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). Morevover, we identified the 126-170-aa region in the C-terminus half of F12-Vif as responsible of its antiviral function. Indeed, Chim3 protein, containing this 45-aa region embedded in a WT-Vif backbone, is as lethal against HIV-1 as F12-Vif is. 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 retrotranscripts accumulation and thereby HIV-1 DNA integration regardless 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.
The F12-Vif derivative Chim3 inhibits HIV-1 replication in CD4+ T lymphocytes and CD34+-derived macrophages by blocking HIV-1 DNA integration / S. Porcellini, L. Alberici, F. Gubinelli, R. Lupo, C. Olgiati, G.P. Rizzardi, C. Bovolenta. - In: BLOOD. - ISSN 0006-4971. - 113:15(2009), pp. 3443-3452.
The F12-Vif derivative Chim3 inhibits HIV-1 replication in CD4+ T lymphocytes and CD34+-derived macrophages by blocking HIV-1 DNA integration
F. Gubinelli;
2009
Abstract
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). Morevover, we identified the 126-170-aa region in the C-terminus half of F12-Vif as responsible of its antiviral function. Indeed, Chim3 protein, containing this 45-aa region embedded in a WT-Vif backbone, is as lethal against HIV-1 as F12-Vif is. 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 retrotranscripts accumulation and thereby HIV-1 DNA integration regardless 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.Pubblicazioni consigliate
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