Immunology
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Ruth M. Ruprecht

Department of Medicine
Dana-Farber Cancer Institute
Jimmy Fund Building, Room 809
44 Binney Street
Boston, MA 02115
Tel: 617-632-3719
Fax: 617-632-3112
email:ruth_ruprecht@dfci.harvard.edu
4 Instructors, 8 Postdoctoral Fellows, 3 Graduate Students
2 Undergraduate Students

 Ruth Ruprecht

The Ruprecht lab conducts a multi-institutional research program that involves collaborators in the United States, Europe, and Africa; the research is focused on understanding the molecular mechanisms of AIDS virus replication and host-virus interactions at the level of infected cells and primates. This innovative approach has provided new insights into lentivirus transmission and virulence. New prevention strategies for which the Ruprecht lab provided the first proof-of-concept have ultimately proved successful in humans.

One of our long-range goals is to prevent maternal HIV transmission during birth and through breastfeeding, using passive plus active immunization. To test the concept of passive immunization, human neutralizing antibodies (hnmAbs) were given to newborn monkeys challenged orally with SHIV, a chimeric virus that encodes the HIV envelope gene. In the first study, four pregnant monkeys were treated with a triple hnmAb combination that completely neutralized HIV in cultured cells. At birth, the monkey infants received further antibody treatment, followed by oral SHIV challenge. None of the treated infants became infected, in contrast to all untreated, virus-challenged control infants, indicating potent protection by hnmAbs. Next, we showed that newborn monkeys were completely protected with hnmAb combinations, even when the latter were given after oral SHIV challenge. Overall, we have treated 31 newborn monkeys with hnmAb combinations; of these, 22 animals were completely protected whereas all 26 untreated, virus-challenged controls became infected. Clearly, passive immunization with hnmAbs yielded potent protection against oral virus challenge. In cultured cells, a quadruple combination of these hnmAbs potently neutralized all primary HIV isolates of the genetic substrains A, B, C, and D we tested. The epitopes recognized by these antibodies are important determinants for achieving complete protection, thus providing a rational basis for the development of active AIDS vaccines. We recently evaluated an active AIDS vaccine strategy in newborn monkeys that were vaccinated against SHIV by DNA priming and boosting with multimeric HIV gp160. Following challenge with homologous virus, several vaccinated animals contained viral infection. These animals also resisted a second homologous virus challenge, and when challenged a third time with a heterologous, highly pathogenic SHIV strain, most of them maintained normal CD4+ T-cell counts despite superinfection and developed high-titer neutralizing antibodies against this second virus. These results indicate that Original Antigenic Sin did not occur in these vaccinated animals with breakthrough infection, as prior B-cell responses against a single SHIV strain did not preclude the later development of neutralizing antibodies against a divergent strain. These data have important implications for AIDS vaccine development in general.

Our group also studies viral evolution in chronically infected primates, using molecular approaches. We and others showed that the HIV envelope gene evolved similarly in three different species, including humans; this selection occurred in chronically infected individuals during disease progression as well as after rapid virus passage in monkeys.

We are now examining the genetic changes that impart high virulence to molecularly cloned parental virus strains.

 

Papers & Publications:

  1. Ferrantelli F, Rasmussen RA, Hofmann-Lehmann R, Xu W, McClure HM, Ruprecht RM. Don1t underestimate the power of antibodies - lessons from adoptive transfer of antibodies. Vaccine 2002a; (Suppl 4):A61-5.
  2. Ferrantelli F, Ruprecht RM. Neutralizing antibodies against HIV - back in the major leagues? Curr Opin Immunol 2002b; 14:495-502.
  3. Ferrantelli F, Hofmann-Lehmann R, Rasmussen RA, Wang T, Xu W, Li P-L, Montefiori DC, Cavacini LA, Karinger H, Stiegler G, Anderson DC, McClure HM, Ruprecht RM. Post-exposure prophylaxis with human monoclonal antibodies prevented SHIV89.6P infection or disease in neonatal macaques. AIDS 2003 17:301-9
  4. Hofmann-Lehmann R, Vlasak J, Chenine A-L, Li P-L, Baba TW, Montefiori DC, McClure HM, Anderson DC, Ruprecht RM. Molecular evolution of human immunodeficiency virus env in humans and monkeys: similar patterns occur during natural disease progression or rapid virus passage. J Virol 2002a; 76:5278-84.
  5. Hofmann-Lehmann R, Vlasak J, Rasmussen RA, Jiang S, Li P-L, Baba TW, Montefiori DC, Bernacky BJ, Rizvi TA, Schmidt R, Hill LR, Keeling ME, Katinger H, Stiegler G, Cavacini LA, Posner MR, Ruprecht RM. Postnatal pre- and post exposure passive immunization strategies: protection of neonatal macaques against oral simian-human immunodeficiency virus challenge. J Med Primatol 2002b; 31:109-19.
  6. Hofmann-Lehmann R, Williams AL, Swenerton RK, Li P-L, Rasmussen RA, Chenine A-L, McClure HM, Ruprecht RM. Quantitation of simian cytokine and ß-chemokine mRNAs using real-time reverse-transcriptase polymerase chain reaction: variations in expression during chronic primate lentivirus infection. AIDS Res Hum Retroviruses 2002c; 18:627-39.
  7. Hofmann-Lehmann R, Vlasak J, Williams AL, Chenine A-L, McClure HM, Anderson DC, O1Neil S, Ruprecht RM. Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS 2003; 17:157-66.
  8. Kitabwalla M, Ferrantelli F, Wang T, Chalmers AS, Katinger H, Stiegler G, Cavacini LA, Chou T-C, Ruprecht RM. Primary African HIV clade A and D isolates: effective cross clade neutralization with a quadruple combination of human monoclonal antibodies raised against clade B infection or disease in neonatal macaques. AIDS Res Hum Retroviruses 2003; 19:125-31.
  9. Rasmussen RA, Hofmann-Lehmann R, Li, P-L, Vlasak J, Schmitz JE, Reimann KA, Kuroda MJ, Letvin NL, Montefiori DC, McClure HM, Ruprecht, RM. Neutralizing antibodies as a potential secondary protective mechanism during chronic SHIV infection in CD8+ T cell depleted macaques. AIDS 2002a; 16:829-38.
  10. Rasmussen RA, Hofmann-Lehmann R, Montefiori DC, Li P-L, Liska V, Vlasak J, Baba TW, Schmitz JE, Kuroda MJ, Robinson HL, McClure HM, Lu S, Hu S-L, Rizvi TA, Ruprecht RM. DNA prime/protein boost vaccine strategy in neonatal macaques against simian human immunodeficiency virus. J Med Primatol 2002b; 31:40-60.