The F12-Vif derivative Chim3 inhibits HIV-1 replication in CD4+ T lymphocytes and CD34+-derived macrophages by blocking HIV-1 DNA integration.
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.
Porcellini
Simona
S
MolMed S.p.A., Milano, Italy.
Alberici
Luca
L
Gubinelli
Francesco
F
Lupo
Rossella
R
Olgiati
Clelia
C
Rizzardi
Gian-Paolo
GP
Bovolenta
Chiara
C
D018952:Antigens, CD34 / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology / Q000821:virology*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D005312:Fetal Blood / Q000166:cytology; D015316:Genetic Therapy / Q000379:methods*; D015658:HIV Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development* / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008264:Macrophages / Q000166:cytology / Q000502:physiology / Q000821:virology*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D014161:Transduction, Genetic; D016662:Virus Integration; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics*
D018952:Antigens, CD34; D011993:Recombinant Fusion Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus