Inhibition of the Replication of Clinical Drug-Resistant HIV-1 Strains by Small Molecule Integrase Inhibitors M522 and M532
Ibrahim S Abd-Elazem and Ru Chih C Huang*
Department of Biology, The Johns Hopkins University, Baltimore, Maryland, 21218, USA
- *Corresponding Author:
- Ru Chih C Huang
Department of Biology
The Johns Hopkins University
Maryland, 21218, USA
E-mail: [email protected]
Received date: October 28, 2014; Accepted date: November 19, 2014; Published date: November 25, 2014
Citation: Abd-Elazem IS, Huang RCC (2014) Inhibition of the Replication of Clinical Drug-Resistant HIV-1 Strains by Small Molecule Integrase Inhibitors M522 and M532. J AIDS Clin Res 5: 378. doi:10.4172/2155-6113.1000378
Copyright: © 2014 Abd-Elazem I, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objective: Integrase (IN) is an enzyme essential for HIV-1 replication that has been a target of antiretroviral drug therapy. Since emerging HIV-1 variants have frequently become clinically resistant to antiretroviral agents, it is necessary to develop alternative IN inhibitors. Methods: We tested IN inhibitors, M522 and M532, against clinically resistant HIV-1 strains to antiretroviral drugs (AZT, non-nucleoside reverse transcriptase inhibitors, IN drug raltegravir, protease inhibitors); wild-type and clinical isolate from HIV-infected patients. We performed disintegration studies to show the interaction of M522 and M532 with the catalytic core domain of HIV-1 IN and time-of-drug-addition experiments to determine the inhibition step of viral replication. We tested selection of HIV-1 with M522 and M532 to examine the emergence of new drug resistant virus. CD4+ cell count was calculated for several groups of cells infected with HIV, cells treated and non-treated with M522 and M532 to evaluate their protective effect. Results: M522 and M532 inhibited the replication of HIV-1 strains (wild-type; drug-resistant; clinical isolate from infected patients; and laboratory strains) with high potency. These inhibitors interacted with the catalytic core domain of HIV-1 IN and blocked its activity, prevented viral integration. M522 and M532 interfered with the viral replication precisely at the integration step. HIV-1 virus did not develop resistance to M522 and M532 for 20 viral passages (160 days). These IN inhibitors protected the infected cells from cytopathic effects and the CD4+ cell counts of these cells treated with M522 and M532 were found to be identical to those of the uninfected cells. Conclusion: M522 and M532 are potent against clinical isolate from HIV-infected patients, wild-type and clinically resistant strains especially the relevant raltegravir-resistant virus. Development of M522 and M532 as new mutationinsensitive drugs aiming for the protection of CD4+ T-cells during HIV infection in the clinical trials is in progress.