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 Blood, 9 April 2009, Vol. 113, No. 15, pp. 3443-3452.
Prepublished online as a Blood First Edition Paper on February 11, 2009; DOI 10.1182/blood-2008-06-158790.

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GENE THERAPY

The F12-Vif derivative Chim3 inhibits HIV-1 replication in CD4+ T lymphocytes and CD34+-derived macrophages by blocking HIV-1 DNA integration

Simona Porcellini1,*, Luca Alberici1,*, Francesco Gubinelli1,*, Rossella Lupo1, Clelia Olgiati1, Gian-Paolo Rizzardi1, and Chiara Bovolenta1

1 MolMed S.p.A., Milano, Italy

The viral infectivity factor (Vif) is essential for HIV-1 infectivity and hence is an ideal target for promising anti–HIV-1/AIDS gene therapy. We previously demonstrated that F12-Vif mutant inhibits HIV-1 replication in CD4+ T lymphocytes. Despite macrophage relevance to HIV-1 pathogenesis, most gene therapy studies do not investigate macrophages because of their natural resistance to genetic manipulation. Here, we confirm the F12-Vif antiviral activity also in macrophages differentiated in vitro from transduced CD34+ human stem cells (HSCs). Moreover, we identified the 126- to 170-amino-acid region in the C-terminal half of F12-Vif as responsible for its antiviral function. Indeed, Chim3 protein, containing this 45-amino-acid region embedded in a WT-Vif backbone, is as lethal as F12-Vif against HIV-1. Of major relevance, we demonstrated a dual mechanism of action for Chim3. First, Chim3 functions as a transdominant factor that preserves the antiviral function of the natural restriction factor APOBEC3G (hA3G). Second, Chim3 blocks the early HIV-1 retrotranscript accumulation and thereby HIV-1 DNA integration regardless of the presence of WT-Vif and hA3G. In conclusion, by impairing the early steps of HIV-1 life cycle, Chim3 conceivably endows engineered cells with survival advantage, which is required for the efficient immune reconstitution of patients living with HIV/AIDS.


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