Exploring HIV-1 Drug Resistance Mechanisms and Therapeutic Enhancements

At UTRGV, our laboratory is focused on next-generation treatment development in basic and translational settings. Our research interest is to address the following questions:

1) What comprises the fundamental mechanism of HIV-1 drug resistance, and how does this mechanism manifest its effectiveness in preventing the efficacy of anti-HIV drugs?

2) What molecular factors contribute to the impact on the HIV reservoir organs such as the brain and Gut gut-associated lymphoid tissue (GALT) during infection, and what strategies can be employed to effectively neutralize these factors?

3) What therapeutic strategies are currently under exploration to identify and enhance treatment options for Alzheimer’s and Parkinson’s Disease that are affecting older adults?

4) We are working on developing a strategy to protect humans as our future generation embarks on Mars. In collaboration with NASA, this research will develop countermeasures to protect the human brain as our future astronauts go for a long-term space mission.

Our primary focus within our research endeavors is directed towards the exploration of the central nervous system (CNS). The brain, being sequestered from the peripheral system by the intricate blood-brain barrier (BBB), presents a formidable challenge in therapeutic drug delivery. This challenge is particularly pronounced in the context of HIV-1, where suboptimal drug penetration into the brain fosters persistent low-level replication of the virus, thereby giving rise to complications collectively known as HIV-associated neurological disorder (HAND).

The impediment to efficient drug penetration into the brain is primarily attributed to the presence of ATP-binding cassette (ABC) transporters, notably P-glycoprotein (P-gp), and multidrug resistance-associated proteins (MRPs) within the confines of the BBB. Our research endeavors are oriented towards a comprehensive examination of the role played by P-gp and MRPs in mediating drug entry through the BBB. Delving into the molecular intricacies of these transporters, we aim to elucidate their contributions to drug resistance in affected individuals. Simultaneously, our investigations extend to exploring therapeutic modalities that can mitigate the impact of P-gp and MRPs, thereby enhancing the prospects for efficacious drug delivery to the CNS.

A secondary focal point within our research endeavors pertains to the refinement of Nano formulated anti-HIV drug delivery, specifically targeting HIV reservoir organs such as the brain and gut-associated lymphoid tissues (GALT). These events have evolved into a meticulous examination of the feasibility of targeted and non-targeted macrophage-mediated nano-drug delivery to organs harboring HIV reservoirs. The investigation encompasses a comprehensive characterization of a series of Nanodrugs, employing a combination of in vitro assessments and in vivo studies conducted on murine and macaque models.

Our research extends to the meticulous examination of two distinct humanized mouse models, namely the HU-PBL and CD34 mice, serving as instrumental platforms to monitor the sustained impact of nanodrugs on therapeutic efficacy and neurobehavior over the long term. The systematic evaluation undertaken in this study seeks to unravel the intricacies of nano-drug performance, thereby contributing to the advancement of targeted drug delivery strategies for heightened precision in addressing HIV reservoirs within vital organs. Utilizing unique humanized mouse models and targeted drug delivery platforms, they lead multidisciplinary collaborations toward developing next-generation therapies for individuals living with HIV and neurological disorders.

Our work is very multidisciplinary and collaborative. We use different techniques, including molecular characterization of host genes and protein in response to disease, physical and chemical characterization of the nano-drug molecule, and the toxicological and neurobehavioral effects of the drug in vivo. Finally, optimize a humanized mouse model to study drug metabolism and disease pathology.