425. Inhibition of HIV-1 Infectivity by Gold(I) Phosphine Compounds is Related to Cytostasis
Session: Poster Abstract Session: HIV - Antiretroviral Therapy
Friday, October 21, 2011
Room: Poster Hall B1
Background: Gold compounds are cystostatic: a mechanism that has been shown for drugs such as hydroxyurea (HU) to be effective in reducing the replication of the human immunodeficiency virus (HIV). The combination of cytostatic agents such as HU with directly anti-viral drugs results in an optimal immune response with a better resistance profile (virostatic combinations) than that seen for current anti-HIV agents (since a cellular and not a viral target is involved). In this study, the cytostatic effect and viral infectivity inhibition of two gold(I) phosphine and four bis(phosphino)hydrazine gold(I) complexes with molecular formulae: C23H25AuClN2P and C23H27AuClN2P, and C28H30Au2Cl2N2P2, C56H64AuClN4P4, C32H38Au2Cl2N2O4P2 and C36H50Au2Cl2N6P2  also designated 1-respectively (synthesized by AuTEK Biomed chemists, Mintek, South Africa) was investigated.  

Methods: Viability studies on two relevant cell types were performed using tetrazolium dyes while proliferation was monitored using the carboxyfluorescein succinimidyl ester (CFSE) assay. Luciferase gene expression from TZM-bl cells was analysed as a measure of HIV infectivity after treating cells with a dual subtype C viral isolate. The effect of complexes 2, 3 and 6 on immune system cells (PBMCs) was determined using multi-parametric flow cytometry.  

Results: The CC50 of the compounds in both cell types was within the clinically relevant range for gold compounds (>1 µM) with being the least toxic. Non toxic but cytostatic effects were noted in the order 3>4>5>1>2>6, in PBMCs with retaining up to 83% of cells in the parent generation. Inhibition of infectivity was observed in the order of 3>1>5>6>2>4 with 3 having an IC50 of 3.6±1.1 µM. Time of addition studies suggested that inhibition was not on viral surface components but was either at entry or post entry steps. The frequency of CD4+ cell expression from PBMCs of twelve treatment naive HIV+ donors was significantly lowered by (p = 0.027), a property also reported for HU and HU-like agents.

Conclusion: Complex 3 and to a lesser extent, 4 and 5 inhibited viral infectivity at cytostatic concentrations and have potential for incorporation in virostatic combinations, which offer better resistance profiles than current anti-HIV drugs.


Subject Category: H. HIV/AIDS and other retroviruses

Pascaline Fonteh, MSc. , Biochemistry, University of Pretoria, Pretoria, South Africa and Debra Meyer, PhD, Biochemistry, University of Pretoria, Pretoria , South Africa

Disclosures:

P. Fonteh, AuTEK Biomed, Mintek and Harmony: Bursar now and anticipate to be employee. AuTEK Biomed also provided access to the compounds screened. , Research support and Subsistence and tuition
L’Oréal/UNESCO: Fellowship award recipient for women in science in Sub-Saharan Africa, Research support and Subsistence

D. Meyer, None

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