OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
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NAME: Per Johan Klasse
eRA COMMONS USER NAME (credential, e.g., agency login): PJKlasse
POSITION TITLE: Professor of Research in Microbiology and Immunology, Weill Cornell Medicine, Cornell University
INSTITUTION AND LOCATION DEGREE
FIELD OF STUDY
Lund University, Sweden MD 1986 Medicine
Lund University, Sweden PhD 1992 Virology
A. Personal Statement
After studying mathematics, I completed medical school at Lund University in Sweden, where I became passionately interested in virology. I worked for two years as a junior clinical virologist mainly in serological diagnosis of HIV-1 infections. After enrolling as a PhD student, I was privileged to be sent to the Pasteur Institute to learn HIV isolation techniques in Francoise Barré-Sinoussi’s and Luc Montagnier’s Laboratory. My first project was focused on the antigenicity of the gp41 subunit of the HIV-1 envelope glycoprotein (Env). While I was delineating the details of different epitopes in what is today known as the immunodominant epitope cluster I in gp41, Marvin Reitz, Marjorie Robert-Guroff, and Robert Gallo contacted us because they had found that a subtle mutation in that region made an HIV-1 clone resistant to neutralizing antibodies (NAbs) in sera from infected persons. Together we showed, first, that although the mutation abolished local binding by antibodies in patient sera, these antibodies did not neutralize the wild-type virus. Second, we demonstrated that the neutralizing capacity of antibodies directed to epitopes on the outer subunit of Env, gp120, and that overlapped the binding site of the CD4 receptor, was selectively reduced by the escape mutation in the other subunit, gp41 . Since then I have been deeply interested in protein-structural explanations for how such viral mutations can cause resistance to neutralizing antibodies; I have continued my focus on Env and its interactions with receptors and antibodies over the years.
During my postdoc as an EMBO Fellow in Robin Weiss’s laboratory at the Institute of Cancer Research, London, I collaborated with John Moore (who soon moved to New York). As an MRC Research Fellow in Mark Marsh’s group at the MRC Laboratory for Molecular Cell Biology, University College London, I studied Env interactions with chemokine receptors during HIV-1 entry. I became a lecturer at Imperial College and continued my studies on HIV-1 neutralization in close collaboration with Quentin Sattentau. Then, I was invited to join John Moore’s group and became a data analyst in a consortium (NIH U19 AI76982) studying microbicides based on HIV-1 entry inhibitors, particularly small-molecule chemokine-receptor inhibitors. As a project analyst I continued my studies on viral resistance to small CCR5 inhibitors (supported by R01 AI41420) (cf. my Perspective ). As a Co-Principal Investigator of R37 AI36082, I have in addition supervised postdoctoral fellows on projects aimed at improving the immunogenicity of HIV-1 Env, and measuring the affinity maturation of NAbs (e.g., ). I lead the Protein Production Core of our NIH-funded program project (P01 AI82362) on the structure-based design of HIV-1 Env immunogens to induce broadly active NAbs, and contribute through the design of experiments and the supply of trimer stocks within and outside our team. This work helped our colleagues at The Scripps Research Institute to obtain the first medium- to high-resolution crystallographic and cryo-electron-microscopic structures of soluble HIV-1 Env trimers. In addition, I have optimized the use of surface plasmon resonance (SPR) to differentiate NAb and non-NAb binding to trimeric Env and its components (for the latest example of sixteen studies in which we have applied SPR, see: ).
My passion for understanding HIV-1 neutralization continues; my hope is buoyed both by our evolving capacity to induce autologous NAbs against insensitive HIV-1 strains and by the recent clinical trials of NAbs. The former development challenges us to identify obstacles to a broadening of those NAb responses; the latter opens the possibility of combining NAbs that have complementary properties. That prospect makes it even more exciting to discover those key properties through the research outlined in this grant application.
1. Klasse PJ, McKeating JA, Schutten M, Reitz MS, Jr., Robert-Guroff M. 1993. An immune-selected point mutation in the transmembrane protein of human immunodeficiency virus type 1 (HXB2-Env:Ala 582(-->Thr)) decreases viral neutralization by monoclonal antibodies to the CD4-binding site. Virology 196, 332-7.
