P-D6 Lasting Reduction Of HIV Replication In Chronically Infected Humanized Mice (HSC-NSG) By Targeting Transcription With A CDK9 Inhibitor. (March 2017)

• Record Type: Journal Article
• Authors: Medina-Moreno, Sandra; Le, Nhut; Zapata, Juan; Bryant, Joseph; Sausville, Edward; Redfield, Robert; Heredia, Alonso
• Is Part Of: Journal of acquired immune deficiency syndromes. Volume 74(2017)Supplement 3
• Publication Date: 2017-03
• Subjects: AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome -- Periodicals; AIDS (Disease); Periodicals; 616.9792005
• DOI: 10.1097/01.qai.0000513996.97128.99
• Languages: English
• ISSNs: 1525-4135

Abstract

Abstract : Current "Shock and Kill" does not cure HIV and has the risks of seeding new waves of HIV infection. An alternative approach to "Shock and Kill" is to prevent infected cells from making new virus particles by targeting HIV transcription. However, inhibitors of HIV transcription are not currently available. We have previously demonstrated that pharmacological inhibition of cellular CDK9, a cofactor of the HIV Tat protein, with Indirubin 3′-monoxime (IM) inhibits HIV transcription in vitro. We have now evaluated the antiviral activity of IM in humanized mice (HSC-NSG model), chronically infected with HIV (BaL strain). Treatment with IM (5 mg/kg) or vehicle (control) was initiated at 5 weeks after infection and continued for 15 weeks. We measured HIV RNA and CD4/CD8 ratios in blood samples at different time points. On week 15 of treatment, mice treated with IM had a mean plasma HIV RNA of 1.2 × 103 copies per milliliter, which was significantly lower than in control mice (2.1 × 105 copies per milliliter; P = 0.01). Consistent with these decreases in HIV viremia, CD4/CD8 ratios were significantly higher in IM treated mice (mean CD4/CD8 of 4.05) than in controls (mean CD4/CD8 of 0.43; P = 0.03). There was no significant difference in the weight of animals in IM treatment versus controls, suggesting treatment was not toxic. We also evaluated the toxicity of IM in immunocompetent Balb/c mice, and demonstrated that IM doses of up to 25 mg/kg (highest dose tested) did not cause hematologic, renal of liver toxicity. These data demonstrate the in vivo anti-HIV activity of IM, an inhibitor of HIV transcription. Studies are ongoing to determine if targeting HIV transcription could also impact the size of the HIV reservoir.