EMERGING INFECTIOUS DISEASES
We use human monoclonal antibodies (MAbs) in functional and structural studies to understand mechanisms of viral entry, identify target epitopes that provide broad-spectrum protection and develop strategies that prevent viruses from undergoing neutralization escape. Our discoveries of highly conserved structural elements on the envelope glycoproteins of several virus families that serve as cross-neutralizing targets for Mab therapy has allowed us to make therapeutic inroads into the prevention and treatment of a wide range of human pathogenic viruses.
The Marasco Laboratory has also contributed to major advances in three areas of therapeutic Mab development through NIH-NIAID product development programs in Influenza A, Severe Acquired Respiratory Syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), West Nile virus (WNV) and HIV-1/AIDS infections. We are also actively involved in Biodefense programs and in the discovery of emerging human pathogens.
The Marasco Laboratory has also contributed to major advances in three areas of therapeutic Mab development through NIH-NIAID product development programs in Influenza A, Severe Acquired Respiratory Syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), West Nile virus (WNV) and HIV-1/AIDS infections. We are also actively involved in Biodefense programs and in the discovery of emerging human pathogens.
Influenza
We have identified a highly conserved epitope in the hemagglutinin (HA) stem of Group 1 and 2 human Influenza A viruses and a panel of broad-spectrum neutralizing human antibodies (BnAbs) against this epitope. Our finding of a “universal” vaccine target that can provide broad-spectrum protection against a wide range of influenza A viruses has lead to a paradigm shift in the field of influenza immunotherapy and vaccine development. We have several active discovery programs in this area of investigation.
We have also made important discoveries related to biased VH germline gene usage. For instance anti-influenza HA stem-directed sBnAb are often encoded by rearranged IGHV1-69 germline genes that alone make contact with HA and prevent virus entry and emergence of escape mutants. In our most recent study, we investigated what structural requirements enable a rearranged IGHV1-69 Ab to become a potent cross-neutralizing antibody. We found that in addition to a critical amino acid triad consisting of a pair of anchor residues in CDR-H2 and a properly positioned CDR-H3 Tyr, distinctive VH-segment substitutions that arise in positions that are distinct from phase I activation-induced cytosine deaminase (AID) somatic hypermutation (SHM) hotspot motifs are often required. As few as two V-segment SHM can fulfill this role which appears to facilitate the optimal binding of CDR-H2 Phe54 and CHR-H3-Tyr into adjacent hydrophobic pockets in the HA stem. These studies provide new information on the SHM requirements for IGHV1-69-encoded B cells to produce IGHV1-69 encoded sBnAbs and suggest that there may exist alternative routes to their elicitation by vaccination.
Fu Y, Zhang Z, Sheehan J, Avnir Y, Ridenour C, Sachnik T, Sun J, Hossain MJ, Chen LM, Zhu Q, Donis RO, Marasco WA. A broadly neutralizing anti-influenza antibody reveals ongoing capacity of hemagglutinin-specific memory B cells to evolve. Nat Commun. 2016 Sep 13;7:12780. doi: 10.1038/ncomms12780. PMID: 27619409. PMCID: PMC5027281.
Avnir Y, Watson CT, Glanville J, Peterson EC, Tallarico AS, Bennett AS, Qin K, Fu Y, Huang CY, Beigel JH, Breden F, Zhu Q, Marasco WA. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. Sci Rep. 2016 Feb 16;6:20842. PMID: 26880249. PMCID: PMC4754645.
Avnir Y, Tallarico AS, Zhu Q, Bennett AS, Connelly G, Sheehan J, Sui J, Fahmy A, Huang CY, Cadwell G, Bankston LA, McGuire AT, Stamatatos L, Wagner G, Liddington RC, Marasco WA. Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog. 2014 May 1;10(5):e1004103. eCollection 2014 May. PMID: 24788925. PMCID: PMC4006906.
Han T, Sui J, Bennett AS, Liddington RC, Donis RO, Zhu Q, Marasco WA. Fine epitope mapping of monoclonal antibodies against hemagglutinin of a highly pathogenic H5N1 influenza virus using yeast surface display. Biochem Biophys Res Commun. 2011 Jun 3;409(2):253-9. Epub 2011 May 5. PMID: 21569761. PMCID: PMC3119598.