2. Klasse PJ. 2013. Structural biology. A new bundle of prospects for blocking HIV-1 entry. Science 341, 1347-8.
3. Alexander MR, Ringe R, Sanders RW, Voss JE, Moore JP, Klasse PJ. 2015. What do chaotrope-based avidity assays for antibodies to HIV-1 Envelope glycoproteins measure? J Virol 89, 5981-95. PMCID: PMC4442429.
4. Lee JH, Andrabi R, Su CY, Yasmeen A, Julien JP, Kong L, Wu NC, McBride R, Sok D, Pauthner M, Cottrell CA, Nieusma T, Blattner C, Paulson JC, Klasse PJ, Wilson IA, Burton DR, Ward AB. 2017. A broadly neutralizing antibody targets the dynamic HIV Envelope trimer apex via a long, rigidified, and anionic beta-hairpin structure. Immunity 46, 690-702. PMCID: PMC5400778.
I have authored or co-authored 111 peer-reviewed original research papers and 31 reviews in peer-reviewed journals, commentaries, or book chapters. I have edited one book: PJ Klasse The molecular basis of viral infection Prog Mol Biol Transl Sci 129 (Academic Press) 2015. According to the Google Scholar website my work has been cited 10,055 times (5,651 times since 2012) with an h-index of 56 and an i10-index of 113.
B. Positions and Honors
1993-1995 EMBO Fellow, The Institute of Cancer Research, Chester Beatty Laboratories, London.
1995-1999 MRC Research Fellow, MRC Laboratory for Molecular Cell Biology (LMCB),
University College London, London
2000-2003 Lecturer, Imperial College, London.
2003-2004 Senior Research Associate, Dept. of Microbiology and Immunology,
Weill Cornell Medical College, New York
2004-2006 Instructor, Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York
2006-2009 Assistant Professor, Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York
2009-2015 Associate Research Professor, Dept. of Microbiology and Immunology,
Weill Cornell Medical College, New York
2016- Professor of Research, Dept. of Microbiology and Immunology,
Weill Cornell Medicine, Cornell University, New York
1986 EMBL stipendiary to study protein expression, Heidelberg
1986 Selected for course led by Dr. Francoise Barré-Sinoussi in HIV isolation at the Pasteur Institute, Paris
1990 Scholarships from The Royal Physiographic Society and
The Knut and Alice Wallenberg Foundation
1992 Howard Hughes Travel Scholarship;
Honor Roll: Protein Purification, Cold Spring Harbor Laboratory
1993 EMBO Long-term Fellowship
1996 MRC Research Fellowship
2003 Invited plenary speaker on Virus Neutralization, WHO, Geneva
2007 Invited lecture at the Pasteur Institute, Paris
2008 Elected to write the entry on Virus Neutralization in The Encyclopedia of Virology (Elsevier) included, 2013, in Reference Module in Biomedical Sciences
(Elsevier BV, Editor-in-Chief Dr. Michael Caplan, Yale University)
2013 Talk at the International AIDS Vaccine Conference, Barcelona
C. Contribution to Science
Studies on HIV-1 neutralization. Which step in the viral life cycle NAbs block had long been debated for many viruses. Quentin Sattentau and I demonstrated that the mechanism of HIV-1 neutralization by antibodies to gp120 (but not to gp41) was a block of viral attachment to target cells . To explain observations in these and other studies, I developed a comprehensive mathematical model for neutralization sensitivity based on the number and functionality of Env trimers on the virion surface . This work contributed to a revised and unified view of virus neutralization by antibody known as the occupancy theory of neutralization, which implies simply that certain antibody concentrations and affinities for functional viral entry-mediating proteins are necessary and sufficient for neutralization . That is still a useful guiding principle in vaccine research. In a single-author paper I presented a comprehensive framework for stoichiometric modeling of HIV-1 Env function, which has been applied in our studies and later corroborated by other groups . I then took on the problem of synergy and designed experiments to generate a large set of data on combinations of NAbs and other inhibitors of HIV-1 entry. I identified flaws in standard methods for synergy analyses and developed algorithms based on non-linear modeling of inhibition, invoking target heterogeneity as an explanation for some apparent synergy and extending the analyses to cooperativity. These innovations are now finding applications in the study of neutralization breadth. All citation counts below are from Google Scholar:
