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FUNCTIONAL STUDIES OF NEW LENTIVIRUS CHIMERAS IN CELL CULTURE AND ANIMAL MODELS

The Human Immunodeficiency Virus (HIV-1) is the zoonotic lentivirus that has jumped from monkeys to human, and following adaptation was responsible for the AIDS pandemic. The transmission in human is still continuing despite efficacious antiviral therapies that became accessible to over half of infected people and slowed the rate of transmission. There is no licensed safe and efficacious vaccine that can prevent and/or cure HIV-1 in human. The search of a vaccine has faced many difficulties linked to the complex strategies that the virus has developed to interact with the host cells, to modulate or neutralize the host specific anti-virus defences and to induce multi-organ degenerative diseases. There is no accessible animal model that support productive infection of HIV-1 and recapitulate the onset of disease. The chimeric Simian-Human Immunodeficiency Virus (SHIV) has been created to use the non-human primates as model for HIV pathogenesis. The existing SHIVs are based on the background genome of SIV in which some genes were replaced with homologous genes from HIV-1 and expressed by the Tat-dependent promoters in the SIV LTRs. We have developed innovative SHIV genomes in which expression of SIV/HIV genes is under control of constitutive Tat-independent promoters in the LTRs of the macrophage-tropic goat lentivirus CAEV (caprine arthritis encephalitis virus). This vaccine is deleted for the viral integrase to prevent the integration of its genome into that of the host. Vaccine genome has the capacity to perform a single cycle of replication. The preclinical trials of this prototype clearly showed that it induces persistent and increased immune responses in both the mouse and the macaque models. Vaccine induced immune responses in macaques characterized in 100% of the vaccinated macaques were shown to control the the challenge viremia to undetectable threshold. This control correlated with the presence of a variety of vaccine-specific T cells including long-lived expandable memory T cells. The goal of this project is to associate expression of natural cytokine adjuvants with the vaccine antigens to further increase the vaccine immunogenicity. We selected the cytokines IL-7 and IL-15, well known in the literature for their potentiating effects of the memory cells production and survival. Cytokine genes are incorporated into the genome of the vaccine and the resulting prototypes are tested for their adjuvanted effects in the mouse and the macaque models. The expected results will help to select the most effective vaccine prototype, inducing the most protective responses in the macaque model in order to consider clinical trials in humans. This work is conducted in collaboration with the New Iberia primate center at the University of Lafayette, Louisiana.