Nancy Haigwood, PhD
(ONPRC Director and Senior Scientist), Adjunct Professor, Molecular Microbiology & Immunology, OHSU
Affiliate Professor of Global Health, University of Washington
Dr. Haigwood's laboratory has a long-standing interest in structure-function studies of recombinant proteins that has led to a current focus in three overlapping areas of research: 1) neutralizing antibodies (NAbs) and immune control of HIV/SIV; 2) perinatal transmission of HIV/SIV; and 3) HIV vaccine development. Envelope (Env) glycoproteins play a major role in immunity and host defense in the primate lentiviruses. Her group has investigated the role of SIV and HIV Envelope-specific NAbs in immune control and as potential therapeutic entities in NHP models. Her group showed in 1991 that NAbs in humans with broad activity are directed in part to conformational determinants. In the SIV system, she found that time to disease can be significantly lengthened by passive treatment with NAbs (IgG) during acute infection. Better outcome correlated with maintenance of low virus load and the development of cellular immunity and NAbs. Importantly, the presence of NAbs during acute infection accelerated the development of effective NAbs, a novel finding that has implications for both vaccines and for therapies.
Her group is currently studying HIV-1 in humans and SIV and SHIV in NHP to explore the development of NAbs in relationship to changing Envelope variants to determine which changes are driving escape from neutralization antibodies. They recently showed that neutralizing antibodies are dynamic, even in those HIV= individuals with a high level of control for many years, so-called "controllers". A second major goal of Dr. Haigwood's group is to understand the role of NAbs in mother-to-child transmission (MTCT) of HIV. Using the pathogenic R5 virus SHIV-SF162P, the group has studied transmission from pregnant macaques to their infants, as well as oral infection of newborns. These studies point toward a role for maternal NAbs in facilitating development of antiviral immunity in vivo, and provide evidence for beneficial roles for NAbs, even at levels lower than those required to fully blocking infection.
These interests converge in the long-term goal of developing HIV vaccines that fully or partially protect from HIV disease. New vaccines currently under study are (1) SHIV-based combination antigen immunogens that include HIV env genes derived from natural plasma variants arising in vivo; and (2) a prokaryotic antigen display system that presents key regions of Env on a highly immunogenic 60-component multimer similar in size to a virus-like particle. Both of these approaches elicit NAbs in rabbits. These approaches are promising models for understanding the mechanisms of antigen presentation and exploiting these mechanisms for effective vaccine design.
Oregon Health & Science University
Juan Pablo Jaworski, D.V.M
Delphine Malherbe, Ph.D.
Bill Sutton, M.S.
Key & Recent Publications
Steimer KS, Scandella, CJ, Skiles, PV, and Haigwood, NL(1991) Neutralization of divergent HIV-1 isolates by conformation-dependent human antibodies to gp120. Science 254:105-08.
Haigwood NL, DC Montefiori, WF Sutton, J McClure, A Watson, G Voss, VM Hirsch, B Richardson, NL Letvin, S-L Hu, and PR Johnson (2004). Passive Immunotherapy in SIV-Infected Macaques Accelerates the Development of Neutralizing Antibodies. J Virol 78:5983-95.
Jayaraman P, T Zhu, L Misher, D Mohan, L Kuller, P Polacino, BA Richardson, H Bielefelt-Ohmann, D Anderson, S-L Hu, and NL Haigwood (2007) Evidence for Persistent, Occult Infection in Neonatal Macaques following Perinatal Transmission of SHIV-SF 162P3. J Virol 81:822-834.
Blay WM, T Kasprzyk, L Misher, BA Richardson, NL Haigwood(2007) Mutations in Envelope gp120 can impact proteolytic processing of the gp160 precursor and thereby affect neutralization sensitivity of human immunodeficiency virus type 1 pseudoviruses. J Virol 81: 13037-13049.
Morgan C, Marthas M, Miller C, Duerr A, Cheng-Mayer C, Desrosiers R, Flores J, Haigwood N, Hu SL, Johnson RP, Lifson J, Montefiori D, Moore J, Robert- Guroff M, Robinson H, Self S, Corey L. (2008) The use of nonhuman primate models in HIV vaccine development. PLoS Med 5(8):e173.
M Mahalanabis, P Jayaraman, T Miura, F Pereyra, EM Chester, B Richardson, B Walker, and NL Haigwood (2009). Continuous Viral Escape and Selection by Autologous Neutralizing Antibodies in Drug-Naive HIV Controllers, J Virol 83: 662-672.