Santosh Kumar, PhD, associate professor of Pharmaceutical Sciences in the College of Pharmacy at the University of Tennessee Health Science Center, has received a five-year, $1.71 million grant from the National Institutes of Health to continue his research on the effects of smoking on HIV-1 patients.
Despite the success of antiretroviral therapy, effective treatment outcomes for people living with HIV-1 occur in only a third of the total population who receive treatment. While reduced adherence to antiretroviral therapy is an increasing concern, substance abuse, in particular smoking tobacco, is one of the major contributing factors for ineffective treatment outcomes.
“Smoking accelerates HIV-1 pathogenesis, in part due to increased oxidative stress,” Dr. Kumar said. “Smoking is also known to exacerbate HIV-1 pathogenesis in monocytes and macrophages (types of immune cells), which serve as sanctuary sites for HIV-1. These HIV-infected monocytes and macrophages infiltrate the brain, further spreading the virus to the central nervous system and ultimately causing neuronal damage leading to the development of NeuroAIDS.”
With Theodore Cory, PhD, PharmD, assistant professor in the Department of Clinical Pharmacy at UTHSC, Dr. Kumar and his team on the project, titled “Monocytic and exosomal Cytochrome P450s in smoking-mediated HIV-1 pathogenesis,” aim to determine the role of monocytic and plasma exosomal CYP enzymes in enhancing HIV-1 replication in smokers. CYP enzymes are involved in metabolizing drugs, toxins, and cellular components. Exosomes (30-100 nanometer structures) derived from a variety of cells are circulated through plasma and deliver their active components (protein, mRNA, microRNA) into recipient cells that are far from the cells of their origin. Exosomes are increasingly considered as novel therapeutic targets, diagnostic tools, and drug carriers for many diseases, including infectious and neuronal disease.
Dr. Kumar aims to accomplish this objective by testing the hypotheses that monocytic CYP enzymes enhance HIV-1 replication in smokers by contributing to increased oxidative stress and decreased efficacy of antiretroviral therapy, and that circulating plasma exosomal CYP enzymes secreted from liver and lung cells are induced in smokers and contribute to enhanced HIV-1 development. These hypotheses are based on his current finding and literature that reports that smoking heightens HIV-1 replication in the viral monocytes and macrophages sanctuary sites.
“Our own studies also suggest that CYP enzymes are induced by tobacco smoking in monocytes and perhaps in plasma exosomes, and play a critical role in oxidative stress and antiretroviral therapy metabolism in macrophages,” he said.
Dr. Kumar expects to determine the molecular mechanism behind this progression and gain a new understanding of a role of monocytic and plasma exosomal CYP enzymes in smoking-related HIV-1 progression.
“Our ultimate goal is that once we know the target, what is causing this progression, we can develop a drug that inhibits the enzymes, either in the exosomes, the brain, or primary sources like the liver and lungs.”
Thus, the project would impact the treatment of HIV-1 patients who smoke by providing a new target for therapeutic interventions, and potential application of exosomes as therapeutic carriers in effectively treating these patients.