Our laboratory studies the interactions between hosts and pathogens, mainly focusing on emerging and reemerging viruses such as SARS-CoV-2, Zika virus, MPXV, and HIV-1, along with their associated comorbidities. We are committed to Open Science, collaborating nationally and internationally to advance our research. We use pre-clinical animal models to explore these viruses, including non-human primates (rhesus macaques), rodents (Golden Syrian Hamsters, transgenic mice), and in-vitro human primary cell culture models. Our research employs cutting-edge biomedical techniques such as multi-color flow cytometry, bulk and single-cell transcriptomic analysis, and untargeted quantitative proteomic and metabolomic analysis to investigate immune metabolic responses during acute and chronic infections.Our antiviral drug discovery pipeline integrates computer-aided drug design, molecular modeling, and high-throughput screening of compound libraries. We aim to develop a combinatorial therapeutic regimen encompassing direct-acting antivirals and host-targeted compounds. These treatments are validated in pre-clinical models and progressed to clinical trials.
Overview of research interests
We welcome all curious minds to join us in our mission to combat some of the most formidable microbes in human history
Summary of detailed research focus of various projects
Research Interests
HIV Cure research studies: The persistence of HIV reservoirs, particularly in the CNS, B cell follicles, and gut tissues, presents a significant obstacle in achieving a functional cure for HIV/AIDS. These areas act as viral sanctuaries where substantial viral replication persists even during ART, with viral rebound occurring upon cessation of therapy. The challenge lies in ART’s limited ability to penetrate deep tissue reservoirs due to barriers like the blood-brain barrier (BBB) and intestinal epithelial barrier, which hinder the entry of therapeutic agents. In collaboration with Drs. Skinner from the University of Minnesota and Ndhlovu from Weill Cornell University are exploring using chimeric antigen receptor (CAR)-based cellular immunotherapies to target and eradicate these reservoirs. Using non-human primate models of HIV infection, the studies focus on two specific approaches: Autologous rhesus CAR (CD4-MBL-CAR)/CXCR5 T cells. These engineered cells are designed to eliminate viral reservoirs in the CNS and peripheral tissues. Gut-homing autologous CAR/CCR9 T cells: In a companion study, we are evaluating the efficacy of these cells in targeting and clearing SIV reservoirs within gut-associated lymphoid tissues. These investigations aim to overcome the sanctuary barriers and provide a potential pathway toward eliminating HIV reservoirs from critical tissues.
The interplay of sex differences, substance use, and HIV/SIV reservoirs: Substance abuse and HIV/AIDS are closely intertwined, with each condition worsening the effects of the other. The relationship between HIV and substance use is further complicated by significant sex-based differences in disease pathogenesis. Anatomical, physiological, hormonal, and genetic variations between men and women contribute to disparities in HIV infection rates and disease progression. Moreover, the pharmacokinetic and pharmacodynamic (PK/PD) profiles of antiretrovirals used in combination antiretroviral therapy (ART) differ between sexes, underscoring the need for personalized therapeutic regimens. Beyond biological factors, social, cultural, and economic differences also influence vulnerability to HIV infection and patterns of substance use. For instance, women often face distinct social and economic challenges that increase their risk of HIV infection and may influence their substance use behaviors and cravings differently than men. This complex interplay of factors affects not only HIV transmission but also the craving and use of substances such as opioids, which have been shown to modulate viral reservoirs and influence HIV disease progression. Our research is focused on understanding how these sex differences in substance use, particularly opioids, interact with HIV and contribute to the persistence of viral reservoirs. By exploring these intricate connections, we aim to identify strategies for more effective, tailored treatments for HIV-infected individuals with substance use disorders.
