Michael R. Farzan

Department of Microbiology and Molecular Genetics
New England Primate Research Center
1 Pine Hill Drive
Southborough, MA 01772
Tel: (508) 624-8019
Fax: (508) 786-3317
Email: farzan@hms.harvard.edu
4 postdoctoral fellows, 1 graduate student

The Farzan laboratory is interested in (1) the identification of cellular receptors of animal viruses of the filo-, flavi- and alphavirus families (2) the process by enveloped viruses enter their target cells, (3) the antibody response to HIV-1 and SIV.

HIV-1 entry. For HIV-1 to enter its target T-cell or macrophage, 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.

The HIV-1 and SIV antibody response. Understanding in depth the antibody response to HIV-1 and SIV is critical in the development of a vaccine capable of preventing infection of a new host. The failure of the antibodies to control viral replication in an infected individual likely reflects partial attenuation of the humoral response.  We have undertaken an effort to characterize the loss of plasticity in the antibody response using pyrosequencing technology, and have begun to quantify the rates of somatic hypermutation in infected animals and humans. This effort is part of a larger goal of viewing the evolving antibody response at high resolution in healthy and immunodeficient individuals, and understanding the correlates of efficient neutralization  in HIV-1.

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.

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.
• Radoshitzky, SR, Abraham J, Spiropoulou CF, Kuhn JH, Nguyen D, Li W, Nagel J, Schmidt PJ, Nunberg JH, Andrews NC, Farzan M, Choe H.  Transferrin receptor 1 is a cellular receptor for New World hemorrhagic fever arenaviruses.  Nature. 2007; 446:92-6
• Radoshitzky SR, Kuhn JH, Spiropoulou CF, Albariño CG, Nguyen DP, Salazar-Bravo J, Dorfman T, Lee AS, Wang E, Ross SR, Choe H, Farzan M. Receptor Determinants of Zoonotic Transmission of New World Hemorrhagic Fever Arenaviruses. Proc Natl Acad Sci U S A. 2008; 105:2664-9.
• Huang IC, Li W, Sui J, Marasco W, Choe H, Farzan M. Influenza A virus neuraminidase limits viral superinfection. J Virol. 2008; 82:4834-43.