15th International AIDS Conference Bangkok, Thailand - July 11-16, 2004

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1233)

Lama J
University of California San Diego, La Jolla, United States

BACKGROUND: CD4 down-modulation is essential for the production of HIV infectious particles. Disease progression correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. Despite multiple evidence highlighting the importance of this function in viral pathogenesis in vivo, to date, HIV-induced CD4 down-modulation has not been used as a target for intervention.

METHODS: We used an HIV-based lentiviral vector system that delivers truncated CD4 molecules resistant to down-modulation by the viral products Nef and Vpu.

RESULTS: Transduction of HIV permissive cells with these vectors led to the production of receptor molecules resistant to the virus-induced down-modulation. Truncated receptors negatively interfered with down-modulation of full-length CD4. Infection of cells previously transduced with these vectors proceeded normally, and viral particles were released in normal amounts. However, the infectivity of the released virions was reduced ~ 1,000-fold. Lentiviral vectors expressing truncated CD4 molecules were efficient at blocking HIV-1 infectivity and replication in several cells lines and in CD4-positive primary lymphocytes.

CONCLUSIONS: The findings presented here provide proof-of-principle that selective inhibition of the virus-induced CD4 down-modulation may constitute the basis for novel anti-HIV therapies.

040711
WeOrA1233

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