The Farzan laboratory is interested in (1) the process by which HIV-1, SARS coronavirus (SARS-CoV), filoviruses, and, yes, the influenza A virus enter their respective target cells, (2) the identity of the cellular receptors for flavi-, bunya-, and filoviruses (3) mass spectrometric and phage-display approaches to the development of antibody and peptide inhibitors of HIV-1 entry.
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 such as the chemokine receptor CCR5 or CXCR4. Association with the coreceptor induces a dramatic conformational change in the envelope glycoprotein gp41 that allows its amino-terminus to associate with the target-cell membrane, facilitating mixing of the viral and cellular lipids and ultimately entry of the viral capsid into the cell. CCR5 is the primary coreceptor used during transmission and replication during the asymptomatic period of infection. We have studied CCR5 extensively, mapping a domain in the amino-terminus of the receptor that is critical for HIV-1 entry. This domain is rich in tyrosine and acidic residues, and we have shown that the tyrosines in this region are modified by the addition of sulfate. These sulfates are quite important for HIV-1 replication. For example, peptides based on the amino-terminus of CCR5 can inhibit HIV-1 entry only if they are sulfated, and sulfated peptides can complement the inability of a CCR5 lacking an amino-terminus to support HIV-1 entry.
The anti-HIV-1 immune response. We have shown that antibodies can mimic CCR5 in a number of ways, including by sulfating the tyrosines in their antigen-binding regions. These antibodies may be important because the virus has greater difficulty escaping from an antibody that so closely mimics its obligate receptor. We are currently investigating these antibodies, their role in controlling infection in the population of long-term non-progressing patients, and how to better elicit them. We are modifying these and other neutralizing antibodies to improve their breadth and potency using a novel mass spectrometric approach and phage-based selection. Our lab runs a state-of-the-art mass spectrometer, which has been invaluable for these studies.
Viral receptors. A few years ago, we identified the receptor, ACE2, necessary (and apparently sufficient) for infection of cells by the SARS virus. This work encouraged use to develop new approaches to identifying receptors of other human viruses, including the receptors of some flaviviruses, Rift Valley Fever virus, and the common filovirus receptor. This work has paid off in one case; with Hyeryun Choe’s lab, we identified transferrin receptor 1 as an obligate receptor for four New World hemorrhagic fever arenaviruses. Again, having a top-line mass spectrometer is of great use in these efforts. Finally, we have begun to examine the complex relationship between sialic acid, the receptor for influenza A virus, and the neuraminidase inhibitors that are used to treat influenza.
A last note. Finally, it may be worth mentioning that I am one of the few investigators who have gone through the graduate program here myself (Immunology, actually), and I therefore make a point of being accessible to graduate students. Please feel very free to contact me with questions or for advice.
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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.
Li W, Zhang C, Sui J, Kuhn JH, Moore MJ, Luo S, Wong SK, Huang IC, Xu K, Vasilieva N, Murakami A, He Y, Marasco WA, Guan Y, Choe H, Farzan M. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 2005; 24:1634-43.
Kuhn JH, Radoshitzky SR, Guth AC, Warfield KL, Li W, Vincent MJ, Towner JS, Nichol ST, Bavari S, Choe H, Aman MJ, Farzan M. Conserved receptor-binding domains of Lake Victoria marburgvirus and Zaire ebolavirus bind a common receptor. J Biol Chem. 2006; 281:15951-8
Dorfman T, Moore MJ, Guth AC, Choe H, Farzan M. A tyrosine-sulfated peptide derived from the heavy-chain CDR3 region of an HIV-1-neutralizing antibody binds gp120 and inhibits HIV-1 infection. J Biol Chem. 2006; 281:28529-35.
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 haemorrhagic 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. |
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