Virology
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Ruth M. Ruprecht, M.D., PH.D.

Professor of Medicine

Dana-Farber Cancer Institute
Jimmy Fund Bldg., Room 809
44 Binney St.
Boston, MA 02115
Tel: 617-632-3719
Fax: 617-632-3112
e-mail:ruth_ruprecht@dfci.harvard.edu
8 postdoctoral fellows, 3 graduate student, 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.

 

References:

  1. Pion M, Sanchez G, Liska V, Bettendroffer L, Candotti D, Chenine A-L, Gandois-Rey F, Tamalet C, Vigne R, Ruprecht RM, Agut H, the French ALT Study Group, Hirsch I. Truncated forms of human and simian immunodeficiency virus in infected individuals and rhesus macaques are unique or rare quasispecies. Virology 2003; 311:157-68.
  2. Ruprecht RM, Ferrantelli F, Kitabwalla M, Xu W, McClure HM. Antibody protection: passive immunization of neonates against oral AIDS virus challenge. Vaccine 2003; 21:3370-3.
  3. Buckley KA, Li P-L, Khimani A, Hofmann-Lehmann R, Liska V, Anderson DC, McClure HM, Ruprecht, RM. Convergent evolution of SIV env after independent inoculation of rhesus macaques with infectious proviral DNA. Virology 2003; 312:470-80.
  4. Ferrantelli F, Kitabwalla M, Rasmussen RA, Cao C, Chou T-C, Katinger H, Stiegler G, Cavacini LM, Bai Y, Cotropia J, Ugen KE, Ruprecht RM. Potent cross-group neutralization of primary HIV isolates with monoclonal antibodies - implications for acquired immunodeficiency syndrome vaccine. J Infect Dis 2004; 189:71-4.
  5. Dabis F, Newell M-L, Fowler MG, Read JS for the Ghent IAS Working Group on IV in Women and Children (Dr. Ruprecht is a member of the group). Prevention of HIV transmission through breast-feeding: strengthening the research agenda. J Acquir Immune Defic Syndr 2004; 35:167-8.
  6. Safrit JT, Ruprecht RM, Ferrantelli F, Xu W, Kitabwalla M, VanRompay K, Marthas M, Haigwood N, Mascola JR, Luzuriaga K, Adeniyi Jones S, Mathieson BJ, Newell M-L for the Ghent IAS Working Group on IV in Women and Children. J Acquir Immune Defic Syndr 2004; 35:169-77.
  7. Ferrantelli F, Rasmussen RA, Buckley KA, Li P-L, Xu W, Wang T, Montefiori DC, Katinger H, Stiegler G, Anderson DC, McClure HM, Ruprecht RM. Complete protection of neonatal rhesus macaques against oral challenge with pathogenic SHIV by human anti-HIV monoclonal antibodies. J Infect Dis, in press