Sui J, Sheehan J, Hwang WC, Bankston, LA, Burchett SK, Huang CY, Liddington R, Beigel JH, Marasco WA. Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza A antibodies. Clin Infect Dis. 2011 Apr 15;52(8):1003-9. PMID: 21460314. PMCID: PMC3070035.
Han T, Marasco, WA. Structural basis of influenza virus neutralization. Ann N Y Acad Sci. 2011 Jan;1217:178-90. Epub 2011 Jan 11. PMID: 21251008. PMCID: PMC3062959.
Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O’Donnell CD, Yewdell J, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med. 2011 Jan 17;208(1):181-93. Epub 2011 Jan 10. Erratum in: J Exp Med. 2011 Feb 14;208(2):411. PMID: 21220454. PMCID: PMC3023136.
Hashem AM, Van Domselaar G, Li C, Wang J, She YM, Cyr TD, Sui J, He R, Marasco WA, Li X. Universal antibodies against the highly conserved influenza fusion peptide cross-neutralize several subtypes of influenza A virus. Biochem Biophys Res Commun. 2010 Dec 10; 403(2):247-51. Epub 2010 Nov 13. PMID: 21078301.
Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009 Mar; 16(3):265-73. Epub 2009 Feb 22. PMID: 19234466. PMCID: PMC2692245.
Huang IC, Li W, Sui J, Marasco WA, Choe H, Farzan M. Influenza A virus neuraminidase limits viral superinfection. J Virol. 2008 May;82(10):4834-43. PMID: 18321971. PMCID: PMC2346733.
We have also made important discoveries related to biased VH germline gene usage. For instance anti-influenza HA stem-directed sBnAb are often encoded by rearranged IGHV1-69 germline genes that alone make contact with HA and prevent virus entry and emergence of escape mutants. In our most recent study, we investigated what structural requirements enable a rearranged IGHV1-69 Ab to become a potent cross-neutralizing antibody. We found that in addition to a critical amino acid triad consisting of a pair of anchor residues in CDR-H2 and a properly positioned CDR-H3 Tyr, distinctive VH-segment substitutions that arise in positions that are distinct from phase I activation-induced cytosine deaminase (AID) somatic hypermutation (SHM) hotspot motifs are often required. As few as two V-segment SHM can fulfill this role which appears to facilitate the optimal binding of CDR-H2 Phe54 and CHR-H3-Tyr into adjacent hydrophobic pockets in the HA stem. These studies provide new information on the SHM requirements for IGHV1-69-encoded B cells to produce IGHV1-69 encoded sBnAbs and suggest that there may exist alternative routes to their elicitation by vaccination.
Fu Y, Zhang Z, Sheehan J, Avnir Y, Ridenour C, Sachnik T, Sun J, Hossain MJ, Chen LM, Zhu Q, Donis RO, Marasco WA. A broadly neutralizing anti-influenza antibody reveals ongoing capacity of hemagglutinin-specific memory B cells to evolve. Nat Commun. 2016 Sep 13;7:12780. doi: 10.1038/ncomms12780. PMID: 27619409. PMCID: PMC5027281.
Avnir Y, Watson CT, Glanville J, Peterson EC, Tallarico AS, Bennett AS, Qin K, Fu Y, Huang CY, Beigel JH, Breden F, Zhu Q, Marasco WA. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. Sci Rep. 2016 Feb 16;6:20842. PMID: 26880249. PMCID: PMC4754645.
Avnir Y, Tallarico AS, Zhu Q, Bennett AS, Connelly G, Sheehan J, Sui J, Fahmy A, Huang CY, Cadwell G, Bankston LA, McGuire AT, Stamatatos L, Wagner G, Liddington RC, Marasco WA. Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog. 2014 May 1;10(5):e1004103. eCollection 2014 May. PMID: 24788925. PMCID: PMC4006906.
Han T, Sui J, Bennett AS, Liddington RC, Donis RO, Zhu Q, Marasco WA. Fine epitope mapping of monoclonal antibodies against hemagglutinin of a highly pathogenic H5N1 influenza virus using yeast surface display. Biochem Biophys Res Commun. 2011 Jun 3;409(2):253-9. Epub 2011 May 5. PMID: 21569761. PMCID: PMC3119598.