5. Ugolini S, Mondor I, Parren PW, Burton DR, Tilley SA, Klasse PJ, Sattentau QJ. 1997. Inhibition of virus attachment to CD4+ target cells is a major mechanism of T cell line-adapted HIV-1 neutralization. J Exp Med 186, 1287-98. PMCID: PMC 2199094. Cited 125 times
6. Klasse PJ, Moore JP. 1996. Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1. J Virol 70, 3668-77. PMCID: PMC 190242. Cited 82 times
7. Klasse PJ, Sattentau QJ. 2002. Occupancy and mechanism in antibody-mediated neutralization of animal viruses. J Gen Virol 83, 2091-108. Cited 260 times
8. Klasse PJ. 2007. Modeling how many envelope glycoprotein trimers per virion participate in human immunodeficiency virus infectivity and its neutralization by antibody. Virology 369, 245-62. PMCID: PMC 2317823. Cited 72 times
Chemokine receptors and HIV entry. Together with Mark Marsh and Thue Schwartz, I determined the dual mechanism of how chemokines prevent HIV-1 and -2 infection, namely, both by blocking Env interactions with the chemokine receptors, mainly CCR5 and CXCR4, at the cell-surface, and by rapidly down-modulating these receptors. I designed and performed the infection-inhibition experiments and contributed to the cell-biological analyses in those studies in a multi-center teamwork. I also demonstrated that a synthetic small molecule, in contrast to the chemokines, blocks viral usage of CXCR4 without down-modulating the receptor . Such small organic ligands for CCR5 became my focus at Weill Cornell Medical College. In collaboration with Ronald Veazey, John Moore and I developed an in vivo macaque model of HIV-1 infection and its inhibition. I was responsible for quantitative and statistical analyses. In key studies (e.g., ) we showed that a small-molecule CCR5 inhibitor, when administered orally or topically, could prevent infection of macaques by a hybrid simian-HIV-1 virus. I contributed similarly to studies of the topical application of NAbs in this macaque model . Furthermore it was through my theoretical and mathematical model, invoking receptor heterogeneity, that the principal features of the resistance mechanism could be explained .
9. Signoret N, Oldridge J, Pelchen-Matthews A, Klasse PJ, Tran T, Brass LF, Rosenkilde MM, Schwartz TW, Holmes W, Dallas W, Luther MA, Wells TN, Hoxie JA, Marsh M. 1997. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J Cell Biol 139, 651-64. PMCID: PMC 2141706. Cited 391 times
10. Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP. 2005. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438, 99-102. Cited 334 times
11. Veazey RS, Shattock RJ, Pope M, Kirijan JC, Jones J, Hu Q, Ketas T, Marx PA, Klasse PJ, Burton DR, Moore JP. 2003. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 9, 343-6. Cited 493 times
12. Anastassopoulou CG, Ketas TJ, Klasse PJ, Moore JP. 2009. Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. Proc Natl Acad Sci U S A 106, 5318-23. PMCID: PMC 2664029. Cited 95 times
The binding of NAbs to neutralization-relevant epitopes on the native HIV-1 Env trimer. I developed surface plasmon resonance (SPR) as a technique for differentiating between NAb and non-NAb binding to native and non-native forms of Env, thereby explaining the activities of the antibodies against the virus . These approaches have been fruitful in 16 studies, mostly together with our colleagues in Amsterdam and at The Scripps Research Institute, complementing other techniques for elucidating the stoichiometry of antibody binding and uniquely revealing its kinetics (e.g., [14-16]).
