Major Areas of Research
- Mechanisms by which extrachromosomal human papillomavirus (HPV) genomes are established, partitioned, and amplified during persistent infection.
- The role of host intrinsic immunity, and DNA damage response and repair pathways in HPV DNA replication
- Analysis of the mechanism and consequences of viral genome integration in HPV-associated cancers
- Keratinocyte biology: Reprogramming Keratinocytes by Rho Kinase inhibition
- PaVE: The PapillomaVirus Episteme, a bioinformatics resource
Papillomaviruses persistently infect and replicate in stratified cutaneous and mucosal epithelia. In most cases, the infections are benign and self-limiting, but persistent infection with certain papillomavirus types can lead to the development of carcinomas. In fact, HPV is the cause of about 5% of human cancers.
HPVs infect the basal cells of stratified epithelia and the viral DNA replicates in these dividing cells as low copy, extrachromosomal circular DNA molecules. Viral genome amplification and synthesis of capsid proteins occurs only in the upper layers of the epithelium. Papillomavirus infections are usually long-lived, and the basal cells provide a reservoir of infected cells for the overlying virus producing tissue. This strategy requires that the papillomaviruses have a faithful and robust mechanism to replicate and retain their extrachromosomal genomes in the nuclei of dividing cells. We study all aspects of HPV replication using primary cell culture, genomics, transcriptomics, proteomics, and advanced imaging techniques.
Gallery of our work:
HPVs will only replicate in host keratinocytes. We discovered that primary keratinocytes could be sustained in a conditionally proliferative state by culture in the presence of Rho kinase inhibitors. This discovery (Patent US8637310) has revolutionized the procurement and culture of primary cells. Video created by Alison McBride.
Dr. McBride received a B.Sc. Hons in molecular biology from the University of Glasgow, Scotland, and a Ph.D. in biochemistry from the Imperial Cancer Research Fund and Imperial College, England, studying Epstein-Barr virus. She began working on human and other papillomaviruses as a postdoctoral fellow in the National Cancer Institute and joined NIAID in 1994. She became a senior investigator in the Laboratory of Viral Diseases in 2000, and a section chief in 2001. Dr. McBride is also adjunct faculty, a member of the Virology Graduate Program at the University of Maryland, and co-director of the NIH-Georgetown University Partnership Program. She is a fellow, American Academy of Microbiology; section editor, PLOS Pathogens; editor, Current Protocols, and editor, Virology.
- Tami Coursey, Ph.D. (Postdoctoral Fellow)
- Simran Khurana, Ph.D. (Research Scientist)
- Ashley Della Fera, B.Sc. (Ph.D. candidate)
- Alix Warburton, Ph.D. (Research Fellow)
- Nicole Anayannis, Ph.D. (Postdoctoral Fellow)
- Dan Chen (Biologist)
Coursey TL, Van Doorslaer K, McBride AA. Regulation of HPV18 Genome Replication, Establishment and Persistence by Sequences in the Viral Upstream Regulatory Region. J Virol. 2021 Jul:JVI0068621.
Porter SS, Liddle JC, Browne K, Pastrana DV, Garcia BA, Buck CB, Weitzman MD, McBride AA. Histone Modifications in Papillomavirus Virion Minichromosomes. mBio. 2021 Feb;12(1):e03274-20.
Warburton A, Redmond CJ, Dooley KE, Fu H, Gillison ML, Akagi K, Symer DE, Aladjem MI, McBride AA. HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. PLoS Genet. 2018 Jan 24;14(1).
Stepp WH, Stamos JD, Khurana S, Warburton A, McBride AA. Sp100 colocalizes with HPV replication foci and restricts the productive stage of the infectious cycle. PLoS Pathog. 2017 Oct 2;13(10)
Van Doorslaer K, Li Z, Xirasagar S, Maes P, Kaminsky D, Liou D, Sun Q, Kaur R, Huyen Y, McBride AA. The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res. 2017 Jan 4;45(D1).
Jang MK, Shen K, McBride AA. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog. 2014 May 15;10(5).
Active Projects and Available Positions
The McBride lab is recruiting post-baccalaureate and post-doctoral trainees. Interested candidates should send their CV, a one-page letter of interest and professional references to LVDResearchOpport@niaid.nih.gov or directly to Dr. McBride.
Project 1: Studying how HPVs hijack nuclear processes for viral replication and transcription using spatial/in situ imaging techniques
Project 2: Defining mechanisms by which papillomavirus genomes are established, partitioned, and amplified in keratinocytes during persistent infection
Project 3: Defining innate immune factors that modulate HPV DNA replication
Project 4: Designing anti-viral therapeutics to resolve persistent HPV infection
Project 5: Studying how HPV replication mechanisms can promote accidental integration and HPV-associated cancers