Sui J, Sheehan J, Hwang WC, Bankston, LA, Burchett SK, Huang CY, Liddington R, Beigel JH, Marasco WA. Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza A antibodies. Clin Infect Dis. 2011 Apr 15;52(8):1003-9. PMID: 21460314. PMCID: PMC3070035.
Han T, Marasco, WA. Structural basis of influenza virus neutralization. Ann N Y Acad Sci. 2011 Jan;1217:178-90. Epub 2011 Jan 11. PMID: 21251008. PMCID: PMC3062959.
Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O’Donnell CD, Yewdell J, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med. 2011 Jan 17;208(1):181-93. Epub 2011 Jan 10. Erratum in: J Exp Med. 2011 Feb 14;208(2):411. PMID: 21220454. PMCID: PMC3023136.
Hashem AM, Van Domselaar G, Li C, Wang J, She YM, Cyr TD, Sui J, He R, Marasco WA, Li X. Universal antibodies against the highly conserved influenza fusion peptide cross-neutralize several subtypes of influenza A virus. Biochem Biophys Res Commun. 2010 Dec 10; 403(2):247-51. Epub 2010 Nov 13. PMID: 21078301.
Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009 Mar; 16(3):265-73. Epub 2009 Feb 22. PMID: 19234466. PMCID: PMC2692245.
Huang IC, Li W, Sui J, Marasco WA, Choe H, Farzan M. Influenza A virus neuraminidase limits viral superinfection. J Virol. 2008 May;82(10):4834-43. PMID: 18321971. PMCID: PMC2346733.
Middle East Respiratory Syndrome (MERS-CoV)
MERS-CoV was first isolated in the Arabian Peninsula in 2012. Similar to the SARS-CoV, MERS-CoV causes severe respiratory tract infection, often in the lower respiratory tract, occasionally accompanied by renal disease and has shown a death rate of around 42%. We are the first laboratory to report on human neutralizing antibodies (nAbs) against the MERS-CoV. Using a well-characterized nonimmune human Ab-phage library and an unique panning strategy with proteoliposomes and cells immobilized Spike protein, we identify seven human nAbs with subnanomolar/nanomolar binding affinities that block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Binding competition and escape mutant assays indicated that these seven nAbs recognize at least three different epitopes at the receptor binding domain (RBD)-hDPP4 interface. The study of viral evolution under Ab mediated immune pressure indicated that these nAbs can restrict MERS-CoV evolution by driving virus down an escape pathway that predominantly results in a significant cost in viral fitness. These human nAbs might serve as a potent ingredient in a therapeutic antibody cocktail that could be used for the prophylaxis and treatment of MERS. In addition, our studies suggest that the vulnerable spike protein-cellular receptor interface is a preferred target for protective vaccines.
Johnson RF, Bagci U, Keith L, Tang X, Mollura DJ, Zeitlin L, Qin J, Huzella L, Bartos CJ, Bohorova N, Bohorov O, Goodman C, Kim do H, Paulty MH, Velasco J, Whaley KJ, Johnson JC, Pettitt J, Ork BL, Solomon J, Oberlander N, Zhu Q, Sun J, Holbrook MR, Olinger GG, Baric RS, Hensley LE, Jahrling PB, Marasco WA. 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012. Virology. 2016 Mar;490:49-58. Epub 2016 Jan 30. PMID: 26828465. PMCID: PMC4769911.
Tang XC, Marasco WA. Human neutralizing antibodies against MERS coronavirus: implications for future immunotherapy. Immunotherapy. 2015;7(6):591-4. Epub 2015 Jun 22. PMID: 26098703.
Tang XC, Agnihothram SS, Jiao Y, Stanhope J, Graham RL, Peterson EC, Avnir Y, Tallarico AS, Sheehan J, Zhu Q, Baric RS, Marasco WA. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc Natl Acad Sci U S A. 2014 May 13;111(19):E2018-26. Epub 2014 Apr 28. PMID: 24778221. PMCID: PMC4024880.
Johnson RF, Bagci U, Keith L, Tang X, Mollura DJ, Zeitlin L, Qin J, Huzella L, Bartos CJ, Bohorova N, Bohorov O, Goodman C, Kim do H, Paulty MH, Velasco J, Whaley KJ, Johnson JC, Pettitt J, Ork BL, Solomon J, Oberlander N, Zhu Q, Sun J, Holbrook MR, Olinger GG, Baric RS, Hensley LE, Jahrling PB, Marasco WA. 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012. Virology. 2016 Mar;490:49-58. Epub 2016 Jan 30. PMID: 26828465. PMCID: PMC4769911.
Tang XC, Marasco WA. Human neutralizing antibodies against MERS coronavirus: implications for future immunotherapy. Immunotherapy. 2015;7(6):591-4. Epub 2015 Jun 22. PMID: 26098703.
Tang XC, Agnihothram SS, Jiao Y, Stanhope J, Graham RL, Peterson EC, Avnir Y, Tallarico AS, Sheehan J, Zhu Q, Baric RS, Marasco WA. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc Natl Acad Sci U S A. 2014 May 13;111(19):E2018-26. Epub 2014 Apr 28. PMID: 24778221. PMCID: PMC4024880.
SARS and Other Emerging Coronoaviruses (CoVs)
We were the first laboratory to report on broadly neutralizing human antibodies against the SARS-CoVs that caused a worldwide outbreak in 2003-2004. While we have not seen a repeat of this zoonotic transfer from animals to humans, we have discovered that a large reservoir of CoVs are circulating in bats globally. We have several active discovery programs in this area, including identification of BnAbs against a wide range of human and bat CoVs, the discovery of novel bat-CoV receptors and characterization of the bat antibodyome.
Chang MR, Ke H, Coherd CD, Wang Y, Mashima K, Kastrunes GM, Huang CY, Marasco WA. Analysis of a SARS-CoV-2 convalescent cohort identified a common strategy for escape of vaccine-induced anti-RBD antibodies by Beta and Omicron variants. EBioMedicine. 2022 May 6;80:104025. PMID: 35533497; PMCID: PMC9073271.
Menachery VD, Yount BL Jr, Sims AC, Debbink K, Agnihothram SS, Gralinski LE, Graham RL, Scobey T, Plante JA, Royal SR, Swanstrom J, Sheahan TP, Pickles RJ, Corti D, Randell SH, Lanzavecchia A, Marasco WA, Baric RS. SARS-like WIV1-CoV poised for human emergence. Proc Natl Acad Sci U S A. 2016 Mar 14. PMID: 26976607. PMCID: PMC4801244.
Menachery VD, Yount BL Jr, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med. 2015 Dec;21(12):1508-13. Epub 2015 Nov 9. PMID: 26552008. PMCID: PMC4797993.
Freund NT, Roitburd-Berman A, Sui J, Marasco WA, Gershoni JM. Reconstitution of the receptor-binding motif of the SARS coronavirus. Protein Eng Des Sel. 2015 Dec;28(12):567-75. Epub 2015 Oct 20. PMID: 26487711.
Huang X, Dong W, Milewska A, Golda A, Qi Y, Zhu QK, Marasco W, Baric RS, Sims AC, Pyrc K, Li W, Sui J. Human coronavirus HKU1 spike protein uses O-acetylated sialic acid as an attachment receptor determinant and employs hemagglutinin-esterase protein as a receptor-destroying enzyme. J Virol. 2015 Jul 15;89(14):7202-13. Epub 2015 Apr 29. PMID: 25926653. PMCID: PMC4473545.
Sui J, Deming M, Rockx B, Liddington RC , Zhu QK, Baric RS, Marasco WA. Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness. J Virol. 2014 Dec;88(23):13769-80. Epub 2014 Sep 17. PMID: 25231316. PMCID: PMC4248992.
Sui J, Aird DR, Tamin A, Murakami A, Yan M, Yammanuru A, Jing H, Kan B, Liu X, Zhu Q, Yuan QA, Adams GP, Bellini WJ, Xu J, Anderson LJ, Marasco WA. Broadening of neutralization activity to directly block a dominant antibody-driven SARS-coronavirus evolution pathway. PLoS Pathog. 2008 Nov; 4(11):e1000197. Epub 2008 Nov 7. PMID: 18989460. PMCID: PMC2572002.
Li W, Sui J, Huang IC, Kuhn JH, Radoshitzky SR, Marasco WA, Choe H, Farzan M. The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ACE2. Virology. 2007 Oct 25;367(2):367-74. Epub 2007 Jul 12. PMID: 17631932. PMCID: PMC2693060.
Hwang WC, Lin Y, Santelli E, Sui J, Jaroszewski L, Stec B, Farzan M, Marasco WA, Liddington RC. Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R. J Biol Chem. 2006 Nov 10;281(45):34610-6. Epub 2006 Sep 5. PMID: 16954221.
Tarnovitski N, Matthews LJ, Sui J, Gershoni JM, Marasco WA. Mapping a neutralizing epitope on the SARS coronavirus spike protein: computational prediction based on affinity-selected peptides. J Mol Biol. 2006 May 26;359(1):190-201. Epub 2006 Mar 22. PMID: 16630634.
Li W, Zhang C, Sui J, Kuhn JH, Moore MJ, Luo S, Wong SK, Huang IC, Xu K, Vasilieva N, Murakami A, He Y, Marasco WA, Guan Y, Choe H, Farzan M. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 2005 Apr 20;24(8):1634-43. PMID: 15791205. PMCID: PMC1142572.
Qin C, Wang J, Wei Q, She M, Marasco WA, Jiang H, Tu X, Zhu H, Ren L, Gao H, Guo L, Huang L, Yang R, Cong Z, Guo L, Wang Y, Liu Y, Sun Y, Duan S, Qu J, Chen L, Tong W, Ruan L, Liu P, Zhang H, Zhang J, Zhang H, Liu D, Liu Q, Hong T, He W. An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus. J Pathol. 2005 Jul;206(3):251-9. PMID: 15892035.
Sui J, Li W, Roberts A, Matthews LJ, Murakami A, Vogel L, Wong SK, Subbarao K, Farzan M, Marasco WA. Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J Virol. 2005 May;79(10):5900-6. PMID: 15857975. PMCID: PMC1091676.
Sui J, Li W, Murakami A, Tamin A, Matthews LJ, Wong SK, Moore MJ, Tallarico AS, Olurinde M, Choe H, Anderson LJ, Bellini WJ, Farzan M, Marasco WA. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2536-41. PMID: 14983044. PMCID: PMC356985.
Chang MR, Ke H, Coherd CD, Wang Y, Mashima K, Kastrunes GM, Huang CY, Marasco WA. Analysis of a SARS-CoV-2 convalescent cohort identified a common strategy for escape of vaccine-induced anti-RBD antibodies by Beta and Omicron variants. EBioMedicine. 2022 May 6;80:104025. PMID: 35533497; PMCID: PMC9073271.
Menachery VD, Yount BL Jr, Sims AC, Debbink K, Agnihothram SS, Gralinski LE, Graham RL, Scobey T, Plante JA, Royal SR, Swanstrom J, Sheahan TP, Pickles RJ, Corti D, Randell SH, Lanzavecchia A, Marasco WA, Baric RS. SARS-like WIV1-CoV poised for human emergence. Proc Natl Acad Sci U S A. 2016 Mar 14. PMID: 26976607. PMCID: PMC4801244.
Menachery VD, Yount BL Jr, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med. 2015 Dec;21(12):1508-13. Epub 2015 Nov 9. PMID: 26552008. PMCID: PMC4797993.
Freund NT, Roitburd-Berman A, Sui J, Marasco WA, Gershoni JM. Reconstitution of the receptor-binding motif of the SARS coronavirus. Protein Eng Des Sel. 2015 Dec;28(12):567-75. Epub 2015 Oct 20. PMID: 26487711.
Huang X, Dong W, Milewska A, Golda A, Qi Y, Zhu QK, Marasco W, Baric RS, Sims AC, Pyrc K, Li W, Sui J. Human coronavirus HKU1 spike protein uses O-acetylated sialic acid as an attachment receptor determinant and employs hemagglutinin-esterase protein as a receptor-destroying enzyme. J Virol. 2015 Jul 15;89(14):7202-13. Epub 2015 Apr 29. PMID: 25926653. PMCID: PMC4473545.
Sui J, Deming M, Rockx B, Liddington RC , Zhu QK, Baric RS, Marasco WA. Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness. J Virol. 2014 Dec;88(23):13769-80. Epub 2014 Sep 17. PMID: 25231316. PMCID: PMC4248992.
