Nancy L. Haigwood
Dr. Haigwood's laboratory has a long-standing interest in the HIV Envelope glycoprotein (Env) that has led to a current focus in three overlapping areas of research: 1) neutralizing antibodies (NAbs) directed to the HIV and SIV Env; 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 were the first toshow that NAbs in human subjects with broad activity are directed to conformational determinants. They have used nonhuman primate (NHP) models to test concepts, reviewed in 2015. In the SIV system in 1996 and in 2004, the group found that time to disease was significantly lengthened by passive treatment with NAbs (IgG) during acute infection. 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 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 (2007, 2010, 2013, and 2016) showed that NAbs have a novel role in controlling viremia and enhancing B cell responses in vivo, resulting in significant protection from disease. These data provide evidence for additional beneficial roles for NAbs beyond direct protection. Using human monoclonal antibodies given as passive therapies to limit MTCT, and they have shown that these antibodies can clear early foci of infection and prevent establishment of the viral reservoir. This establishes a new paradigm for antibodies in the antiviral approaches.
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 (2014); 2) a prokaryotic-scaffold that focuses the immune response on key regions of Env displayed on this highly immunogenic 60-component multimer (2014); and 3) human and simian adenovirus vectors to enrich immunity as partners for combination protein and DNA vaccines to improve chances for protection. Vaccines based on these concepts elicit strong NAbs in rabbits and macaques and show evidence of viral control following challenge with SHIV. These approaches are promising models for understanding mechanisms of antigen presentation and exploiting these mechanisms to design vaccines that can elicit protective antibodies.
Ann J. Hessell, Ph.D.William F. (Bill) Sutton, M.S.
Shilpi Pandey, 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.
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.
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.J
JP Jaworski, Z Brower, EJ Leon, DC Malherbe, G Landucci, WF Sutton, B Guo, F Engelmann, B Zheng, A Legasse, B Park, M Dickerson, AD Lewis, LMA Colgin, M Axthelm, I Messaoudi, J Kobie, JB Sacha, DR Burton, DN Forthal, AJ Hessell, and NL Haigwood (2013) Passive neutralizing antibodies alter the dynamics of infection and enhance survival of SHIVSF162P3-infected infant rhesus macaques, J Virol 87: 10447-59.
Pissani F, Malherbe DC, Schuman JT, Robins H, Park BS, Krebs SJ, Barnett SW, Haigwood NL. (2014) Improvement of antibody responses by HIV envelope DNA and protein co-immunization. Vaccine 32:507-513.
Krebs, SJ, SP McBurney, DN Kovarik, CD Waddell, JP Jaworski, WF Sutton, MM Gomes, M Trovato, G Waagmeester, SJ Barnett, P DeBerardinis, NL Haigwood (2014) Multimeric scaffolds displaying the HIV-1 Envelope MPER induce MPER-specific antibodies and cross-neutralizing antibodies when co-immunized with gp160 DNA. PLoS One 9: e113463. PMCID: 4267727.
Malherbe DC, Pissani F, Sather DN, Guo B, Pandey S, Sutton WF, Stuart AB, Robins H, Park B, Krebs SJ, Schuman JT, Kalams S, Hessell AJ, Haigwood NL. (2014) Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits. J Virology 88:12949-12967.
Hessell AJ, Malherbe DC, Pissani F, McBurney S, Krebs SJ, Gomes M, Pandey S, Sutton WF, Burwitz BJ, Gray M, Robins H, Park BS, Sacha JB, LaBranche CC, Fuller DH, Montefiori DC, Stamatatos L, Sather DN, Haigwood NL. (2016) Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens. J Immunol 196:3064-78. PMID: 26944928
Hessell AJ, Jaworski JP, Epson E, Matsuda K, Pandey S, Kahl C, Reed J, Sutton WF, Hammond KB, Cheever TA, Barnette PT, Legasse AW, Planer S, Stanton JJ, Pegu A, Chen X, Wang K, Siess D, Burke D, Park BS, Axthelm MK, Lewis A, Hirsch VM, Graham BS, Mascola JR, Sacha JB, Haigwood NL (2016) Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med. Mar 21. doi: 10.1038/nm.4063. PMID: 26998834