTER: Akinsiku OT

PROVIDER: S-EPMC3391567 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Interleukin-2 production by polyfunctional HIV-1-specific CD8 T cells is associated with enhanced viral suppression.

Akinsiku Olusimidele T OT Bansal Anju A Sabbaj Steffanie S Heath Sonya L SL Goepfert Paul A PA

Journal of acquired immune deficiency syndromes (1999) 20111001 2

<h4>Background</h4>Assays to measure the induction of HIV-1-specific CD8 T-cell responses often rely on measurements of indirect effector function such as chemokine and cytokine production, which may not reflect direct elimination of an invading pathogen. Assessment of the functional ability of CD8 T cells to suppress HIV-1 replication has been viewed as a surrogate marker of an effectual immune response. To further investigate this, we measured the capacity of virus-specific CD8 T cells to inhi ...[more]

PMID: 21637109

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Project description:Our objective is to create gene immunogens targeted against drug-resistant HIV-1, focusing on HIV-1 enzymes as critical components in viral replication and drug resistance. Consensus-based gene vaccines are specifically fit for variable pathogens such as HIV-1 and have many advantages over viral genes and their expression-optimized variants. With this in mind, we designed the consensus integrase (IN) of the HIV-1 clade A strain predominant in the territory of the former Soviet Union and its inactivated derivative with and without mutations conferring resistance to elvitegravir. Humanized IN gene was synthesized; and inactivated derivatives (with 64D in the active site mutated to V) with and without elvitegravir-resistance mutations were generated by site-mutagenesis. Activity tests of IN variants expressed in E coli showed the consensus IN to be active, while both D64V-variants were devoid of specific activities. IN genes cloned in the DNA-immunization vector pVax1 (pVaxIN plasmids) were highly expressed in human and murine cell lines (>0.7 ng/cell). Injection of BALB/c mice with pVaxIN plasmids followed by electroporation generated potent IFN-? and IL-2 responses registered in PBMC by day 15 and in splenocytes by day 23 after immunization. Multiparametric FACS demonstrated that CD8+ and CD4+ T cells of gene-immunized mice stimulated with IN-derived peptides secreted IFN-?, IL-2, and TNF-?. The multi-cytokine responses of CD8+ and CD4+ T-cells correlated with the loss of in vivo activity of the luciferase reporter gene co-delivered with pVaxIN plasmids. This indicated the capacity of IN-specific CD4+ and CD8+ T-cells to clear IN/reporter co-expressing cells from the injection sites. Thus, the synthetic HIV-1 clade A integrase genes acted as potent immunogens generating polyfunctional Th1-type CD4+ and CD8+ T cells. Generation of such response is highly desirable for an effective HIV-1 vaccine as it offers a possibility to attack virus-infected cells via both MHC class I and II pathways.

Project description:Despite the suppression of viral replication induced by the highly active anti-retroviral therapy (HAART), an increased immune activation and inflammatory state persists in HIV-infected patients, contributing to lower treatment response and immune reconstitution, and development of non-AIDS conditions. The chronic activation and inflammation affect the functionality and differentiation of CD8+ T-cells, particularly reducing their cytotoxic capacity, which is critical in the control of HIV replication. Although previous studies have shown that HAART induce a partial immune reconstitution, its effect on CD8+ T-cells cytotoxic function, as well as its relationship with the inflammatory state, is yet to be defined. Here, we characterized the functional profile of polyclonal and HIV-specific CD8+ T cells, based on the expression of cell activation and differentiation markers, in individuals chronically infected with HIV, under HAART. Compared with seronegative controls, CD8+ T-cells from patients on HAART exhibited a low degranulation capacity (surface expression of CD107a), with consequent low secreted levels and high intracellular expression of granzyme B and perforin. This degranulation defect was particularly observed in those cells expressing the activation marker HLA-DR, which were further characterized as effector memory cells with high expression of CD57. The expression of CD107a, but not of granzyme B and perforin, in CD8+ T-cells from HIV-infected patients on HAART reached levels similar to those in seronegative controls when the treatment duration was higher than 25 months. In addition, the expression of CD107a was negatively correlated with the expression of exhaustion markers on CD8+ T-cells and the plasma inflammatory molecule sCD14. Thus, despite HAART-induced viral suppression, CD8+ T-cells from HIV-infected patients have an alteration in their cytotoxic program. This defect is associated with the cellular activation, differentiation and exhaustion state, as well as with the inflammation levels, and can be partially recovered with a long and continuous treatment.

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Interleukin-2 production by polyfunctional HIV-1-specific CD8 T cells is associated with enhanced viral suppression.

Publications

Interleukin-2 production by polyfunctional HIV-1-specific CD8 T cells is associated with enhanced viral suppression.

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