Sui J, Aird DR, Tamin A, Murakami A, Yan M, Yammanuru A, Jing H, Kan B, Liu X, Zhu Q, Yuan QA, Adams GP, Bellini WJ, Xu J, Anderson LJ, Marasco WA. Broadening of neutralization activity to directly block a dominant antibody-driven SARS-coronavirus evolution pathway. PLoS Pathog. 2008 Nov; 4(11):e1000197. Epub 2008 Nov 7. PMID: 18989460. PMCID: PMC2572002.
Li W, Sui J, Huang IC, Kuhn JH, Radoshitzky SR, Marasco WA, Choe H, Farzan M. The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ACE2. Virology. 2007 Oct 25;367(2):367-74. Epub 2007 Jul 12. PMID: 17631932. PMCID: PMC2693060.
Hwang WC, Lin Y, Santelli E, Sui J, Jaroszewski L, Stec B, Farzan M, Marasco WA, Liddington RC. Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R. J Biol Chem. 2006 Nov 10;281(45):34610-6. Epub 2006 Sep 5. PMID: 16954221.
Tarnovitski N, Matthews LJ, Sui J, Gershoni JM, Marasco WA. Mapping a neutralizing epitope on the SARS coronavirus spike protein: computational prediction based on affinity-selected peptides. J Mol Biol. 2006 May 26;359(1):190-201. Epub 2006 Mar 22. PMID: 16630634.
Li W, Zhang C, Sui J, Kuhn JH, Moore MJ, Luo S, Wong SK, Huang IC, Xu K, Vasilieva N, Murakami A, He Y, Marasco WA, Guan Y, Choe H, Farzan M. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 2005 Apr 20;24(8):1634-43. PMID: 15791205. PMCID: PMC1142572.
Qin C, Wang J, Wei Q, She M, Marasco WA, Jiang H, Tu X, Zhu H, Ren L, Gao H, Guo L, Huang L, Yang R, Cong Z, Guo L, Wang Y, Liu Y, Sun Y, Duan S, Qu J, Chen L, Tong W, Ruan L, Liu P, Zhang H, Zhang J, Zhang H, Liu D, Liu Q, Hong T, He W. An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus. J Pathol. 2005 Jul;206(3):251-9. PMID: 15892035.
Sui J, Li W, Roberts A, Matthews LJ, Murakami A, Vogel L, Wong SK, Subbarao K, Farzan M, Marasco WA. Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J Virol. 2005 May;79(10):5900-6. PMID: 15857975. PMCID: PMC1091676.
Sui J, Li W, Murakami A, Tamin A, Matthews LJ, Wong SK, Moore MJ, Tallarico AS, Olurinde M, Choe H, Anderson LJ, Bellini WJ, Farzan M, Marasco WA. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2536-41. PMID: 14983044. PMCID: PMC356985.
West Nile Virus (WNV), Zika, and Other Flaviviruses
WNV is the causative agent of West Nile Virus encephalitis, an infection of the central nervous system in man that can result is severe debilitation or even death. There is currently no FDA approved WNV vaccine for man. We have isolated human Mabs that protect against WNV encephalitis in animal models. These Mabs are directed against a highly conserved neutralizing epitope on WNV E-protein. Importantly, these Mabs cross-neutralize a wide range of other human pathogenic flavirivuses including Denge virus serotypes 1-4. We are involved in US army (WRAIR) studies aimed at preventing flavivirus (Denge 1-4 viruses) infection of our special forces and as potentiating agents for Denge virus vaccines.
Sultana H, Foellmer HG, Neelakanta G, Oliphant T, Engle M, Ledizet M, Krishnan MJ, Bonafé N, Anthony K, Marasco WA, Kaplan P, Montgomery RR, Diamond MS, Koski RA, Fikrig E. Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody. J Immunol. 2009 Jul 1;183(1):650-60. Epub 2009 Jun 17. PMID: 19535627. PMCID: PMC3690769.
Kanai R, Kar K, Anthony K, Gould LH, Ledizet M, Fikrig E, Marasco WA, Koski RA, Modis Y. Crystal structure of west nile virus envelope glycoprotein reveals viral surface epitopes. J Virol. 2006 Nov;80(22):11000-8. Epub 2006 Aug 30. PMID: 16943291. PMCID: PMC1642136.
