This abstract was recently presented at the International Workshop on HIV and Hepatitis in Sitges
Abstract 37 by RF Schinazi and colleagues was on the topic of a novel series of inhibitors of HIV replication called Jak inhibitors. These compounds are able to interfere with the Jak-STAT pathway in activated lymphocytes and macrophages in the aftermath of HIV infection. Activation and reactivation of cells was performed using monoclonal antibodies against CD3 and/or CD28 and activation was monitored by flow cytometry. The Jak-STAT pathway is routinely stimulated in HIV-infected cells and can therefore be perceived as a logical target for drug development. Now, in this proof of concept study, it has been shown that two lead compounds termed Tofacitinib and Jakafi demonstrated excellent inhibition of HIV replication at concentrations ranging between 0.02-0.3 µM in cultured human lymphocytes and macrophages as well as against replication of a SHIV in lymphocytes and macrophages obtained from rhesus macaques. Moreover, these compounds were not toxic and the selectivity index for each of these compounds was high. This is the first demonstration that targeted blockage of the Jak-STAT pathway might be an effective way of interfering with HIV replication in both macrophages and lymphocytes. Moreover, the data suggest that these compounds might interfere with the ability of HIV to achieve latency in a variety of target cell types and that they were active against all of a variety of forms of drug-resistant HIV-1 that were tested. In addition, activity was demonstrated in regard to latently infected cells that were re-activated so as to become overt producers of HIV. The field will now await further studies on some of the molecules in this series, at least some of which are already approved by the Food and Drug Administration in regard to other disease indications, such as rheumatoid arthritis and myeleofibrosis.