Michael R. Farzan
Department of Microbiology and Immunobiology
1 Pine Hill Drive
Southborough, MA 01772
Tel: 508-624-8019
Fax: 508-786-3317
Email: farzan@hms.harvard.edu
Lab Members: 3 postdoctoral fellows, 3 graduate students, 1 instructor
The Farzan laboratory is interested in: (1) the process by HIV-1 enters its target cells, (2) controlling an ongoing SHIV infection using AAV-delivered antibodies and inhibitors, (3) identification of cellular receptors for members of the filo-, flavi- and alphavirus families, and (4) understanding how the IFITM-family of restriction factors inhibit viral entry.
HIV-1 entry. For HIV-1 to enter its target cell, its envelope glycoprotein gp120 binds the cellular receptor CD4. This induces a conformational change in gp120 that allows it to associate with a coreceptor usually the chemokine receptor CCR5. We have studied CCR5 extensively, mapping a domain in the amino-terminus of the receptor that is critical for HIV-1 entry. We have shown that the tyrosines in this region are modified by the addition of sulfate, and this modification is important for HIV-1 replication. Sulfated peptide mimetics of CCR5 are the basis of a series of entry inhibitors we are developing as therapeutics and as probes of the sequential process of HIV-1 entry. Our current efforts use fusions these sulfated CCR5 mimetics with CD4-Ig, delivered by adeno-associated virus (AAV), to control an ongoing SHIV infection.
Entry and receptors of other viruses. Some time ago we identified the receptor, ACE2, necessary and apparently sufficient) for infection of cells by the SARS virus. More recently we have identified TfR1 as the obligate receptor of a set of highly pathogenic arenaviruses. These efforts have generated insight into the fusion mechanisms of these viruses, and into their virulence and their capacity for efficient zoonotic transmission. Our current targets for similar studies include the filoviruses (Ebola and Marburg viruses), the flaviviruses (Dengue, West Nile, Yellow Fever viruses), and the alphaviruses (Eastern and Western encephalitis, and Chikungunya virus). Beyond identifying their receptors, we also seek to understand their diverse entry mechanisms, and explore novel approaches for blocking their entry into target cells.
The IFITM family of restriction factors. The IFITM proteins are key regulators of the entry and replication of a number of viruses, notably influenza A virus, and dengue and West Nile virus. Unique among restriction factors, they prevent infection before an enveloped virus can fuse with the cellular membrane. We are interested in every aspect of these proteins including their mechanism of action, their activity against other pathogens, there role in modulating adaptive immune responses, and their contribution to human variation in the control of viruses.
References:
Choe H, Li W, Wright PL, Vasilieva N, Venturi M, Huang CC, Grundner C, Zwick MB, Wang L,Rosenberg ES, Kwong PD, Burton DR, Robinson JE,Sodroski, JG, Farzan M. Tyrosine Sulfation of Human Antibodies Contributes to Recognition of the CCR5-binding Region of HIV-1 gp120. Cell 2003;114:161-70.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC,Choe H and Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4.
Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan B, JL. Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ. IFITM Proteins Mediate the Innate Immune Response to Influenza A H1N1 Virus, West Nile Virus and Dengue Virus. Cell. 2009; 139:1243-54.
Kwong JA, Dorfman T, Quinlan BD, Chiang JJ, Ahmed AA, Choe H, Farzan M. A tyrosine-sulfated CCR5-mimetic peptide promotes conformational transitions in the HIV-1 envelope glycoprotein. J Virol. 2011. 85:7563-71
Huang IC, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, Chiang JJ, Brass AL, Ahmed AA, Chi X, Dong L, Longobardi LE, Boltz D, Kuhn JH, Elledge SJ, Bavari S, Denison MR, Choe H, Farzan M. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathogens 2011. 7:e1001258
For a complete listing of publications click here.
Last Update: 7/26/2012