Avindra Nath, M.D.

Dr. Nath received his MD degree from Christian Medical College in India in 1981 and completed a residency in Neurology from University of Texas Health Science Center in Houston, followed by a fellowship in Multiple Sclerosis and Neurovirology at the same institution and then a fellowship in Neuro-AIDS at NINDS. He held faculty positions at the University of Manitoba (1990-97) and the University of Kentucky (1997-02). In 2002, he joined Johns Hopkins University as Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections. He joined NIH in 2011 as the Clinical Director of NINDS, the Director of the Translational Neuroscience Center and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases.

Research Interests:

The overarching goal of the Section of Infections of The Nervous System is to understand how the human brain adapts to invasion by viruses and if failure of this adaptation leads to neurological diseases. When the brain encounters a new pathogen, an acute encephalitis occurs, which is accompanied by a massive inflammatory response. Over time either the pathogen is eliminated, or it adapts to the environment in the brain and can survive in the brain for extended periods of time or for the lifespan of the individual. Retroviruses are particularly adept at such processes, but some RNA viruses can acquire novel mutations to aid their spread and persistence in the brain. Studies from our lab and those of others on SARS-CoV-2 suggest that antigenic persistence may contribute to the long-term complications in these patients. 

These diseases provide an opportunity to study these complex viral-host relationships. Indeed, the human genome has been invaded by retroviruses over millions of years. These proviruses and retroviral elements have established a process of equilibrium and a symbiotic relationship with the human genome and play important roles in embryogenesis and brain development. A breakdown in this relationship may lead to a disease state. The most recent retrovirus to infect humans is the human immunodeficiency virus (HIV). Soon after infection, the virus establishes a reservoir in the brain where it may reside indefinitely. It also undergoes multiple mutations resulting in defective viral sequences, a phenomenon that is similar to the endogenized retroviruses (HERVs). However, these sequences may have intact open reading frames that code for specific viral proteins and have the potential for affecting cellular function. Our laboratory is interested in studying these phenomena in the context of HIV and HERV-K subtype HML-2; both of which have been associated with neurodegenerative diseases. We are also interested in determining if other RNA viruses act in a similar manner. Here the focus is on SARS-CoV-2.

• Neuropathogenesis of HIV infection: HIV reservoirs get established in the brain early during infection and current antiretroviral therapy does not impact the size of the reservoir. The brain also accumulates defective viral sequences, the role of which is poorly understood but is reminiscent of the endogenous retroviruses in the human genome. Our laboratory is focused on characterizing the virus in the brain and studying the mechanisms by which the virus persists for extended periods of time. We have shown that viral transcripts and viral proteins produced in the brain despite adequate antiretroviral therapy, hence we are developing means to block its effects. We have established a well characterized cohort of HIV-infected individuals to determine the various forms of neurological manifestations and underlying disease pathophysiology in the context of viral persistence.
   
• Role of endogenous retroviruses in neurological diseases:  Retroviral sequences remain dormant in the human genome and occupy nearly 8% of the genomic sequence. We have shown that one of these viruses termed HERV-K (HML-2) is activated in patients with amyotrophic lateral sclerosis (ALS), and transgenic animals that express the envelope protein of HERV-K develop ALS like symptoms. Hence, we are now using a wide variety of in vitro, and in vivo studies to determine the physiological role of HERV-K in early stages of development and the mechanisms by which its expression is regulated and causes neurotoxicity to motor neurons. We are also developing new antiviral compounds and molecular techniques for blocking HERV-K.
   
• Undiagnosed Neuroimmune and neuroinfectious diseases: Undiagnosed neuroinflammatory diseases carry a huge burden with devastating consequences. In collaboration with other researchers in NINDS and other institutes, we are investigating these patients and developing new diagnostic methods and modes of treatment for these diseases. An example of which is our observation that patients with Nodding syndrome have autoantibodies to a newly discovered protein in the brain, liemodin-1, caused by a molecular mimicry with a protein in a parasite, onchocerca. We have also discovered that under certain circumstances, RNA viruses such as Dengue, Yellow Fever and likely West Nile virus can persist in the brain and present as a neurodegenerative disease.
   

Lab Members

Selected Publications

HIV and Endogenous retroviruses

1. Garcia-Montojo, M., Fathi, S., Rastegar, C. et al. Nath A. 
   
   TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression. 
   
