HIV is an elusive virus. Affecting more than 30 million people worldwide, the virus thrives in the human immune system by adapting in a number of ways, which makes effective treatments and an eventual cure exceedingly difficult. However, scientists at the University of Rochester and Emory University recently unveiled one of the mechanisms by which HIV is able to replicate itself inside the human immune system: dNTP substitution in macrophages.1 With this discovery, it is possible that new treatments are on the horizon.
HIV drugs typically target helper T Cells (CD4+ T cells)—the white blood cells that are eventually depleted by the virus. However, HIV also infects macrophages2—a derivative of monocytes—but until recently, scientists were unable to determine how the virus was able to thrive inside this kind of cell.
To replicate, HIV ordinarily uses the host’s own protein machinery—specifically the nucleoside dNTP (deoxynucleoside triphosphate), which is broken down to become a building block for DNA and RNA. However, dNTP is absent in macrophages, because macrophages don’t replicate. In lieu of dNTP, researchers Baek Kim and Raymond Schinazi found that the virus recruits a closely related molecule, rNTP (ribonucleoside triphosphate), to replicate. Kim and Schinazi then confirmed their findings by showing that when they blocked the ability of the virus to interact with rNTP, they reduced HIV’s ability to replicate in macrophages by more than 90%.
The ability to thwart HIV reproduction in macrophages could be a more effective than existing treatments at limiting the ravages of the virus for several reasons:
- Macrophages appear to be the first cells infected by HIV.
- Once helper T cells become depleted, macrophages may serve as the source of HIV production.
- Infected macrophages eventually spreads HIV to the central nervous system.
Some drugs that are already being tested for other purposes also happen to offer rNTP-targeting potential. Cordycepin, a compound derived from wild mushrooms, is one such drug; currently it is being tested as an anti-cancer drug, but it has also been shown to efficiently inhibit HIV-1 replication in macrophages.
|Resources from Wiley on This Topic|
Antiviral Drugs: From Basic Discovery Through Clinical Trials
by Wieslaw M. Kazmierski
HIV-1 Integrase: Mechanism and Inhibitor Design
by Nouri Neamati, Binghe Wang
AIDS and Tuberculosis: A Deadly Liaison
by Stefan H. E. Kaufmann and Bruce D. Walker
1. Kennedy EM, Gavegnano C, Nguyen L, Slater R, Lucas A, Fromentin E, Schinazi RF, & Kim B (2010). Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. The Journal of biological chemistry, 285 (50), 39380-91 PMID: 20924117
2. Benaroch, P., Billard, E., Gaudin, R., Schindler, M., & Jouve, M. (2010). HIV-1 assembly in macrophages Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-29