OHSU

Nancy L. Haigwood

Nancy L. Haigwood, Ph.D. (ONPRC Director and Senior Scientist), Adjunct Professor, Molecular Microbiology & Immunology, OHSU

Dr. Haigwood's laboratory has a long-standing interest in structure-function studies of recombinant glycoproteins that has led to a current focus in three overlapping areas of research: 1) neutralizing antibodies (NAbs) directed to the HIV and SIV Envelope (Env) glycoproteins; 2) mother-to-child transmission (MTCT) of HIV/SIV; and 3) HIV vaccine development. 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 nonhuman primate (NHP) models. In 1991, they showed that NAbs in human subjects with broad activity are directed to conformational determinants. In the SIV system in 2004, the group found that time to disease was significantly lengthened by passive treatment with NAbs (IgG) during acute infection. Better outcome correlated with maintenance of low virus load and the development of antiviral immunity. Importantly, the presence of NAbs during acute SIV infection accelerated the development of effective NAbs, a novel finding that has implications for both vaccines and for therapies.

The Haigwood group is currently studying HIV-1 in humans and SIV and SHIV in NHPs to explore the development of NAbs in relationship to changing Env variants. They recently (2009) showed that NAbs are dynamic, even in those HIV-positive individuals with a high degree 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 MTCT. Using the virus SHIV-SF162P3, the group has studied transmission from pregnant macaques to their infants, and oral infection of newborns, where this virus is highly pathogenic. These studies (2010) have shown that NAbs have a novel role in controlling viremia and enhancing B cell responses in vivo. These data provide evidence for beneficial roles for NAbs, even at levels lower than those required to fully block infection. They are currently exploring NHP models for passive therapies with human monoclonal antibodies to limit MTCT.

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 plasma viral variants arising in vivo (2011); 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, or nanoparticle (2010). Vaccines based on these concepts elicit strong NAbs in rabbits and can be used to display different antigens on the same particles. These approaches are promising models for understanding mechanisms of antigen presentation and exploiting these mechanisms to design vaccines that can elicit protective antibodies.

Lab Members

Zachary Brower

Biwei Guo, M.S.

Ann J. Hessell, Ph.D.

Juan Pablo Jaworski, D.V.M

Shelly J. Krebs, Ph.D.

Delphine Malherbe, Ph.D.

Erin McNelley, M.D.

Shilpi Pandey, M.S.

Franco Pissani
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 254:105-108.

Mahalanabis M, Jayaraman P, Miura T, Pereyra F, Chester EM, Richardson B, Walker B, and Haigwood NL (2009). Continuous viral escape and selection by autologous neutralizing antibodies in drug-naive HIV controllers. J Virol 83: 662-672.

Ng CT, Jaworski JP, Jayaraman P, Sutton WF, Delio P, Kuller L, Anderson D, Landucci G, Richardson BA, Burton DR, Forthal DN, and Haigwood NL. (2010) Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques. Nat Med 16(10):1117-1119.

Caivano A, Doria-Rose NA, Buelow B, Sartorius R, Trovato M, D'Apice L, Domingo GJ, Sutton WF, Haigwood NL, and De Berardinis P. (2010) HIV-1 Gag p17 presented as virus-like particles on the E2 scaffold from Geobacillus stearothermophilus induces sustained humoral and cellular immune responses in the absence of IFNgamma production by CD4+ T cells. Virology 407(2):296-305.

Malherbe DC, Doria-Rose NA, Misher L, Beckett T, Puryear WB, Schuman JT, Kraft Z, O’Malley J, Mori M, Srivastava I, Barnett S, Stamatatos L and Haigwood, NL (2011). Sequential immunization with a subtype B HIV-1 Envelope quasispecies partially mimics the in vivo development of neutralizing antibodies. J Virol 85:5262-5274.