Exploiting Drug Repositioning for Discovery of a Novel HIV Combination Therapy

Abstract

The development of HIV drugs is an expensive and a lengthy process. In this study, we used drug repositioning, a process whereby a drug approved to treat one condition is used to treat a different condition, to identify clinically approved drugs that have anti-HIV activity. The data presented here show that a combination of two clinically approved drugs, decitabine and gemcitabine, reduced HIV infectivity by 73% at concentrations that had minimal antiviral activity when used individually. Decreased infectivity coincided with a significant increase in mutation frequency and a shift in the HIV mutation spectrum. These results indicate that an increased mutational load is the primary antiviral mechanism for inhibiting the generation of infectious progeny virus from provirus. Similar results were seen when decitabine was used in combination with another ribonucleotide reductase inhibitor. Our results suggest that HIV infectivity can be decreased by combining a nucleoside analog that forms noncanonical base pairs with certain ribonucleotide reductase inhibitors. Such drug combinations are relevant since members of these drug classes are used clinically. Our observations support a model in which increased mutation frequency decreases infectivity through lethal mutagenesis.

New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations: Potential for incorporation into virostatic cocktails

“…Lori et al, in 2005 [13] showed that a cytostatic 10 µM concentration of HU inhibited cell proliferation and suppressed HIV-1 replication in vitro. In a virostatic combination with didanosine, the indirect antiviral effect of HU and the direct antiviral effect of didanosine resulted in an overall beneficial effect [13,19,20,23,24]. On its own, compound 4 exhibited antiviral activity (lowering infectivity of TZM-bl cells by Du…”

“…The HU-didanosine combination decreases deoxyribonucleotides (dNTPs) resulting in an increase in the dNTP analogue (didanosine) which is a nucleotide reverse transcriptase inhibitor resulting in an increase in anti-HIV activity [21,22]. The combination of cytostatic drugs with anti-viral agents, results in an overall significantly beneficial anti-HIV effect [13,19,20,23,24]. Lori and colleagues [13,19] named this combination virostatics and defined it as a class of emerging anti-HIV agents which are characterised by the combination of a drug directly inhibiting virus production (viro) e.g.…”

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

“…Mammalian innate immune systems have developed a mechanism to exploit this high mutation rate against the virus; in a phenomenon termed "lethal mutagenesis," (6)(7)(8)(9)(10)(11)(12)(13)(14) the immune system employs nucleic acid-modifying enzymes (e.g., APOBEC and ADAR) to increase the viral mutation rate sharply, stressing the functional gene product repertoire of the virus to the point that the viral population collapses (15)(16)(17). Several antiviral agents are proposed to work at least in part by a chemical version of lethal mutagenesis [e.g., ribavirin against hepatitis C virus (18-22), 5-hydroxy-2′-deoxycytidine against HIV (7), and T-705 against influenza viruses (23)].…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…The main advantage is that host-acting BSAs can cover multiple viruses and genotypes while reducing at the same time the likelihood of resistance development 69,70 . In the clinical setting, applications of BSAs might range from rapid management of new or DAA-resistant viral strains 71 and of viral outbreaks 12 to reducing therapy complexity of viral co-infections [72][73][74][75] . In addition, BSAs would be ideal as a first-line treatment or the prophylaxis of acute virus infections such as respiratory tract or sexually transmitted infections 76,77 .…”