While antiretroviral therapy (ART) has been effective in stopping or slowing disease progression for most HIV infected individuals, it is not curative. ART must instead be continuous for life, requires strict compliance, is costly, and is implicated i numerous health problems attributed to long-term chemo-exposure. Eradication of the virus would address these problems, however this has proven extremely difficult. One potential means of reducing or eliminating HIV reservoirs is to administer agents to flush the virus out of hiding while on ART, which should induce death of the cell either by virus-mediated cytotoxicity, or immune-mediated clearance. Alternatively, additional reagents specific for newly expressed viral antigens could be administered to complete this kick and kill strategy. Protein kinase C (PKC) modulators are among the most active HIV latency reversing agents identified to date. However, natural PKC modulators have inherent toxicities and sub-optimal potencies. This proposal brings together several laboratories with relevant expertise in chemistry, virology and animal modeling, to advance the study of synthetic PKC modulators with reduced toxicities and improved latency reversal activities through a suite of pre-clinical assessments. We will scale-up synthesis of several (already identified) improved PKC modulators, and create novel slow release versions of these compounds with the potential to further reduce toxicities. We will subject these molecules to in vitro assessment of activity in various assays including primary cells from patients on suppressive ART, and perform in vivo modeling of latency reversal in humanized mice. This in turn will inform proposed pharmacology and efficacy studies in non-human primates. Together the studies proposed herein will provide important information regarding kick and kill approaches for HIV eradication, and advance these unique and superior compounds towards clinical testing.
Antiretroviral therapy (ART) has been effective in stopping or slowing disease progression for most HIV infected individuals, however it is not curative. This project brings together several laboratories with diverse expertise to design and advance several unique and promising synthetic protein kinase C activators through pre-clinical assessments to develop a 'kick and kill' strategy to eliminate HIV reservoirs. A suite of state-of-the- art in vitro assessments as well as efficacy studies in humanized mice and non-human primates will be utilized to advance these molecules towards clinical trials.
|Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93|
|Marsden, Matthew D; Loy, Brian A; Wu, Xiaomeng et al. (2017) In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell ""kick"" and ""kill"" in strategy for virus eradication. PLoS Pathog 13:e1006575|
|Wender, Paul A; Hardman, Clayton T; Ho, Stephen et al. (2017) Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV. Science 358:218-223|