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Definition of the viral targets of protective HIV-1-specific T cell responses.

ABSTRACT: The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.

SUBMITTER: Mothe B

PROVIDER: S-EPMC3292987 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Definition of the viral targets of protective HIV-1-specific T cell responses.

Mothe Beatriz B Llano Anuska A Ibarrondo Javier J Daniels Marcus M Miranda Cristina C Zamarreño Jennifer J Bach Vanessa V Zuniga Rosario R Pérez-Álvarez Susana S Berger Christoph T CT Puertas Maria C MC Martinez-Picado Javier J Rolland Morgane M Farfan Marilu M Szinger James J JJ Hildebrand William H WH Yang Otto O OO Sanchez-Merino Victor V Brumme Chanson J CJ Brumme Zabrina L ZL Heckerman David D Allen Todd M TM Mullins James I JI Gómez Guadalupe G Goulder Philip J PJ Walker Bruce D BD Gatell Jose M JM Clotet Bonaventura B Korber Bette T BT Sanchez Jorge J Brander Christian C

Journal of translational medicine 20111207

<h4>Background</h4>The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.<h4>Methods</h4>Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP ...[more]

PMID: 22152067

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Project description:UnlabelledEffector CD4 T cell responses have been shown to be critically involved in the containment and clearance of viral pathogens. However, their involvement in the pathogenesis of HIV infection is less clear, given their additional role as preferred viral targets. We previously demonstrated that the presence of HIV-specific CD4 T cell responses is somewhat associated with HIV control and that specific CD4 T cell functions, such as direct cytolytic activity, can contribute to control of HIV viremia. However, little is known about how the induction of HIV-specific CD4 T cell responses during acute HIV infection influences disease progression and whether responses induced during the early phase of infection are preferentially depleted. We therefore longitudinally assessed, in a cohort of 55 acutely HIV-infected individuals, HIV-specific CD4 T cell responses from acute to chronic infection. Interestingly, we found that the breadth, magnitude, and protein dominance of HIV-specific CD4 T cell responses remained remarkably stable over time. Moreover, we found that the epitopes targeted at a high frequency in acute HIV infection were recognized at the same frequency by HIV-specific CD4 T cells in chronic HIV infection. Interestingly the induction of Gag-specific CD4 T cell responses in acute HIV infection was significantly inversely correlated with viral set point in chronic HIV infection (R = -0.5; P = 0.03), while the cumulative contribution of Env-specific CD4 T cell responses showed the reverse effect. Moreover, individuals with HIV-specific CD4 T cell responses dominantly targeting Gag over Env in acute HIV infection remained off antiretroviral therapy significantly longer (P = 0.03; log rank). Thus, our data suggest that the induction of HIV-specific CD4 T cell responses during acute HIV infection is beneficial overall and does not fuel disease progression.ImportanceCD4 T cells are critical for the clearance and control of viral infections. However, HIV preferentially infects HIV-specific CD4 T cells. Thus, their contribution to the control of HIV viremia is uncertain. Here, we study HIV-specific CD4 T cell responses from acute to chronic HIV infection and show that the generation of certain CD4 responses is associated with control rather than disease progression.

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Definition of the viral targets of protective HIV-1-specific T cell responses.

Publications

Definition of the viral targets of protective HIV-1-specific T cell responses.

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