International Mentored Scientist Award

Current antiviral regimens for HIV have been highly successful in limiting viral HIV replication and reducing viral loads to undetectable levels in most patients. However, these antiviral drug regimens do not cure the infection because HIV is able to establish a latent reservoir within memory CD4 cells that are not attacked by combined anti-retroviral therapy (cART). One attractive approach to viral latency is to reduce the size of the reservoir using latency reversing agents and simultaneously to employ a therapeutic HIV vaccine to elicit an antiviral immune response that is capable of controlling the smaller, residual reservoir in the absence of cART. A missing key in this “reduce and control” strategy is latency reversing agents (LRAs) that are both effective and safe. Thus far histone deacetylase inhibitors like vorinostat, panobinostat, and romedepsin or protein kinase C activators like bryostatin and ingenol-3-angelate have been tested. Unfortunately, their performance has been disappointing. They lack potency and are plagued by significant toxicities, they impair the effector function of CTL and NK cells that likely will be needed to clear reactivated reservoir cells. We hypothesize that potent and safe LRAs exist in nature and can be found within medicinal plants in African rain forests. We propose to work with the Department of Botany at Makerere University to procure and curate up to 100 different medicinal plants found in Central Uganda, to prepare water and hexane extracts from each of these plants, and to test their potential LRA activity using J-LAT 5A8 cells, a leukemic CD4 T cell model of HIV latency. The top 10% of extracts from the initial screen will then be tested in a primary CD4 T cell model of HIV latency. Finally, the top 3 compounds (or any compound showing 5-fold effects above baseline) will be tested for activity in cells from HIV-infected patients on suppressive cART. If positive extracts are identified, dose-response curves will be established, and each extract will be carefully evaluated for toxic effects in human cells. Each extract will be benchmarked against the latency reversing activity and toxicity of bryostatin, ingenol, vorinostat, panobinostat, and romidespsin. Ultimately, if we succeed in identifying a non-toxic plant extract with high LRA activity, scaled up extracts will be used for biochemical purification of the active chemical component.