title: APOBEC3G-Augmented Stem Cell Therapy to Modulate HIV Replication: A Computational Study.
abstract: The interplay between the innate immune system restriction factor APOBEC3G and the HIV protein Vif is a key host-retrovirus interaction. APOBEC3G can counteract HIV infection in at least two ways: by inducing lethal mutations on the viral cDNA; and by blocking steps in reverse transcription and viral integration into the host genome. HIV-Vif blocks these antiviral functions of APOBEC3G by impeding its encapsulation. Nonetheless, it has been shown that overexpression of APOBEC3G, or interfering with APOBEC3G-Vif binding, can efficiently block in vitro HIV replication. Some clinical studies have also suggested that high levels of APOBEC3G expression in HIV patients are correlated with increased CD4+ T cell count and low levels of viral load; however, other studies have reported contradictory results and challenged this observation. Stem cell therapy to replace a patient's immune cells with cells that are more HIV-resistant is a promising approach. Pre-implantation gene transfection of these stem cells can augment the HIV-resistance of progeny CD4+ T cells. As a protein, APOBEC3G has the advantage that it can be genetically encoded, while small molecules cannot. We have developed a mathematical model to quantitatively study the effects on in vivo HIV replication of therapeutic delivery of CD34+ stem cells transfected to overexpress APOBEC3G. Our model suggests that stem cell therapy resulting in a high fraction of APOBEC3G-overexpressing CD4+ T cells can effectively inhibit in vivo HIV replication. We extended our model to simulate the combination of APOBEC3G therapy with other biological activities, to estimate the likelihood of improved outcomes.
authors.affiliation: Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. ihossei1@jhu.edu
authors.forename: Iraj
authors.initials: I
authors.lastname: Hosseini
authors.forename: Feilim
authors.initials: F
authors.lastname: Mac Gabhann
mesh_terms: D000071480:APOBEC-3G Deaminase; D000465:Algorithms; D017209:Apoptosis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D064987:Cell- and Tissue-Based Therapy; D003198:Computer Simulation; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015316:Genetic Therapy; D015658:HIV Infections / Q000378:metabolism* / Q000628:therapy / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D008954:Models, Biological; D014779:Virus Replication
chemical_list: D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase