Susan Zolla-Pazner Explained

Susan Zolla-Pazner is an American research scientist who is a Professor of Medicine in the Division of Infectious Diseases and the Department of Microbiology at Mount Sinai School of Medicine and a guest investigator in the Laboratory of Molecular Immunology at The Rockefeller University,[1] both in New York City. Zolla-Pazner's work has focused on how the immune system responds to the human immunodeficiency virus (HIV) and, in particular, how antibodies against the viral envelope develop in the course of infection.

In 1981, Zolla-Pazner and other researchers initially described the immunologic abnormalities afflicting homosexual men in New York City who were dying from an unknown sickness.[2] In the years since, she has examined the body's immune response to the virus.[3] She is the co-inventor on 23 patents[4] and the author of more than 325 scientific publications.[5]

Research

Zolla-Pazner’s work helped establish the central role of antibodies in protection from HIV infection. She proposed quantifying the antibodies directed at the second and third variable loops (V2 and V3) of the HIV envelope protein gp120,[6] [7] [8] [9] [10] [11] [12] as observed in the Phase 3 RV144 clinical HIV vaccine trial, which involved 16,402 participants in Thailand.[13] Her research indicated that high levels of antibodies to the second variable region of the virus envelope protein, V2, correlated with a reduced rate of infection.[14] Antibodies to V3 were subsequently identified as an additional correlate of protection, exerting immune pressure on viruses infecting individuals who had received the vaccine.[15] Zolla-Pazner's research indicated that the search for an effective vaccine should focus not only on inducing specific types of antibodies but on eliciting a durable antibody response, as post-hoc analysis showed the levels of antibodies waned within 6 months of the last dose of the vaccine.[16] Her findings established the key role of antibodies specific for the virus envelope's variable regions in protection from HIV infection; they also validated her hypothesis that antibodies to variable regions could be protective—a highly controversial point until then.

In the early days of the AIDS epidemic, the Zolla-Pazner lab described the hyperactivation of B lymphocytes in the blood of HIV-infected individuals.[17] [18] [19] [20] This discovery led her to develop methods to generate anti-HIV human monoclonal antibodies (mAbs) from the blood cells of HIV-infected individuals.[21] Her lab isolated and described human mAbs capable of neutralizing the infectivity of the virus,[21] [22] and, later, isolated a mAb with strong neutralizing potency targeting a complex conformational region on the surface of the virus' envelope protein composed of V2 and V3.[23] [24] [25] [26] This was the first isolation and description of a family of antibodies known for their extreme potency in neutralizing HIV. Her lab also described how antibodies to V2 and V3 could bind and neutralize viruses from all over the globe, despite extreme variations in amino acid sequences.[27] [28] [29] [30] [31] [32] [33] [34] [35]

In 1981, Zolla-Pazner participated in the description of the immunologic abnormalities of patients presenting with Kaposi’s sarcoma, which was associated with the then-mysterious illness that later became known as AIDS.[36] She initiated systemic testing to enumerate CD4 and CD8 cells and antibodies in order to diagnose HIV infection and follow the effects of treatment with antiretroviral drugs. She was also responsible for the description of immunologic abnormalities in the first patients with AIDS-related Mycobacterium avium-intracellulare infections[37] and for identifying similar immunologic abnormalities in apparently healthy gay men who later developed AIDS.[38] This latter work was an early indication of the chilling reality that one-third of gay men in New York City were suffering from this fatal but as-yet-unidentified illness. In 1989, Zolla-Pazner became Director of AIDS Research at the Manhattan Veterans Administration Medical Center,[39] [40] part of the NYU School of Medicine,[41] [42] [43] where she was a member of the Department of Pathology[44] for 46 years. In 2015, Zolla-Pazner moved to Mount Sinai School of Medicine.

Building on her correlation of levels of V2 antibodies with reduced infection rates in the RV144 vaccine trial, Zolla-Pazner and her colleagues have spent the last 10 years developing “designer vaccines,” i.e., V2- and V3-scaffold proteins that focus the immune response on the production of antibodies specific for these two regions of gp120.[45] [46] Studies of these recombinant vaccine constructs in both rabbits and nonhuman primates have demonstrated that they induce antibodies that react with the envelopes of diverse viruses within the various subgroups of HIV and have biologic activities that have been associated with protection from infection.[47] [48]

Notes and References

  1. Web site: Mount Sinai Profiles. Mount Sinai.
  2. Web site: LaGuardia and Wagner Archives, Koch Oral History Collection- Koch Scholars interview, Dr. Michael Simberkoff_04-07-2015. April 7, 2015. La Guardia and Wagner Archives. 3. Koch Oral History Collection, Koch Scholars interview. 2017-03-31.
  3. News: Susan-Zolla Pazner is an antibody person. Miley. Marissa. 2012-10-15. AAAS - The World's Largest General Scientific Society. 2017-03-30. en.
  4. News: Wipo Publishes Patent of New York University School of Medicine, Timothy Cardozo, Kong Xiangpeng and Susan Zolla-Pazner for "Peptides Mimicking HIV-1 Viral Epitopes in the V2 Loop for the Gp120 Surface Envelope Glycoprotein" (American Inventors). https://web.archive.org/web/20181117175005/https://www.highbeam.com/doc/1P3-2925767211.html. dead. November 17, 2018. March 23, 2017. HighBeam Research. News Wire. US Fed News Service, Including US State New. March 25, 2013.
  5. Web site: Susan Zolla-Pazner - Google Scholar. scholar.google.com. 2017-04-19.
  6. Gorny. M. K.. Xu. J. Y.. Gianakakos. V.. Karwowska. S.. Williams. C.. Sheppard. H. W.. Hanson. C. V.. Zolla-Pazner. S.. 1991-04-15. Production of site-selected neutralizing human monoclonal antibodies against the third variable domain of the human immunodeficiency virus type 1 envelope glycoprotein. Proc Natl Acad Sci U S A. 88. 8. 3238–3242. 0027-8424. 51421. 2014246. 10.1073/pnas.88.8.3238. 1991PNAS...88.3238G. free.
  7. Gorny. MK. Moore. JP. Conley. A J. Karwowska. S. Sodroski. J. Williams. C. Burda. S. Boots. LJ. Zolla-Pazner. S. 1994-12-01. Human anti-V2 monoclonal antibody that neutralizes primary but not laboratory isolates of human immunodeficiency virus type 1. J Virol. 68. 12. 8312–8320. 10.1128/JVI.68.12.8312-8320.1994. 0022-538X. 237300. 7525987.
  8. Pinter. A. Honnen. WJ. He. Y. Gorny. MK. Zolla-Pazner. S. Kayman. SC. 2004-05-01. The V1/V2 domain of gp120 is a global regulator of the sensitivity of primary human immunodeficiency virus type 1 isolates to neutralization by antibodies commonly induced upon infection. J Virol. 78. 10. 5205–5215. 10.1128/JVI.78.10.5205-5215.2004. 0022-538X. 400352. 15113902.
  9. Burke. V. Williams. C. Sukumaran. M. Kim. S-S. Li. H. Wang. XH. Gorny. MK. Zolla-Pazner. S. Kong. X-P. 2009-11-11. Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: implications for design of V3-based immunogens. Structure. 17. 11. 1538–1546. 10.1016/j.str.2009.09.012. 1878-4186. 3683248. 19913488.
  10. Jiang. X. Burke. V. Totrov. M. Williams. C. Cardozo. T. Gorny. MK. Zolla-Pazner. S. Kong. X-P. Conserved structural elements in the V3 crown of HIV-1 gp120. Nat Struct Mol Biol. 17. 8. 955–961. 10.1038/nsmb.1861. 20622876. 2010. 23441848. free.
  11. Pan. R. Gorny. MK. Zolla-Pazner. S. Kong. X-P. 2015-08-01. The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel. J Virol. en. 89. 15. 8003–8010. 10.1128/JVI.00754-15. 0022-538X. 4505664. 26018158.
  12. Zolla-Pazner. S. Cohen. SS. Boyd. D. Kong. X-P. Seaman. M. Nussenzweig. M. Klein. F. Overbaugh. J. Totrov. M. 2015-10-21. Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity. J Virol. 90. 2. 636–649. 10.1128/JVI.01645-15. 1098-5514. 4702699. 26491157.
  13. Rerks-Ngarm. S. Pitisuttithum. P. Nitayaphan. S. Kaewkungwal. J. Chiu. J. Paris. R. Premsri. N. Namwat. C. de Souza. M. 2009-12-03. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N Engl J Med. 361. 23. 2209–2220. 10.1056/NEJMoa0908492. 0028-4793. 19843557. 4356367. free.
  14. Haynes. Barton F.. Gilbert. Peter B.. McElrath. M. Juliana. Zolla-Pazner. Susan. Tomaras. Georgia D.. Alam. S. Munir. Evans. David T.. Montefiori. David C.. Karnasuta. Chitraporn. 2012. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. The New England Journal of Medicine. 366. 14. 1275–1286. 10.1056/NEJMoa1113425. 1533-4406. 3371689. 22475592.
  15. Gottardo. Raphael. Bailer. Robert T.. Korber. Bette T.. Gnanakaran. S.. Phillips. Joshua. Shen. Xiaoying. Tomaras. Georgia D.. Turk. Ellen. Imholte. Gregory. Eckler. Larry. Wenschuh. Holger. Zerweck. Johannes. Greene. Kelli. Gao. Hongmei. Berman. Phillip W.. Francis. Donald. Sinangil. Faruk. Lee. Carter. Nitayaphan. Sorachai. Rerks-Ngarm. Supachai. Kaewkungwal. Jaranit. Pitisuttithum. Punnee. Tartaglia. James. Robb. Merlin L.. Michael. Nelson L.. Kim. Jerome H.. Zolla-Pazner. Susan. Haynes. Barton F.. John R. Mascola . Mascola. John R.. Self. Steve. Gilbert. Peter. Montefiori. David C.. 2013. Plasma IgG to linear epitopes in the V2 and V3 regions of HIV-1 gp120 correlate with a reduced risk of infection in the RV144 vaccine efficacy trial. PLOS ONE. 8. 9. e75665. 10.1371/journal.pone.0075665. 1932-6203. 3784573. 24086607. 2013PLoSO...875665G. free.
  16. Karasavvas. N. Billings. E. Rao. M. Williams. C. Zolla-Pazner. S. Bailer. RT. Koup. RA. Madnote. S. Arworn. D. 2012-11-01. The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AIDS Res Hum Retroviruses. 28. 11. 1444–1457. 10.1089/aid.2012.0103. 1931-8405. 3484815. 23035746.
  17. Book: The possible pathogenic role of hyperactive B lymphocytes in AIDS. A Friedman Kien Masson Publications. 1983. Zolla-Pazner. Susan. New York, NY. Sidhu. G.
  18. Mizuma. H.. Zolla-Pazner. S.. Litwin. S.. el-Sadr. W.. Sharpe. S.. Zehr. B.. Weiss. S.. Saxinger. W. C.. Marmor. M.. 1987-04-01. Serum IgD elevation is an early marker of B cell activation during infection with the human immunodeficiency viruses. Clinical and Experimental Immunology. 68. 1. 5–14. 0009-9104. 1542677. 3498566.
  19. Mizuma. H.. Litwin. S.. Zolla-Pazner. S.. 1988-03-01. B-cell activation in HIV infection: relationship of spontaneous immunoglobulin secretion to various immunological parameters. Clinical and Experimental Immunology. 71. 3. 410–416. 0009-9104. 1541680. 3260155.
  20. Edelman. A. S.. Zolla-Pazner. S.. 1989-01-01. AIDS: a syndrome of immune dysregulation, dysfunction, and deficiency. FASEB Journal. 3. 1. 22–30. 0892-6638. 2562947. 10.1096/fasebj.3.1.2562947. free . 21021109.
  21. Gorny. M. K.. Gianakakos. V.. Sharpe. S.. Zolla-Pazner. S.. 1989-03-01. Generation of human monoclonal antibodies to human immunodeficiency virus. Proceedings of the National Academy of Sciences of the United States of America. 86. 5. 1624–1628. 0027-8424. 286751. 2922401. 10.1073/pnas.86.5.1624. 1989PNAS...86.1624G. free.
  22. Conley. A. J.. Gorny. M. K.. Kessler. J. A.. Boots. L. J.. Ossorio-Castro. M.. Koenig. S.. Lineberger. D. W.. Emini. E. A.. Williams. C. Zolla-Pazner. S. 1994. Neutralization of primary human immunodeficiency virus type 1 isolates by the broadly reactive anti-V3 monoclonal antibody, 447-52D. Journal of Virology. 68. 11. 6994–7000. 10.1128/JVI.68.11.6994-7000.1994. 0022-538X. 237136. 7933081.
  23. Gorny. Miroslaw K.. Stamatatos. Leonidas. Volsky. Barbara. Revesz. Kathy. Williams. Constance. Wang. Xiao-Hong. Cohen. Sandra. Staudinger. Robert. Zolla-Pazner. Susan. 2005-04-01. Identification of a new quaternary neutralizing epitope on human immunodeficiency virus type 1 virus particles. Journal of Virology. 79. 8. 5232–5237. 10.1128/JVI.79.8.5232-5237.2005. 0022-538X. 1069558. 15795308.
  24. Honnen. W. J.. Krachmarov. C.. Kayman. S. C.. Gorny. M. K.. Zolla-Pazner. S.. Pinter. A.. February 1, 2001. Type-specific epitopes targeted by monoclonal antibodies with exceptionally potent neutralizing activities for selected strains of human immunodeficiency virus type 1 map to a common region of the V2 domain of gp120 and differ only at single positions from the clade B consensus sequence. 17121806. J Virol. 81. 3. 1424–1432. 10.1128/JVI.02054-06. 0022-538X. 1797533.
  25. Changela. Anita. Wu. Xueling. Yang. Yongping. Zhang. Baoshan. Zhu. Jiang. Nardone. Glenn A.. O'Dell. Sijy. Pancera. Marie. Gorny. Miroslaw K. 2011-03-01. Crystal structure of human antibody 2909 reveals conserved features of quaternary structure-specific antibodies that potently neutralize HIV-1. Journal of Virology. 85. 6. 2524–2535. 10.1128/JVI.02335-10. 1098-5514. 067962. 21191009. Zolla-Pazner. S. Mascola. JR. Kwong. PD.
  26. Wu. Xueling. Changela. Anita. O'Dell. Sijy. Schmidt. Stephen D.. Pancera. Marie. Yang. Yongping. Zhang. Baoshan. Gorny. Miroslaw K.. Phogat. Sanjay. Robinson. James E.. Stamatatos. Leonidas. Zolla-Pazner. Susan. Kwong. Peter D.. Mascola. John R.. 2011-05-01. Immunotypes of a Quaternary Site of HIV-1 Vulnerability and Their Recognition by Antibodies. Journal of Virology. en. 85. 9. 4578–4585. 10.1128/JVI.02585-10. 0022-538X. 3126226. 21325411.
  27. Gorny. M. K.. VanCott. T. C.. Hioe. C.. Israel. Z. R.. Michael. N. L.. Conley. A. J.. Williams. C.. Kessler. J. A.. Chigurupati. P.. 1997-11-15. Human monoclonal antibodies to the V3 loop of HIV-1 with intra- and interclade cross-reactivity. Journal of Immunology. 159. 10. 5114–5122. 0022-1767. 9366441. Burda. S.. Zolla-Pazner. S.. 10.4049/jimmunol.159.10.5114 . 20610847 . free.
  28. Gorny. M. K.. Mascola. J. R.. Israel. Z. R.. VanCott. T. C.. Williams. C.. Balfe. P.. Hioe. C.. Brodine. S.. Burda. S.. 1998-02-10. A human monoclonal antibody specific for the V3 loop of HIV type 1 clade E cross-reacts with other HIV type 1 clades. AIDS Research and Human Retroviruses. 14. 3. 213–221. 10.1089/aid.1998.14.213. 0889-2229. 9491911. Zolla-Pazner. S..
  29. Nyambi. P. N.. Gorny. M. K.. Bastiani. L.. van der Groen. G.. Williams. C.. Zolla-Pazner. S.. 1998-11-01. Mapping of epitopes exposed on intact human immunodeficiency virus type 1 (HIV-1) virions: a new strategy for studying the immunologic relatedness of HIV-1. Journal of Virology. 72. 11. 9384–9391. 10.1128/JVI.72.11.9384-9391.1998. 0022-538X. 110366. 9765494.
  30. Nyambi. P. N.. Mbah. H. A.. Burda. S.. Williams. C.. Gorny. M. K.. Nádas. A.. Zolla-Pazner. S.. 2000-08-01. Conserved and exposed epitopes on intact, native, primary human immunodeficiency virus type 1 virions of group M. Journal of Virology. 74. 15. 7096–7107. 0022-538X. 112228. 10888650. 10.1128/JVI.74.15.7096-7107.2000.
  31. Gorny. MK. Williams. C. Volsky. B. Revesz. K. Cohen. S. Polonis. Victoria R.. Honnen. WJ. Kayman. SC. Krachmarov. C. 2002-09-01. Human monoclonal antibodies specific for conformation-sensitive epitopes of V3 neutralize human immunodeficiency virus type 1 primary isolates from various clades. Journal of Virology. 76. 18. 9035–9045. 10.1128/JVI.76.18.9035-9045.2002. 0022-538X. 136433. 12186887. Pinter. A. Zolla-Pazner. S.
  32. Gorny. Miroslaw K.. Williams. Constance. Volsky. Barbara. Revesz. Kathy. Wang. Xiao-Hong. Burda. Sherri. Kimura. Tetsuya. Konings. Frank A. J.. Nádas. Arthur. 2006-07-01. Cross-clade neutralizing activity of human anti-V3 monoclonal antibodies derived from the cells of individuals infected with non-B clades of human immunodeficiency virus type 1. Journal of Virology. 80. 14. 6865–6872. 10.1128/JVI.02202-05. 0022-538X. 1489067. 16809292. Anyangwe. CA. Nyambi. P. Krachmarov. C. Pinter. A. Zolla-Pazner. S.
  33. Hioe. Catarina E.. Wrin. Terri. Seaman. Michael S.. Yu. Xuesong. Wood. Blake. Self. Steve. Williams. Constance. Gorny. Miroslaw K.. Zolla-Pazner. Susan. 2010-04-21. Anti-V3 monoclonal antibodies display broad neutralizing activities against multiple HIV-1 subtypes. PLOS ONE. 5. 4. e10254. 10.1371/journal.pone.0010254. 1932-6203. 2858080. 20421997. 2010PLoSO...510254H. free.
  34. Gorny. Miroslaw K.. Pan. Ruimin. Williams. Constance. Wang. Xiao-Hong. Volsky. Barbara. O'Neal. Timothy. Spurrier. Brett. Sampson. Jared M.. Li. Liuzhe. 2012-06-05. Functional and immunochemical cross-reactivity of V2-specific monoclonal antibodies from HIV-1-infected individuals. Virology. 427. 2. 198–207. 10.1016/j.virol.2012.02.003. 1096-0341. 3572902. 22402248. Kong. XP. Zolla-Pazner. Susan.
  35. deCamp. Allan. Hraber. Peter. Bailer. Robert T.. Seaman. Michael S.. Ochsenbauer. Christina. Kappes. John. Gottardo. Raphael. Edlefsen. Paul. Self. Steve. 2014-03-01. Global panel of HIV-1 Env reference strains for standardized assessments of vaccine-elicited neutralizing antibodies. Journal of Virology. 88. 5. 2489–2507. 10.1128/JVI.02853-13. 1098-5514. 3958090. 24352443. Tang. H. Greene. K. Gao. H. Daniell. X. Sarzotti-Kelsoe. M. Gorny. MK. Zolla-Pazner. S. LaBranche. CC. Mascola. JR. Korber. BT. Montefiori. CD.
  36. Friedman-Kien. A. E.. Laubenstein. L. J.. Rubinstein. P.. Buimovici-Klein. E.. Marmor. M.. Stahl. R.. Spigland. I.. Kim. K. S.. Zolla-Pazner. S.. 1982-06-01. Disseminated Kaposi's sarcoma in homosexual men. Annals of Internal Medicine. 96. 6 Pt 1. 693–700. 0003-4819. 6283973. 10.7326/0003-4819-96-6-693.
  37. Greene. J. B.. Sidhu. G. S.. Lewin. S.. Levine. J. F.. Masur. H.. Simberkoff. M. S.. Nicholas. P.. Good. R. C.. Zolla-Pazner. S. B.. 1982-10-01. Mycobacterium avium-intracellulare: a cause of disseminated life-threatening infection in homosexuals and drug abusers. Annals of Internal Medicine. 97. 4. 539–546. 0003-4819. 6289714. 10.7326/0003-4819-97-4-539.
  38. Stahl. R. E.. Friedman-Kien. A.. Dubin. R.. Marmor. M.. Zolla-Pazner. S.. 1982-08-01. Immunologic abnormalities in homosexual men. Relationship to Kaposi's sarcoma. The American Journal of Medicine. 73. 2. 171–178. 0002-9343. 7114072. 10.1016/0002-9343(82)90174-7.
  39. Web site: VA NY Harbor Health Care System. System. VA NY Harbor Healthcare. www.nyharbor.va.gov. en. 2017-05-09.
  40. Web site: Employee Profile of Susan B. Zolla-Pazner — Microbiologist. www.federalpay.org. en. 2017-05-09.
  41. Nature.com. March 2004. Nature Reviews Immunology. 4. 3. 199–210. 10.1038/nri1307. 15039757. Zolla-Pazner. Susan. 7097025.
  42. News: A Collective Effort to Save Decades of Research as the Water Tose. Carey. Benedict. November 5, 2012. The New York Times. March 23, 2017.
  43. News: VA-NYU scientist leads $8.4-million effort toward AIDS vaccine. September 2006. VA Research Currents. March 23, 2017.
  44. News: Susan-Zolla Pazner is an antibody person. 2016-06-10. AAAS - The World's Largest General Scientific Society. 2017-03-23. en.
  45. Totrov. Maxim. Jiang. Xunqing. Kong. Xiang-Peng. Cohen. Sandra. Krachmarov. Chavdar. Salomon. Aidy. Williams. Constance. Seaman. Michael S.. Abagyan. Ruben. Cardozo. T. Gorny. MK. Wang. S. Lu. S. Pinter. A. Zolla-Pazner. S. 2010-09-30. Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold. Virology. 405. 2. 513–523. 10.1016/j.virol.2010.06.027. 1096-0341. 2942080. 20663531.
  46. Spurrier. Brett. Sampson. Jared M.. Totrov. Maxim. Li. Huiguang. O'Neal. Timothy. Williams. Constance. Robinson. James. Gorny. Miroslaw K.. Zolla-Pazner. Susan. 2011-05-11. Structural analysis of human and macaque mAbs 2909 and 2.5B: implications for the configuration of the quaternary neutralizing epitope of HIV-1 gp120. Structure. 19. 5. 691–699. 10.1016/j.str.2011.02.012. 1878-4186. 3096878. 21565703.
  47. Zolla-Pazner. Susan. Kong. X.-P.. Jiang. Xunqing. Cardozo. Timothy. Nádas. Arthur. Cohen. Sandra. Totrov. Maxim. Seaman. Michael S.. Wang. Shixia. 2011-10-01. Cross-clade HIV-1 neutralizing antibodies induced with V3-scaffold protein immunogens following priming with gp120 DNA. Journal of Virology. 85. 19. 9887–9898. 10.1128/JVI.05086-11. 1098-5514. 3196418. 21795338.
  48. Zolla-Pazner. Susan. Powell. Rebecca. Yahyaei. Sara. Williams. Constance. Jiang. Xunqing. Li. Wei. Lu. Shan. Wang. Shixia. Upadhyay. Chitra. 2016-12-15. Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response. Journal of Virology. 90. 24. 10993–11006. 10.1128/JVI.01403-16. 1098-5514. 5126359. 27630234.

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