Gould LH, Sui J, Foellmer H, Oliphant T, Wang T, Ledizet M, Murakami A, Noonan K, Lambeth C, Kar K, Anderson JF, de Silva AM, Diamond MS, Koski RA, Marasco WA, Fikrig E. Protective and therapeutic capacity of human single-chain Fv-Fc fusion proteins against West Nile virus. J Virol. 2005 Dec;79(23):14606-13. PMID: 16282460. PMCID: PMC1287547.
Sultana H, Foellmer HG, Neelakanta G, Oliphant T, Engle M, Ledizet M, Krishnan MJ, Bonafé N, Anthony K, Marasco WA, Kaplan P, Montgomery RR, Diamond MS, Koski RA, Fikrig E. Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody. J Immunol. 2009 Jul 1;183(1):650-60. Epub 2009 Jun 17. PMID: 19535627. PMCID: PMC3690769.
Kanai R, Kar K, Anthony K, Gould LH, Ledizet M, Fikrig E, Marasco WA, Koski RA, Modis Y. Crystal structure of west nile virus envelope glycoprotein reveals viral surface epitopes. J Virol. 2006 Nov;80(22):11000-8. Epub 2006 Aug 30. PMID: 16943291. PMCID: PMC1642136.
Gould LH, Sui J, Foellmer H, Oliphant T, Wang T, Ledizet M, Murakami A, Noonan K, Lambeth C, Kar K, Anderson JF, de Silva AM, Diamond MS, Koski RA, Marasco WA, Fikrig E. Protective and therapeutic capacity of human single-chain Fv-Fc fusion proteins against West Nile virus. J Virol. 2005 Dec;79(23):14606-13. PMID: 16282460. PMCID: PMC1287547.
HIV-1/AIDS
The Marasco Lab is developing genetic microbicides that can result in the prevention of mucosal transmission of HIV-1 with emphasis on blocking cervicovaginal transmission. We are also testing new human Mab-based immunotherapies against HIV-1 infection that are designed to reverse T-and B-cell exhaustion and restore a functional immune system so that these immune cells can kill HIV-1-infected cells and eliminate HIV-1 reservoirs. We have developed new “humanized mice” models that are being used to evaluate these strategies.
Kang W, Marasco WA, Tong HI, Byron M, Wu C, Shi Y, Sun S, Sun Y, Lu Y. Anti-tat Hutat2:Fc mediated protection against tat-induced neurotoxicity and HIV-1 replication in human monocyte-derived macrophages. J Neuroinflammation. 2014 Nov 22;11:195. PMID: 25416164. PMCID: PMC4256057.
Abdel-Motal UM, Harbison C, Han T, Pudney J, Anderson DJ, Zhu Q, Westmoreland S, Marasco W. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. Gene Ther. 2014 Sep;21(9):802-10. Epub 2014 Jun 26. PMID: 24965083. PMCID: PMC5530589.
Braun SE, Taube R, Zhu Q, Wong FE, Murakami A, Kamau E, Markryan Dwyer M, Qiu G, Daigle J, Carville A, Johnson RP, Marasco WA. In vivo selection of CD4+ T cells transduced with a gamma-retroviral vector expressing a single-chain intrabody targeting HIV-1 tat. Hum Gene Ther. 2012 Sep;23(9):917-31. PMID: 22734618. PMCID: PMC3440024.
Abdel-Motal UM, Sarkis PT, Han T, Pudney J, Anderson DJ, Zhu Q, Marasco WA. Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro. PLoS One. 2011;6(10):e26473. Epub 2011 Oct 21. PMID: 22031835. PMCID: PMC31987773.
Herschhorn A, Marasco WA, Hizi A. Antibodies and lentiviruses that specifically recognize a T cell epitope derived from HIV-1 Nef protein and presented by HLA-C. J Immunol. 2010 Dec 15; 185(12):7623-32. Epub 2010 Nov 12. PMID: 21076072.
Si Z, Vandegraaff N, O'huigin C, Song B, Yuan W, Xu C, Perron M, Li X, Marasco WA, Engelman A, Dean M, Sodroski J. Evolution of a cytoplasmic tripartite motif (TRIM) protein in cows that restricts retroviral infection. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7454-9. Epub 2006 Apr 28. PMID: 16648259. PMCID: PMC1464360.
