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Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.

ABSTRACT: The role of regulatory T cells (Tregs) in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic-cells (DC) loaded with HIV-lipopeptides (LIPO-5-DC vaccine) in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI) were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co-expression of CD25, CD134, CD39 and FoxP3 was used to delineate both antigen-specific Tregs and effectors T cells (Teffs). Median LIPO-5 specific-CD25+CD134+ polyfunctional T cells increased from 0.1% (IQR 0-0.3) before vaccination (week -4) to 2.1% (IQR 1.1-3.9) at week 16 following 4 immunizations (p=0.001) and were inversely correlated with maximum viral load following ATI (r=-0.77, p=0.001). Vaccinees who displayed lower levels of HIV-specific CD4+CD134+CD25+CD39+FoxP3+ Tregs responded better to the LIPO-5-DC vaccine. After vaccination, the frequency of HIV-specific Tregs decreased (from 69.3 at week -4 to 31.7% at week 16) and inversely correlated with HIV-specific IFN-?-producing cells (r=-0.64, p=0.002). We show that therapeutic immunization skewed the HIV-specific response from regulatory to effector phenotype which impacts on the magnitude of viral replication following ATI.

SUBMITTER: Brezar V

PROVIDER: S-EPMC4376642 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.

Brezar Vedran V Ruffin Nicolas N Richert Laura L Surenaud Mathieu M Lacabaratz Christine C Palucka Karolina K Thiébaut Rodolphe R Banchereau Jacques J Levy Yves Y Seddiki Nabila N

PLoS pathogens 20150327 3

The role of regulatory T cells (Tregs) in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic-cells (DC) loaded with HIV-lipopeptides (LIPO-5-DC vaccine) in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI) were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co ...[more]

PMID: 25816350

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Project description:People with HIV infection are at increased risk for community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs). Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified. We aimed to determine the immunologic perturbations that predispose HIV-infected people to MRSA SSTIs. Participants with or without HIV infection and with MRSA SSTI, MRSA colonization or negative for MRSA were enrolled. Peripheral blood and skin biopsies from study participants were collected. Flow cytometry, flow cytometry with microscopy, multiplex assays of cell culture supernatants and immunohistochemistry were used to evaluate the nature of the immune defect predisposing HIV-infected people to MRSA infections. We found deficient MRSA-specific IFN?+ CD4 T-cell responses in HIV-infected people with MRSA SSTIs compared to MRSA-colonized participants and HIV-uninfected participants with MRSA SSTIs. These IFN?+ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs. However, IFN? responses to cytomegalovirus and Mycobacterium avium antigens and MRSA-specific IL-17 responses by CD4 T cells were intact. Upon stimulation with MRSA, peripheral blood mononuclear cells from HIV-infected participants produced less IL-12 and IL-15, key drivers of IFN? production. There were no defects in CD8 T-cell responses, monocyte responses, opsonization, or phagocytosis of Staphylococcus aureus. Accumulation of CD3 T cells, CD4 T cells, IL-17+ cells, myeloperoxidase+ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry. Together, these results indicate that MRSA-specific IFN?+ CD4 T-cell responses are essential for the control of initial and recurrent MRSA infections in HIV-infected people.

Dataset Information

Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.

Publications

Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.

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