HIV Vaccine

HIV Vaccine

Overview

The development of a protective vaccine remains the most attractive option for halting the global spread of HIV. An ideal vaccine would be effective against a broad spectrum of diverse HIV strains. However, the sobering reality is that most current vaccine candidates usually elicit a weak or no response. A plausible solution may be to develop a vaccine platform that mimics the steps that protect in natural infection. In other words, to implicitly solve the challenges of vaccine development in a stepwise manner.

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Studies

The Binley group

A preventive vaccine would be the most cost-effective solution to halting the spread of HIV, the etiologic agent of AIDS. Dr. Binley’s lab is developing a vaccine that can induce HIV-fighting molecules in the blood, called neutralizing antibodies. For these antibodies to be effective, they must bind to the virus’ coat protein (a trimer of gp120/gp41) and thereby prevent the virus from infecting human cells. However, HIV cleverly displays decoy forms of its coat protein. The decoy proteins induce strong antibody responses that fail to kill the virus. This antibody response might also delay the appearance of neutralizing antibodies, thus allowing the virus to operate unchecked.

Dr. Binley’s group has developed HIV “virus-like particles” (VLPs) as a vaccine platform. Like infectious HIV-1 particles, these VLPs display both “native” gp120/gp41 trimers, as well as other decoy forms of the same coat protein, but are modified to render them non-infectious and safe. Recently, we found a way to eliminate decoy forms of the coat protein, resulting in “Trimer VLPs.” Tests have shown that Trimer VLPs can induce potent neutralizing antibodies. This marks an important step towards the long-term goal of developing a broadly protective VLP-based HIV vaccine.

In a parallel project, Dr. Binley is developing fluorescently labeled “Trimer VLPs” as tools to rescue broadly neutralizing antibodies from HIV-infected patient samples. These neutralizing antibodies develop naturally in about 20% of HIV-infected patients. Although they have little effect on established HIV infection, they are valuable as “blueprints” for the types of antibodies we would like to induce using a vaccine because they exhibit unusual potency and strength that might be useful to fight off an initial HIV exposure. However, these antibodies form only a tiny fraction of the total antibodies present in these patients, and so detecting them is like finding a needle in a haystack. We have designed Trimer VLPs to selectively label patients’ cells that produce these rare antibodies, thus facilitating their efficient rescue. In an exciting collaboration with researchers at the Vaccine Research Center at the NIH, we have been able to selectively recover several broadly neutralizing antibodies from HIV infected patients. These antibodies will be useful to help us develop vaccines that can induce similar antibodies.

The Verkoczy group

Difficulties in inducing broadly neutralizing antibodies (bnAbs) continue to hamper efforts towards developing an efficacious HIV vaccine. A critical roadblock has been the lack of practical animal models for tracking development of bnAb responses to HIV vaccination. “bnAb knock-in” mice engineered by the Verkoczy group and others to express rearranged or unrearranged V(D)J segments of bnAb precursors, are proving to be useful lead discovery platforms for identifying promising priming immunogens, vaccine approaches, and for conducting basic studies of humoral responses to a highly complex antigen: the HIV envelope. We are currently using a variety of immunization strategies in our models, that provide insights into the feasibility of eliciting neutralizing antibodies at distinct HIV envelope targets.

Select Publications

Crooks ET, Tong T, Chakrabarti B, Narayan K, Georgiev IS, Menis S, Huang X, Kulp D, Osawa K, Muranaka J, Stewart-Jones G, Destefano J, O’Dell S, LaBranche C, Robinson JE, Montefiori DC, McKee K, Du SX, Doria-Rose N, Kwong PD, Mascola JR, Zhu P, Schief WR, Wyatt RT, Whalen RG, Binley JM. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog. 2015 May 29;11(5):e1004932

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Cale EM, Doria-Rose NA, Tong T, Crooks ET, Nguyen R, Ambrozak DR, Perfetto SP, Roederer M, Binley JM, Mascola JR. Use of enzyme-digested virus-like particles as probes for flow cytometric sorting of HIV-specific neutralizing Ab-producing B-cells. AIDS Res Hum Retroviruses. 2014;30 Suppl 1:A20

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Tong T, Crooks ET, Osawa K, Robinson JE, Barnes M, Apetrei C, Binley JM. Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques. Virology. 2014;456–457:55–69.

