Non-Integrating Lentiviral Vectors: Potential as Vaccines

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DESCRIPTION (provided by applicant): Despite major advancements in HIV-1 therapeutics, the HIV-1/AIDS epidemic continues to grow, highlighting the need for the development of an effective vaccine. Although an attenuated replication competent HIV-1 vaccine presents unacceptable risks, prior work with attenuated strains of SIV has led to several important observations concerning vaccine efficacy in the primate model. Chronic presentation of low levels of viral antigens in the setting of a viral infection provides protection. During retroviral infection, high levels of unintegrated extrachromosomal DNA (E-DNA) accumulate in the infected cells in addition to integrated provirus responsible for production of new viral progeny. E- DNA has been shown to persist in vivo even in the absence of detectable plasma viremia. We, as well as others, have shown that E-DNA is stable in vitro in non-dividing cells and is transcriptionally active producing functional viral proteins. However, despite the production of viral protein, E-DNA does not sustain viral replication. The central hypothesis of this proposal is that sustained viral protein production from HIV-1 E-DNA is an efficient and safe way to express viral proteins and induce an immune response. Viral proteins are presented in the context of an infectious cycle with the safety features including the lack of production of replicating virus and the absence of integration. To test this hypothesis, we will test the efficiency of integrase defective lentiviral vectors to produce viral E-DNA and proteins in professional antigen presenting cells (APC) including dendritic cells (DC). The ability of these transduced cells to be recognized by and induce a response in effector T-cells will be evaluated as well. Finally we will use a murine model to determine the kinetics of E-DNA and viral protein production from IN-defective vectors delivered intramuscularly as well as determine if the expression is associated with a measurable immune response. These feasibility studies will establish whether IN-defective vectors should be exploited for vaccine development.