Photo of Ruth M. Ruprecht,  MD, PhD

Ruth M. Ruprecht, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3719
Fax: (617) 632-3112


ruth_ruprecht@dfci.harvard.edu

Ruth M. Ruprecht, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Professor of Medicine, Cancer Immunology/AIDS, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our research is focused on primate immunodeficiency virus pathogenesis and AIDS vaccine development. Using passive immunization with broadly neutralizing monoclonal anti-HIV-1 antibodies in primates that were challenged with chimeric simian-human immunodeficiency viruses (SHIVs) carrying HIV-1 envelope genes, we demonstrated that infection is completely preventable, even after virus exposure. We now seek to induce protective immunity with active vaccination. Our strategy is to induce humoral as well as cellular immunity using recombinant viral protein immunogens and/or vectors. To test vaccine efficacy, we have developed a set of novel, pathogenic challenge SHIVs that are uniquely CCR5 tropic and encode recently transmitted HIV-1 envelope genes isolated from African individuals with newly acquired HIV-1 clade C infection. Thus, we have generated biologically relevant tools to develop vaccines against HIV-1 clade C, the world's most prevalent HIV-1 subtype. Our bimodal vaccine strategy has achieved partial protection, including protection from viremia, in rhesus macaques against challenge with heterologous SHIVs that encode HIV-1 envelopes that are mismatched with regards to the immunogen. We are now developing immunogens designed to induce higher titers of neutralizing antibodies with increased breadth.

In another set of vaccine studies, we have developed a peptide-based approach that is applicable for all members of a genetically heterogeneous population. Our strategy obviates the need to know the dominant epitope(s) and the MHC class I alleles of the vaccine recipients; using overlapping synthetic peptides (OSP), we were able to induce CD4+ and CD8+ T-cell responses against viral and cellular targets in all outbred and inbred mice tested. In a murine model of breast cancer, targeting a cellular oncogene by an OSP vaccine yielded a highly significant survival benefit after tumor cell challenge with a dose of malignant cells that induced lethal pulmonary metastases within about two months in the control mice. Importantly, no side effects were noted in the vaccinated, protected mice after extended follow-up. Our OSP-vaccine strategy represents a promising new concept for the development of cancer vaccines.

