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307 A Glycoprotein-Deficient Rhabdovirus Expressing HIV-1 gp160 Mimics an HIV-1-Like Tropism: Indication for a Novel HIV-1 Vaccine Approach
H. D. Foley1, J. McGettigan1, C. A. Siler1, J. Orenstein2, R. J. Pomerantz1, and M. J. Schnell*1
1Thomas Jefferson Univ., Philadelphia, PA, USA and 2George Washington Univ. Med. Ctr., Washington, DC, USA
Background: No live-viral vector with an HIV-1-like tropism that does not integrate into the host cell genome is under investigation as an HIV-1 vaccine. We have shown previously that rabies virus (RV) vaccine strain-based vectors induce vigorous immune responses against the expressed HIV-1 proteins. On the basis of the results that attenuated, nef-deleted SIV protects against SIV infection, a novel glycoprotein-deficient rabies virus (RV)-based vector using HIV-1 envelope protein was utilized. We hypothesize that a viral vector, which targets the same cells as HIV-1, may be an excellent HIV-1 vaccine candidate.
Methods: RV-based vectors were deleted of their own single glycoprotein (G) and expressed instead a chimeric HIV-1 gp160/RV envelope protein containing the HIV-1 ecto- and trans-membrane domains fused to the RV G cytoplasmic domain. Both an envelope protein from a laboratory-adapted strain (NL4-3) and a primary isolate (89.6) were used. Recombinant viruses were recovered by standard methods and characterized on nonhuman and human cell lines and primary cells.
Results: The recombinant RV vectors infected only cells expressing human CD4 and an HIV-1 coreceptor. Moreover infection was blocked by pre-treating the viruses with anti-gp160 antibodies or soluble CD4, or incubation of the target cell with different chemokines. In addition, the G-deficient RVs expressing HIV-1gp160 were able to infect efficiently and replicate in human mononuclear peripheral blood cell (PBMCs) and human macrophages.
Conclusions: Recombinant viruses with a similar tropism to HIV-1 that do not integrate into the host cell genome may be useful for both vaccine approaches and the establishment of a small animal model for HIV-1 entry. In addition, the vectors allow us to uncouple HIV-1entry from replication.
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