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Professor
Department of Medicine
2043 Genetic Medicine Building

Research Summary

Viral pathogenesis, drug delivery, HIV CURE, Stem cell biology and therapy

Throughout evolution, humans have been challenged by viral pathogens new to the species. For the most part, our immune system mounts an adequate response that protects us from the fatal consequences of infection. However, in some instances viruses can circumvent the immune system and cause fatal diseases such as cancer (EBV, KSHV, HCV), hemorrhagic fever (Ebola virus),  AIDS (HIV) and new emerging pandemics (SARS, MERS, SARS-CoV-2). Understanding the host pathogen relationship at a molecular level provides rational approaches to therapy and vaccine development. In addition, it also provides a better understanding of human biology and immunology. We are interested in how human viruses cause human cancer, how HIV causes AIDS and why the immune system is not able to control viral infections. Our working hypothesis is that specific viral genes are the key determinants of viral pathogenesis and are responsible for disease progression. To evaluate the role of these genes in disease progression, we have developed in vitro and in vivo models that recapitulate specific aspects of viral infection. Our emphasis has been placed on precision animal models where human specific pathogens can be studied and where novel therapeutic interventions can be evaluated. For example, lymphotropic viruses are responsible for a vast number of human cancers. Unfortunately, their study has been severely limited due to fact that the majority of these viruses do not infect other mammals. Thus the lack of animal models susceptible to infection by these human viruses has severely limited our ability to develop novel treatments and effective vaccines. Our laboratory has established novel animal models that recapitulate key aspect of infection by human-specific viruses such as CMV, Zika, RSV, EBV, HIV, HHV-8, dengue virus and more recently human and bat coronaviruses. We are currently using these systems to evaluate novel interventions to treat and/or prevent the devastating diseases caused by these agents.

Awards and Honors

  • Oliver Smithies Investigator
  • American Academy of Microbiology Fellow
  • American Society for Microbiology Diversity Lecture
  • American Society for Cell Biology E. E. Just Lecture
  • International Society for Neurovirology and Society for Neuroimmune pharmacology Opendra Narayan Lecture

Publications:

Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH 3rd, Liu H, Madden VJ, Krzystek HM, De C, White KK, Gully K, Schäfer A, Zaman T, Leist SR, Grant PO, Bluemling GR, Kolykhalov AA, Natchus MG, Askin FB, Painter G, Browne EP, Jones CD, Pickles RJ, Baric RS, Garcia JV. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 591, 451-457 (2021) PMID: 33561864

Nixon CC, Mavigner M, Sampey GC, Brooks AD, Spagnuolo RA, Irlbeck DM, Mattingly C, Ho PT, Schoof N, Cammon CG, Tharp GK, Kanke M, Wang Z, Cleary RA, Upadhyay AA, De C, Wills SR, Falcinelli SD, Galardi C, Walum H, Schramm NJ, Deutsch J, Lifson JD, Fennessey CM, Keele BF, Jean S, Maguire S, Liao B, Browne EP, Ferris RG, Brehm JH, Favre D, Vanderford TH, Bosinger SE, Jones CD, Routy JP, Archin NM, Margolis DM, Wahl A, Dunham RM, Silvestri G, Chahroudi A, Garcia JV. Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo. Nature.  578(7793) 160-165 (2020) PMID: 31969707

Margolis DM, Archin NM, Cohen MS, Eron JJ, Ferrari G, Garcia JV, Gay CL, Goonetilleke N, Joseph SB, Swanstrom R, Turner AMW, Wahl A. Curing HIV: Seeking to target and clear persistent infection. Cell. 181(1): 189–206 (2020) PMID: 32220311

McBrien JB, Mavigner M, Franchitti L, Smith SA, White E, Tharp GK, Walum H, Busman-Suhay K, Aguilera-Sandoval CR, Thayer WO, Spagnuolo RA, Kovarova M, Wahl A, Cervasi B, Margolis DM, Vanderford TH, Carnathan DG, Paiardini M, Lifson JD, Lee JH, Safrit JT, Bosinger SE, Estes JD, Derdeyn CA, Garcia JV, Kulpa DA, Chahroudi A, Silvestri G. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ Nature 578(7793): 154-159 (2020) PMID: 31969705

Wahl A, De C, Abad Fernandez M, Lenarcic EM, Xu Y, Cockrell AS, Cleary RA, Johnson CE, Schramm NJ, Rank LM, Newsome IG, Vincent HA, Sanders W2, Aguilera-Sandoval CR, Boone A, Hildebrand WH, Dayton PA, Baric RS, Pickles RJ2, Braunstein M, Moorman NJ, Goonetilleke N, Garcia JV. Precision mouse models with expanded tropism human pathogens. Nature Biotechnology. 37(10):1163-1173 (2019) PMID: 31451733

Deuse T, Hu X, Gravina A, Wang D, Tediashvili G, De C, Thayer W, Wahl A, Garcia JV, Reichenspurner H, Davis M, Lanier L, Schrepfer S. Hypoimmunogenic derivatives of induced spluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nature Biotechnology. 37(3):252-258 (2019) PMID: 30778232

 Thompson CG, Rosen EP, Prince HMA, White N, Sykes C, de a Cruz G, Mathews M, Deleage C, Estes JD, Charlins P, Mulder LR, Kovarova M, Adamson L, Arora S, Dellon ES, Peery AF, Shaheen NJ, Gay C, Muddiman DC, Akkina R, Garcia JV, Luciw P, Kashuba ADM Heterogeneousantiretroviral drug distribution and HIV/SHIV detection in the gut of three species. Science Translational Medicine.11(499) :eaap8758.doi: 10.1126/scitranslmed.aap8758 (2019) PMID: 31270274

Honeycutt JB, Thayer WO, Baker CE, Ribeiro RM, Lada SM, Cao Y, Cleary RA, Hudgens MG, Richman DD, Garcia JV. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nature Medicine. 23(5):638-643 (2017) PMID: 28414330

Margolis DM, Garcia JV, Hazuda DJ, Haynes BF. Latency reversal and viral clearance to cure HIV-1. Science. 353(6297):aaf6517 (2016) PMID: 27463679

Swanson MD, Boudreaux DM, Salmon L, Chugh J, Winter HC, Meagher JL, André S, Murphy PV, Oscarson S, Roy R, King S, Kaplan MH, Goldstein IJ, Tarbet EB, Hurst BL, Smee DF, De la Fuente C, Hoffmann HH, Xue Y, Rice CM, Schols D, Garcia JV, Stuckey JA, Gabius HJ, Al-Hashimi HM, Markovitz DM. Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity. Cell. 163(3):746-758 (2015) PMID: 26496612

Link to My Bibliography