Masiero S, Del Vecchio C, Gavioli R, Mattiuzzo G, Cusi MG, Micheli L, Gennari F, Siccardi A, Marasco WA, Palù G, Parolin C. T-cell engineering by a chimeric T-cell receptor with antibody-type specificity for the HIV-1 gp120. Gene Ther. 2005 Feb;12(4):299-310. PMID: 15496956.
Zhang D, Murakami A, Johnson RP, Sui J, Cheng J, Bai J, Marasco WA. Optimization of ex vivo activation and expansion of macaque primary CD4-enriched peripheral blood mononuclear cells for use in anti-HIV immunotherapy and gene therapy strategies. J Acquir Immune Defic Syndr. 2003 Mar:1;32(3):245-54. PMID: 12626883.
Bai J, Sui J, Zhu RY, Tallarico AS, Gennari F, Zhang D, Marasco WA. Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti-hCyclinT1 intrabodies. J Biol Chem. 2003 Jan 17;278(3):1433-42. PMID: 12401780.
Kang W, Marasco WA, Tong HI, Byron M, Wu C, Shi Y, Sun S, Sun Y, Lu Y. Anti-tat Hutat2:Fc mediated protection against tat-induced neurotoxicity and HIV-1 replication in human monocyte-derived macrophages. J Neuroinflammation. 2014 Nov 22;11:195. PMID: 25416164. PMCID: PMC4256057.
Abdel-Motal UM, Harbison C, Han T, Pudney J, Anderson DJ, Zhu Q, Westmoreland S, Marasco W. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. Gene Ther. 2014 Sep;21(9):802-10. Epub 2014 Jun 26. PMID: 24965083. PMCID: PMC5530589.
Braun SE, Taube R, Zhu Q, Wong FE, Murakami A, Kamau E, Markryan Dwyer M, Qiu G, Daigle J, Carville A, Johnson RP, Marasco WA. In vivo selection of CD4+ T cells transduced with a gamma-retroviral vector expressing a single-chain intrabody targeting HIV-1 tat. Hum Gene Ther. 2012 Sep;23(9):917-31. PMID: 22734618. PMCID: PMC3440024.
Abdel-Motal UM, Sarkis PT, Han T, Pudney J, Anderson DJ, Zhu Q, Marasco WA. Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro. PLoS One. 2011;6(10):e26473. Epub 2011 Oct 21. PMID: 22031835. PMCID: PMC31987773.
Herschhorn A, Marasco WA, Hizi A. Antibodies and lentiviruses that specifically recognize a T cell epitope derived from HIV-1 Nef protein and presented by HLA-C. J Immunol. 2010 Dec 15; 185(12):7623-32. Epub 2010 Nov 12. PMID: 21076072.
Si Z, Vandegraaff N, O'huigin C, Song B, Yuan W, Xu C, Perron M, Li X, Marasco WA, Engelman A, Dean M, Sodroski J. Evolution of a cytoplasmic tripartite motif (TRIM) protein in cows that restricts retroviral infection. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7454-9. Epub 2006 Apr 28. PMID: 16648259. PMCID: PMC1464360.
Masiero S, Del Vecchio C, Gavioli R, Mattiuzzo G, Cusi MG, Micheli L, Gennari F, Siccardi A, Marasco WA, Palù G, Parolin C. T-cell engineering by a chimeric T-cell receptor with antibody-type specificity for the HIV-1 gp120. Gene Ther. 2005 Feb;12(4):299-310. PMID: 15496956.
Zhang D, Murakami A, Johnson RP, Sui J, Cheng J, Bai J, Marasco WA. Optimization of ex vivo activation and expansion of macaque primary CD4-enriched peripheral blood mononuclear cells for use in anti-HIV immunotherapy and gene therapy strategies. J Acquir Immune Defic Syndr. 2003 Mar:1;32(3):245-54. PMID: 12626883.
Bai J, Sui J, Zhu RY, Tallarico AS, Gennari F, Zhang D, Marasco WA. Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti-hCyclinT1 intrabodies. J Biol Chem. 2003 Jan 17;278(3):1433-42. PMID: 12401780.