Publications

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  • Chenine AL, Siddappa NB, Kramer VG, Sciaranghella G, Rasmussen RA, Lee SJ, Santosuosso M, Poznansky MC, Velu V, Amara RR, Souder C, Anderson DC, Villinger F, Else JG, Novembre FJ, Strobert E, O'Neil SP, Evan Secor W, Ruprecht RM. Relative Transmissibility of an R5 Clade C Simian-Human Immunodeficiency Virus Across Different Mucosae in Macaques Parallels the Relative Risks of Sexual HIV-1 Transmission in Humans via Different Routes. J Infect Dis 2010; 201:1155-63. PubMed
  • Van Rhijn I,Young DC,De Jong A,Vazquez J,Cheng TY,Talekar R,Barral D,Leon L,Brenner MB,Katz JT,Riese R,Ruprecht RM,O'Connor PB,Costello CE,Porcelli SA,Briken V,Moody DB. CD1c bypasses lysosomes to present a lipopeptide antigen with 12 amino acids. J Exp Med 2009; 206:1409-22. PubMed
  • Siddappa NB,Song R,Kramer VG,Chenine AL,Velu V,Ong H,Rasmussen RA,Grisson RD,Wood C,Zhang H,Kankasa C,Amara RR,Else JG,Novembre FJ,Montefiori DC,Ruprecht RM. Neutralization-sensitive R5-tropic simian-human immunodeficiency virus SHIV-2873Nip, which carries env isolated from an infant with a recent HIV clade C infection. J Virol 2008; 83:1422-32. PubMed
  • Ruprecht RM. Passive immunization with human neutralizing monoclonal antibodies against HIV-1 in macaque models: experimental approaches. Methods Mol Biol 2009; 525:559-66, xiv. PubMed
  • Ho O, Larsen K, Polacino P, Li Y, Anderson D, Song R, Ruprecht RM, Hu SL. Pathogenic infection of Macaca nemestrina with a CCR5-tropic subtype-C simian-human immunodeficiency virus. Retrovirology 2009; 6:65. PubMed
  • Zhang MY,Vu BK,Choudhary A,Lu H,Humbert M,Ong H,Alam M,Ruprecht RM,Quinnan G,Jiang S,Montefiori DC,Mascola JR,Broder CC,Haynes BF,Dimitrov DS. Cross-reactive human immunodeficiency virus type 1-neutralizing human monoclonal antibody that recognizes a novel conformational epitope on gp41 and lacks reactivity against self-antigens. J Virol 2008; 82:6869-79. PubMed
  • Polonis VR, Brown BK, Borges AR, Zolla-Pazner S, Dimitrov DS, Zhang MY, Barnett SW, Ruprecht RM, Scarlatti G, Fenyo EM, Montefiori DC, McCutchan FE, Michael NL. Recent advances in the characterization of HIV-1 neutralization assays for standardized evaluation of the antibody response to infection and vaccination. Virology 2008; 375:315-20. PubMed
  • Humbert M,Rasmussen RA,Song R,Ong H,Sharma P,Chenine AL,Kramer VG,Siddappa NB,Xu W,Else JG,Novembre FJ,Strobert E,O'Neil SP,Ruprecht RM. SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys. Retrovirology 2008; 5:94. PubMed
  • Chenine AL,Shai-Kobiler E,Steele LN,Ong H,Augostini P,Song R,Lee SJ,Autissier P,Ruprecht RM,Secor WE. Acute Schistosoma mansoni Infection Increases Susceptibility to Systemic SHIV Clade C Infection in Rhesus Macaques after Mucosal Virus Exposure. PLoS Negl Trop Dis 2008; 2:e265. PubMed
  • Humbert M,Rasmussen RA,Ong H,Kaiser FM,Hu SL,Ruprecht RM. Inducing cross-clade neutralizing antibodies against HIV-1 by immunofocusing. PLoS ONE 2008; 3:e3937. PubMed
  • Kramer VG, Siddappa NB, Ruprecht RM. Passive immunization as tool to identify protective HIV-1 Env epitopes. Curr HIV Res 2007; 5:642-55. PubMed
  • Jiang S, Rasmussen RA, Nolan KM, Frankel FR, Lieberman J, McClure HM, Williams KM, Babu US, Raybourne RB, Strobert E, Ruprecht RM. Live attenuated Listeria monocytogenes expressing HIV Gag: immunogenicity in rhesus monkeys. Vaccine 2007; 25:7470-9. PubMed
  • Ayash-Rashkovsky M, Chenine AL, Steele LN, Lee SJ, Song R, Ong H, Rasmussen RA, Hofmann-Lehmann R, Else JG, Augostini P, McClure HM, Secor WE, Ruprecht RM. Coinfection with Schistosoma mansoni reactivates viremia in rhesus macaques with chronic simian-human immunodeficiency virus clade C infection. Infect Immun 2007; 75:1751-6. PubMed
  • Gruber A, Chalmers AS, Rasmussen RA, Ong H, Popov S, Andersen J, Hu SL, Ruprecht RM. Dendritic cell-based vaccine strategy against human immunodeficiency virus clade C: skewing the immune response toward a helper T cell type 2 profile. Viral Immunol 2007; 20:160-9. PubMed
  • Ferrantelli F, Buckley KA, Rasmussen RA, Chalmers A, Wang T, Li PL, Williams AL, Hofmann-Lehmann R, Montefiori DC, Cavacini LA, Katinger H, Stiegler G, Anderson DC, McClure HM, Ruprecht RM. Time dependence of protective post-exposure prophylaxis with human monoclonal antibodies against pathogenic SHIV challenge in newborn macaques. Virology 2006; 358:69-78. PubMed
  • Jiang S, Song R, Popov S, Mirshahidi S, Ruprecht RM.. Overlapping synthetic peptides as vaccines. Vaccine 2006; 24:6356-65.
  • Mirshahidi S, Kramer VG, Whitney JB, Essono S, Lee S, Dranoff G, Anderson KS, Ruprecht RM . Overlapping synthetic peptides encoding TPD52 as breast cancer vaccine in mice: prolonged survival Vaccine 2009; 27:1825-33.
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