THC and Cannabis: Modulating the Gut-Brain Axis: Cannabis, mainly THC, is increasingly being studied for its potential therapeutic benefits in managing complications related to HIV. People living with HIV (PLWH) frequently experience intestinal dysbiosis, epithelial barrier dysfunction, and microbial translocation, all of which contribute to chronic immune activation and accelerate disease progression. Our research, conducted in collaboration with Dr. Mohan at the Texas Biomedical Research Center, focuses on how oral cannabinoids modulate gut microbiota, strengthen gut epithelial barriers, and reduce inflammation. THC has shown promise in enhancing the antimicrobial defense of the intestinal epithelium and mitigating neuroinflammation in HIV-infected models. By positively influencing the microbiota-gut-brain axis, cannabis offers a potential therapeutic avenue for addressing HIV-related complications, not only improving gut health but also enhancing the overall quality of life for those living with HIV. Moreover, our work delves into the role of the gut as a viral reservoir and examines the effects of cannabis on immune responses in this critical site. By exploring the interplay between cannabis, the gut, and viral persistence, we aim to uncover novel strategies for managing HIV more effectively and reducing the burden of the disease.
Development of a pre-clinical animal model to study post-acute sequelae of COVID-19 (PASC): Post-acute sequelae of COVID-19 (PASC) is a chronic syndrome that affects some individuals after recovering from acute COVID-19 and can significantly impact their quality of life. While the exact causes of PASC remain unclear, several mechanisms have been proposed as potential drivers of the condition. These include chronic immune activation and inflammation, persistent viral reservoirs, epigenetic changes, autoimmunity, pulmonary fibrosis, endocrine and endothelial dysregulation, and tissue damage from microthrombosis. Studying these mechanisms in clinical cohorts is challenging due to the overlap of PASC symptoms with pre-existing comorbidities. To address these limitations, we have successfully developed a Golden Syrian Hamster (GSH) model to study SARS-CoV-2 pathogenesis. This model has proven effective for pre-clinical screening of antivirals against SARS-CoV-2. Notably, we have observed that post-recovery hamsters exhibit symptoms similar to those seen in humans with PASC, making them an excellent model for further study. Our current research focuses on understanding the molecular mechanisms underlying PASC using SARS-CoV-2-infected GSH as a model. We are employing a multimodal systems biology approach, incorporating transcriptomics, proteomics, and metabolomics analyses to study major organs affected by PASC.
Figure depicting detailed steps in understanding molecular mechanisms of Long-COVID using Hamster models.
In addition, we are conducting MRI scans of the hamsters' brains and performing behavioral studies to assess their cognitive function post-recovery from acute illness. This comprehensive approach aims to shed light on the complex biological processes driving PASC and may lead to the development of targeted interventions for this syndrome
Host factor directed antiviral discovery against emerging and reemerging viruses: We have assembled a unique protease inhibitor library targeting host cell proteases and critical signaling pathways, including TGF-ß/SMAD, PI3K/Akt/mTOR, JAK/STAT, autophagy, MAPK, NF-kß, and angiogenesis, among others. Molecular modeling suggests that many compounds in this collection also possess direct-acting antiviral activity against viral proteases of emerging and reemerging pathogens, making them valuable in the context of global viral outbreaks. Our antiviral drug discovery pipeline employs high-throughput screening of these drug-like compounds to identify candidates effective against SARS-CoV-2 and its emerging variants. This strategy aims to develop a combinatorial therapeutic regimen that includes direct-acting antivirals and compounds targeting host factors. The compounds undergo rigorous validation in pre-clinical animal models, aiming to translate successful candidates into clinical trials. By combining host-targeting and antiviral approaches, we strive to address the evolving challenges of viral pandemics, focusing on developing broad-spectrum treatments capable of combating multiple viral threats.
Collaborators
Francois Villinger; New Iberia Research Center, University of Louisiana, Lafayette
Uday Kumar Ranga, Jawaharlal Nehru Centre for Advanced Scientific Research
Mirko Paiardini, Emory University
Pamela Skinner, University of Minnesota – Twin Cities
Lishomwa Ndhlovu, Cornell University
Mahesh Mohan, Texas Biomedical Research Institute
Kamal Singh, University of Missouri, Columbia
Ujjwal Neogi, Karolinska Institute, Swdeen
Infectious Disease Society of India (IDSI)
Molekule Inc. (https://molekule.com)
Celularity Inc. (https://celularity.com
Funding
Dr. Byrareddy's laboratory is funded by 1) the National Institute of Allergy and Infectious Diseases, 2) the National Institute of Mental Health, 3) the National Institute of Drugs of Abuse, 4) the National Institute of Diabetes and Digestive and Kidney Diseases, 5) NIH Office of the Director, 6) Industry and Foundation grants.
