Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9.

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2011-11-23

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Abstract

Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.

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10.1038/nature10696

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McLellan, JS, M Pancera, C Carrico, J Gorman, JP Julien, R Khayat, R Louder, R Pejchal, et al. (2011). Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature, 480(7377). pp. 336–343. 10.1038/nature10696 Retrieved from https://hdl.handle.net/10161/13795.

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Scholars@Duke

Crump

John Andrew Crump

Adjunct Professor in the Department of Medicine

I am based in northern Tanzania where I am Site Leader for Duke University’s collaborative research program based at Kilimanjaro Christian Medical Centre and Director of Tanzania Operations for the Duke Global Health Institute. I oversee the design and implementation of research studies on infectious diseases, particularly febrile illness, invasive bacterial disease, HIV-associated opportunistic infections, clinical trials of antiretroviral therapy and prevention of mother-to-child transmission of HIV, and infectious diseases diagnostics. In addition, I am a medical epidemiologist with the US Centers for Disease Control and Prevention (CDC). My CDC work focuses on enteric infection epidemiology and prevention in developing countries, particularly invasive salmonelloses.

Haynes

Barton Ford Haynes

Frederic M. Hanes Distinguished Professor of Medicine

Barton F. Haynes, M.D. is the Frederic M. Hanes Professor of Medicine and Immunology, and Director of the Duke Human Vaccine Institute. Prior to leading the DHVI, Dr. Haynes served as Chief of the Division of Rheumatology, Allergy and Clinical Immunology, and later as Chair of the Department of Medicine. As Director of the Duke Human Vaccine Institute, Bart Haynes is leading a team of investigators working on vaccines for emerging infections, including tuberculosis, pandemic influenza, emerging coronaviruses, and HIV/AIDS.

To work on the AIDS vaccine problem, his group has been awarded two large consortium grants from the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) known as the Center for HIV/AIDS Vaccine Immunology (CHAVI) (2005-2012), and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) (2012-2019) to conduct discovery science to speed HIV vaccine development. In July 2019, his team received the third of NIH “CHAVI” awards to complete the HIV vaccine development work - CHAV-D.

Since the beginning of the COVID-19 pandemic, Haynes and the DHVI Team has been working non-stop to develop vaccines, rapid and inexpensive tests and therapeutics to combat the pandemic. Since March 2020, he has served as a member of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) committee to advise on COVID-19 vaccine development, and served as the co-chair of the ACTIV subcommittee on vaccine safety. Haynes is the winner of the Alexander Fleming Award from the Infectious Disease Society of America and the Ralph Steinman Award for Human Immunology Research from the American Association of Immunologists. He is a member of the National Academy of Medicine, National Academy of Inventors and the American Academy of Arts and Sciences.

About the Haynes Laboratory
The Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.

Mucosal Immune Responses in Acute HIV Infection

The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.

The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.

The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.

Immunogen Design

To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.

Mucosal Immune Responses in TB and Influenza

The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.

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