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Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.

ABSTRACT: The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy.In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined.Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed.Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control.NCT00270465.

SUBMITTER: Casazza JP

PROVIDER: S-EPMC3654747 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.

Casazza Joseph P JP Bowman Kathryn A KA Adzaku Selorm S Smith Emily C EC Enama Mary E ME Bailer Robert T RT Price David A DA Gostick Emma E Gordon Ingelise J IJ Ambrozak David R DR Nason Martha C MC Roederer Mario M Andrews Charla A CA Maldarelli Frank M FM Wiegand Ann A Kearney Mary F MF Persaud Deborah D Ziemniak Carrie C Gottardo Raphael R Ledgerwood Julie E JE Graham Barney S BS Koup Richard A RA

The Journal of infectious diseases 20130312 12

<h4>Background</h4>The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy.<h4>Methods</h4>In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular inject ...[more]

PMID: 23482645

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Project description:Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4(+) T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4(+) T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4(+) T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4(+) T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4(+) T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-?) by NK cells. Our data show that reconstitution of HIV-1-specific CD4(+) T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals.NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.

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Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.

Publications

Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.

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