   Nature Communication 15, 4163 (2024). https://doi.org/10.1038/s41467-024-48488-7
    
2. C DeMarino, J Denniss, M Cowen, G Norato, DK Dietrich, L Henderson, E Gollomp, J Snow, D Pandya B Smith A Nath. 
   
   HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes
   
   Nature Communication 2024; 15 (1), 4391
    
3. Shah AH, Rivas SR, Douchet-O’Hare TT, Govindarajan V, DeMarino C, Wang T, Ampie L, Zhang Y, Banasavadi-Siddegowda VK, Walbridge S, Maric D, Garcia-Montojo M, Suter R, Lee M-H, Zaghloul K, Steiner J, Elkahloun AG, Chandar J, Seetharam D, Desgrave J, Li W, Johnson K, Ivan ME, Komotar RJ, Gilbert MR, Heiss JD, Nath A.
   
   Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma. The Journal of Clinical Investigation, 2023; 133 (13) e167929. Commentary by Hothi and Cobbs, Journal of Clinical Investigation e170885. Cited by Newsweek. Nature World News 
    
4. Steiner JP, Bachani M, Malik N, DeMarino C, Li W, Sampson K, Lee M-H, Kowalak J, Baskar M, Doucet-O’Hare T, Garcia-Montojo M, Cowen M, Smith B, Reoma LR, Medina, J, Brunel, J, Piequin J, Charvet B, Perron H, Nath A. 
   
   Human endogenous retrovirus K envelope in spinal fluid of Amyotrophic Lateral Sclerosis in toxic. 
   
   Annals of Neurology 2022; 92 (4), 545-561. NIH News Release ; Neurology Live, PMID: 35801347, PMC9489628
    
5. Garcia-Montojo M, Simula ER, Fathi S, McMahan C, Ghosal A, Berry JD, Cudkowicz M, Elkahloun A, Johnson K, Norato G, Jenen P, James T, Sechi LA, Nath A. 
   
   Antibody response to HML-2 may be protective in Amyotrophic Lateral Sclerosis. 
   
   Annals of Neurology 2022. 92 (5), 782-792. NIH News Release ; Neurology Live, PMID: 36053951, PMC9805205
    
6. Henderson^, LJ, Johnson TP, Smith B, Reoma LB, Santamaria UA, Bachani M, DeMarino C, Barclay RA, Sacktor N, McArthur JC, Letendre S, Steiner J, Kashanchi F, Nath A. Presence of Tat and Trans-activation response (TAR) element in spinal fluid despite antiretroviral therapy. AIDS. 2019 Dec 1;33 Suppl 2:S145-S157 PMID: 31789815
    
7. Hategan A, Bianchet MA, Steiner J, Karnaukhova E, Masliah E, Fields A, Lee MH, Dickens AM, Haughey N, Dimitriadis EK, Nath A. HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity. Nat Struct Mol Biol. 2017 Apr;24(4):379-386.
    
8. Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, Campanac E, Hoffman DA, von Geldern G, Johnson K, Maric D, Morris HD, Lentz M, Pak K, Mammen A, Ostrow L, Rothstein J, Nath A. Human endogenous retrovirus-K contributes to motor neuron disease. 
   
   Sci Transl Med. 2015 Sep 30;7(307):307ra153. Citations: 483
   
   DOI: 10.1126/scitranslmed.aac8201  PMID: 26424568  PMCID: PMC6344353
   
   Editorial: by Brown R and Al-Chalabi A. Endogenous retroviruses in ALS: A reawakening. 
   
   DOI: 10.1126/scitranslmed.aad3533
   
   Science, NBC News, ABC News, Future Virology, Neurology Today, The Scientist. NIH Research Matters

Emerging infections and Post-infection syndromes

1. Walitt B, Singh K, LaMunion SR, Hallett M, Jacobson S, Chen K, Enose-Akahata Y, Apps R, Barb JJ, Bedard P, Brychta RJ, Buckley AW, Burbelo PD, Calco B, Cathay B, Chen L, Chigurupati S, Chen J, Cheung F, Chin LMK, Coleman BW, Courville AB, Deming MS, Drinkard B, Feng LR, Ferrucci L, Gabel SA, Gavin A, Goldstein DS, Hassanzadeh S, Horan SC, Horovitz SG, Johnson KR, Govan AJ, Knutson KM, Kreskow JD, Levin M, Lyons JJ, Madian N, Malik N, Mammen AL, McCulloch JA, McGurrin PM, Milner JD, Moaddel R, Mueller GA, Mukherjee A, Muñoz-Braceras S, Norato G, Pak K, Pinal-Fernandez I, Popa T, Reoma LB, Sack MN, Safavi F, Saligan LN, Sellers BA, Sinclair S, Smith B, Snow J, Solin S, Stussman BJ, Trinchieri G, Turner SA, Vetter CS, Vial F, Vizioli C, Williams A, Yang SB; Center for Human Immunology, Autoimmunity, and Inflammation (CHI) Consortium; Nath A. 
   
   Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. 
   
   Nature Communication. 2024 Feb 21;15(1):907. doi: 10.1038/s41467-024-45107-3. PMID: 3833456. 
   
   Interviews and coverage by Science, New York Times, Medscape, Scientific American, NPR, Medlink, AP, STAT, Health Rising, The Guardian, The Independent, Bloomberg, EurekAlert AAAS, NIH News Release, LiveScience, Bloomberg News, Washington Post, Neurology Today, Healio Rheumatology
    
2. Lee MH, Perl DP, Steiner JP, Pasternack N, Li W, Maric D, Safavi F, Horkayne-Szakaly I, Jones RI, Stram MN, Moncur JT, Hefti M, Folkerth RD, Nath A. 
   
   Neurovascular injury with complement activation and inflammation in COVID-19. 
   
   Brain, 2022; DOI: 10.1093/brain/awac151. 
   
   Scientific Commentary: How COVID-19 affects microvessels in the brain by Jan Wenzel and Markus Schwaninger. Brain, 
   (Featured in Science News; NINDS Director’s Message; Neurology Today; Stem cell Science News; News Medical; Medpage Today;  Science for me; 
   PMID: 35788639, PMC9278212

3. Lee M-H, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J,  Hefti M, Folkerth RD, Nath A. Microvascular Injury in the Brains of Patients with COVID-19. 

   New England Journal of Medicine, 384 (5) 481-483; 2021. 
   
   DOI: 10.1056/NEJMc2033369  PMID: 33378608.  PMCID: PMC7787217
   
   Covered by many major news outlets including filming of our lab by NBC Nightly News, NPR, Nature podcast, NBC Today.

4. Lee M-H, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J,  Hefti M, Folkerth RD, Nath A. Microvascular Injury in the Brains of Patients with COVID-19. New England Journal of Medicine, 384 (5) 481-483; 2021. >550 Citations. 
   DOI: 10.1056/NEJMc2033369  PMID: 33378608.  PMCID: PMC7787217
   Covered by many major news outlets including filming of our lab by NBC Nightly News, NPR, Nature podcast, NBC Today.

5. Wang T, Medynets M, Johnson KR, Douchet-O’Hare TT, DiSanza B, Li W, Xu Y, Bagnell A, Tyagi R, Sampson K, Malik N, Steiner J, Hadegan A, Kowalak J, O’Malley JO, Maric G, Nath A. Regulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway. Proc Natl Acad Sci, 2020; 117; 17842-17853. July 13, 2020 PMID32669437, PMC7395438

   https://www.nih.gov/news-events/news-releases/turning-junk-dna-may-free…

   https://www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Rel…

6. Cortese, I, Muranski P, Enose-Akahata Y, Ha SK, Smith B, Monaco MC, Ryschewitsch C, Major EO, Ohayon J, Schindler MK, Beck E, Reoma LB, Jacobson S, Reich DS, Nath A. Pembrolizumab Treatment of Progressive Multifocal Leukoencephalopathy. New England Journal of Medicine, April 10, 2019 PMID:30969503

   Editorial: Koralnik I. Can Immune Checkpoint Inhibitors Keep JC Virus in Check? New England Journal of Medicine. PMID:30969507

   NEJM Journal Watch: Immune Checkpoint Inhibitor for Progressive Multifocal Leukoencephalopathy (editor: Robert T. Naismith)

7. Johnson TP, Tyagi R, Lee PR, Lee M-H, Johnson K, Kowalak J, Elkahloun A, Medynets M, Hategan A, Kubofcik J, Sejvar J, Ratto J, Bunga S, Makumbi I, Aceng J, Nutman T, Dowell S, Nath A. Nodding syndrome may be an autoimmune reaction to a parasitic infection Onchocerca volvulus. Science Translational Medicine Feb 2017; 9:377: DOI: 10.1126, eaaf6953.

   DOI: 10.1126/scitranslmed.aaf6953  PMID: 28202777. PMCID: PMC5434766

   Editorial: Colebunders R, Titulear M. Nodding syndrome: preventable and treatable. Science Translational Medicine 2017 Feb 15;9(377):eaam8532. 

   Science, Nature, National Public Radio, Medscape, NIH Directors Blog NIH News Release EurekAlert AAAS interview