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Tong T, Crooks ET, Osawa K, Binley JM. HIV-1 virus-like particles bearing pure env trimers expose neutralizing epitopes but occlude nonneutralizing epitopes. J Virol. 2012;86(7):3574–87.

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Crooks ET, Tong T, Osawa K, Binley JM. Enzyme digests eliminate nonfunctional Env from HIV-1 particle surfaces, leaving native Env trimers intact and viral infectivity unaffected. J Virol. 2011;85(12):5825–39.

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Crooks ET, Osawa K, Tong T, Grimley SL, Dai YD, Whalen RG, Kulp DW, Menis S, Schief WR, Binley JM. Effects of partially dismantling the CD4 binding site glycan fence of HIV-1 Envelope glycoprotein trimers on neutralizing antibody induction. Virology. 2017 505:193-209.

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Crooks ET, Grimley SL, Cully M, Osawa K, Dekkers G, Saunders K, Rӓmisch S, Menis S, Schief WR, Doria-Rose N, Haynes B, Murrell B, Cale EM, Pegu A, Mascola JR, Vidarsson G, Binley JB. Glycoengineering HIV-1 Env Creates ‘Supercharged’ and ‘Hybrid’ Glycans to Increase Neutralizing Antibody Potency, Breadth and Saturation. PLoS Pathog. 2018 In press.

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Cale EM, Gorman J, Radakovich NA, Crooks ET, Osawa K, Tong T, Li J, Nagarajan R, Ozorowski G, Ambrozak DR, Asokan M, Bailer RT, Bennici AK, Chen X, Doria-Rose NA, Druz A, Feng Y, Joyce MG, Louder MK, O’Dell S, Oliver C, Pancera M, Connors M, Hope TJ, Kepler TB, Wyatt RT, Ward AB, Georgiev IS, Kwong PD, Mascola JR, Binley JM. Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop. Immunity. 2017 46:777-791.

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Verkoczy L, Kelsoe G, Haynes BF. HIV-1 envelope gp41 broadly neutralizing antibodies: hurdles for vaccine development. PLoS Pathog. 2014 10:e1004073.

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Haynes BF, Verkoczy L. AIDS/HIV. Host controls of HIV neutralizing antibodies. Science. 2014 344:588-9.

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Verkoczy L. Humanized Immunoglobulin Mice: Models for HIV Vaccine Testing and Studying the Broadly Neutralizing Antibody Problem. Adv Immunol. 2017 134:235-352

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Williams WB, Zhang J, Jiang C, Nicely NI, Fera D, Luo K, Moody MA, Liao HX, Alam SM, Kepler TB, Ramesh A, Wiehe K, Holland JA, Bradley T, Vandergrift N, Saunders KO, Parks R, Foulger A, Xia SM, Bonsignori M, Montefiori DC, Louder M, Eaton A, Santra S, Scearce R, Sutherland L, Newman A, Bouton-Verville H, Bowman C, Bomze H, Gao F, Marshall DJ, Whitesides JF, Nie X, Kelsoe G, Reed SG, Fox CB, Clary K, Koutsoukos M, Franco D, Mascola JR, Harrison SC, Haynes BF, Verkoczy L. Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations. Nat Commun. 2017 8:1732.

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Zhang R, Verkoczy L, Wiehe K, Munir Alam S, Nicely NI, Santra S, Bradley T, Pemble CW 4th, Zhang J, Gao F, Montefiori DC, Bouton-Verville H, Kelsoe G, Larimore K, Greenberg PD, Parks R, Foulger A, Peel JN, Luo K, Lu X, Trama AM, Vandergrift N, Tomaras GD, Kepler TB, Moody MA, Liao HX, Haynes BF. Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages. Sci Transl Med. 2016 8:336ra62.

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Zhang J, Alam SM, Bouton-Verville H, Chen Y, Newman A, Stewart S, Jaeger FH, Montefiori DC, Dennison SM, Haynes BF, Verkoczy L. Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies. J Immunol. 2014 192:1693-706.

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Verkoczy L, Diaz M. Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function and induction by vaccination. Curr Opin HIV AIDS. 2014 9:224-34.

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