13. Yasmeen A, Ringe R, Derking R, Cupo A, Julien JP, Burton DR, Ward AB, Wilson IA, Sanders RW, Moore JP, Klasse PJ. 2014. Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits. Retrovirology 11, 41. PMCID: PMC 4067080. Cited 77 times
14. de Taeye SW, Ozorowski G, Torrents de la Pena A, Guttman M, Julien JP, van den Kerkhof TL, Burger JA, Pritchard LK, Pugach P, Yasmeen A, Crampton J, Hu J, Bontjer I, Torres JL, Arendt H, DeStefano J, Koff WC, Schuitemaker H, Eggink D, Berkhout B, Dean H, LaBranche C, Crotty S, Crispin M, Montefiori DC, Klasse PJ, Lee KK, Moore JP, Wilson IA, Ward AB, Sanders RW. 2015. Immunogenicity of stabilized HIV-1 Envelope trimers with reduced exposure of non-neutralizing epitopes. Cell 163, 1702-15. PMCID: PMC PMC4732737. Cited 64 times
15. Ringe RP, Sanders RW, Yasmeen A, Kim HJ, Lee JH, Cupo A, Korzun J, Derking R, van Montfort T, Julien JP, Wilson IA, Klasse PJ, Ward AB, Moore JP. 2013. Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. Proc Natl Acad Sci U S A 110, 18256-61. PMCID: PMC 3831437. Cited 104 times
16. Sanders RW, Derking R, Cupo A, Julien JP, Yasmeen A, de Val N, Kim HJ, Blattner C, de la Pena AT, Korzun J, Golabek M, de Los Reyes K, Ketas TJ, van Gils MJ, King CR, Wilson IA, Ward AB, Klasse PJ, Moore JP. 2013. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog 9, e1003618. PMCID: PMC 3777863. Cited 266 times
Structural and immunogenicity studies of HIV-1 Env trimers. I collaborated with our colleagues at Scripps and in Amsterdam to design Env proteins that trimerize properly, expose NAb epitopes while hiding non-NAb epitopes, and do not aggregate . This work enabled our colleagues at Scripps to obtain the first medium- to high-resolution crystallographic and cryo-electron-microscopic structures of soluble HIV-1 Env trimers in complex with NAbs [18, 19]. Since these trimers have the requisite antigenic properties, we thought they might also induce neutralizing responses. Indeed, they soon became the first Env-trimer vaccine candidates to elicit autologous responses against resistant viral strains in animals. Combinations of trimers derived from different clades show promise in broadening the responses, a principal goal of HIV-1 vaccine research .
17. Klasse PJ, Depetris RS, Pejchal R, Julien JP, Khayat R, Lee JH, Marozsan AJ, Cupo A, Cocco N, Korzun J, Yasmeen A, Ward AB, Wilson IA, Sanders RW, Moore JP. 2013. Influences on trimerization and aggregation of soluble, cleaved HIV-1 SOSIP envelope glycoprotein. J Virol 87, 9873-85. PMCID: PMC 3754145. Cited 61 times
18. Julien JP, Cupo A, Sok D, Stanfield RL, Lyumkis D, Deller MC, Klasse PJ, Burton DR, Sanders RW, Moore JP, Ward AB, Wilson IA. 2013. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342, 1477-83. PMCID: PMC 3886632. Cited 476 times
19. Lyumkis D, Julien JP, de Val N, Cupo A, Potter CS, Klasse PJ, Burton DR, Sanders RW, Moore JP, Carragher B, Wilson IA, Ward AB. 2013. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342, 1484-90. PMCID: PMC 3954647. Cited 384 times
20. Klasse PJ, LaBranche CC, Ketas TJ, Ozorowski G, Cupo A, Pugach P, Ringe RP, Golabek M, van Gils MJ, Guttman M, Lee KK, Wilson IA, Butera ST, Ward AB, Montefiori DC, Sanders RW, Moore JP. 2016. Sequential and simultaneous immunization of rabbits with HIV-1 Envelope glycoprotein SOSIP.664 trimers from clades A, B and C. PLoS Pathog 12, e1005864. PMCID: PMC5023125. Cited 12 times since 2016.
Complete List of Published Work:
140 documents via the following link from NIH eRa Commons: https://www.scopus.com/authid/detail.uri?authorId=7003797817
Primary Affiliation: Weill Cornell Medicine, Cornell University - New York, NY , United States
Research Interests: HIV neutralization by antibodies