Augmentation of the dose resulted in modest increases in vaccine-induced cellular immunity, with no difference in humoral responses. Analysis of cytokine responses revealed a transient systemic signature characterized by the release of type I interferon, IL and IFN-related chemokines. The introduction of highly efficient antiretroviral drugs ART for the treatment of HIV infection dramatically improved the disease prognosis and extended the life expectancy of infected individuals [reviewed in 1 β 6 ].
Nevertheless, ART fails to eradicate infected cells, and upon ART discontinuation, viral rebound occurs within weeks. Therefore, life-long continuous ART is required to prevent disease progression. To eliminate the burden of chronic drug consumption and associated long-term toxicities, immune therapeutic strategies aiming to eliminate the long-term reservoir of HIV-infected cells or achieve a functional cure are being explored. Therapeutic vaccination has a potential role either as a component of a strategy to eliminate cells latently infected with HIV-1 reduction of latent reservoir , or as a functional cure to achieve permanent host control of HIV-1 infection to undetectable levels off ART without complete eradication of the latent reservoir 7 β 9.
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Due to control of virus replication under ART, only very low or no virus-specific T cell responses are present in the circulation. An effective therapeutic HIV-1 vaccine should induce potent cytotoxic T cell responses which could contribute to control of viremia and thereby reduce the pool of infected cells.
We and others have introduced the concept of directing T cell responses towards conserved regions in the HIV proteome 13 β We showed that mutations in Gag CE are much more likely to disable virus replication in cell culture than mutations outside of CE 26 β We reported novel CE vaccination regimens that modified the hierarchy of T cell epitope recognition otherwise imposed by the dominant variable regions within the full-length viral proteins 16 , These optimized DNA vaccine regimens, aiming to induce an adaptive response that makes virus escape difficult, broadened epitope recognition and improved the functionality of the vaccine-induced T cell responses, eliciting cytotoxic T cells targeting conserved epitopes in immunized rhesus macaques.
The T cells targeting these conserved epitopes were activated upon SIV-infection which demonstrated that the CE-specific T cells recognize infected cells in vivo. Thus, the use of immunogens encoding CE epitopes may be a promising therapeutic strategy for the management of HIV-1 infected individuals. Nucleic acid-based vaccines have several significant advantages over other vaccine platforms, including streamlined and predictable scale-up production, and flexibility to enable rapid vaccine design.
