Broad TCR Usage in Functional HIV-1-Specific CD8+ T Cell Expansions Driven by Vaccination during Highly Active Antiretroviral Therapy

Abstract

During chronic HIV-1 infection, continuing viral replication is associated with impaired proliferative capacity of virus-specific CD8+ T cells and with the expansion and persistence of oligoclonal T cell populations. TCR usage may significantly influence CD8+ T cell-mediated control of AIDS viruses; however, the potential to modulate the repertoire of functional virus-specific T cells by immunotherapy has not been explored. To investigate this, we analyzed the TCR Vβ usage of CD8+ T cells populations which were expanded following vaccination with modified vaccinia virus Ankara expressing a HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected patients receiving highly active antiretroviral therapy. Vaccinations induced the re-expansion of HIV-1-specific CD8+ T cells and these showed broad TCR Vβ usage which was maintained for at least 1 year in some individuals. By contrast, virus-specific CD8+ T cell populations in the same donors which failed to expand after vaccination and in unvaccinated controls were oligoclonal. Simultaneously, we observed that CD8+ T cells recognizing vaccine-derived HIV-1 epitopes displayed enhanced capacity to proliferate and to inhibit HIV-1 replication in vitro, following MVA.HIVA immunizations. Taken together, these data indicate that an attenuated viral-vectored vaccine can modulate adaptive CD8+ T cell responses to HIV-1 and improve their antiviral functional capacity. The potential therapeutic benefit of this vaccination approach warrants further investigation.

Novel RecombinantMycobacterium bovisBCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques

“…However, there is no appropriate challenge available for the vaccinated animals because HIVA is designed for humans and is, therefore, derived from HIV-1 antigens; HIV-1 does not replicate in rhesus macaques. As for human efficacy, broad Gag-specific responses have been associated with good control of HIV-1 replication in chronically infected patients (27,35,53), responses to HIVA have been readily detected in exposed uninfected children in Kenya (55), and it has been demonstrated that HIVA boosts specific CD8 and CD4 T cell responses effectively in patients infected with a variety of HIV-1 clades (10,11,66). Thus, HIVA as a Gag-based immunogen concurs at several levels with the emerging correlates of T-cell-mediated control of HIV-1 replication.…”

Limited Maintenance of Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 T-Cell Receptor Clonotypes after Virus Challenge

“…A recent study has shown that therapeutic vaccination can modulate CD8 T-cell repertoires in HIV-infected individuals (40), although the long-term impact of such manipulations on viral control has not been evaluated. Investigating the preferred clonotypic characteristics of effective CD8 T cells and how to elicit them through prophylactic or therapeutic vaccination remains an important field of enquiry.…”

Preclinical Studies of a Modified Vaccinia Virus Ankara-Based HIV Candidate Vaccine: Antigen Presentation and Antiviral Effect

“…It is being considered for vaccination against infectious diseases, including HIV infection, malaria, and influenza, and against cancers (for a review, see reference 19). In preclinical studies, vaccination with an MVA vector encoding HIV-1 Gag linked to a string of CTL epitopes (so called MVA-HIVA), used alone or in combination with DNA in a primeboost strategy, induced HS T cells (21,63). Moreover, vaccination of NHP with MVA encoding SIV Gag, Pol, Nef, and Env induced a robust polyfunctional SIV-specific T-cell response leading to reduced viral replication and prolonged survival upon simian/human immunodeficiency virus (SHIV) challenge (40).…”