Research Department

Cancer Immunology and AIDS

Area of Research

Biography

Dr. Ruprecht received a PhD in human genetics from Columbia University in 1973 and an MD from the University of Miami School of Medicine in 1977. She completed her residency training in internal medicine at the University of California, Los Angeles, followed by a fellowship in hematology-oncology at Memorial Sloan-Kettering Cancer Center. She joined DFCI in 1984.

Recent Awards

• World AIDS Day: amfAR honoree for contributions to prevent maternal HIV transmission, 2004
• NIH Merit Award, 2003
• Honorary Professor, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, PRC, 2001
• Governor's Award in Recognition of Outstanding Contributions to AIDS Research, Massachusetts, 1986

Research

Our research, which involves collaborators in the US, Europe, China and Africa, seeks to understand the mechanisms of AIDS virus replication and host-virus interactions in infected cells and primates. One key goal has been to define the correlates of immune protection against AIDS virus infection. We used the tool of passive immunization to examine the protective potential of antibodies. We limited our studies to human neutralizing monoclonal antibodies (nmAbs) that target conserved regions of the HIV envelope. We identified combinations of such nmAbs that in cultured blood cells neutralized all primary HIV isolates of multiple substrains (so-called clades) that we tested; we also achieved substantial neutralization of strains that belong to a genetically more distant HIV group.

We then tested combinations of human nmAbs in newborn rhesus monkeys that were challenged orally with simian HIV (SHIV), a chimeric AIDS virus that encodes the HIV envelope gene. None of the antibody-treated infants became infected, in contrast to all untreated, virus-challenged controls that rapidly progressed to AIDS. We also achieved complete protection from infection when the nmAbs were given after virus challenge. Clearly, passive immunization with nmAbs yielded potent protection against oral virus challenge. The epitopes recognized by these antibodies are important determinants for achieving complete protection and provide a rational basis for developing active AIDS vaccines.

We maintain a strong focus on developing an active AIDS vaccine. We have generated a new SHIV strain that encodes the envelope gene of HIV clade C, the most prevalent substrain in the world. Our new SHIV construct will serve as a tool for preclinical vaccine efficacy studies against HIV clade C. We have also provided convincing evidence that a live attenuated form of the simian immunodeficiency virus (SIV) with a deletion in the nef gene is pathogenic in monkeys, regardless of the age at which vaccinations are given. In a detailed functional study of the nef gene product, we discovered a new interaction between Nef and protein kinase A, a signal transduction molecule that plays an important role during immune activation of T cells.

Using molecular tools, we studied viral evolution in chronically infected primates and showed that the SIV envelope gene followed similar evolutionary paths in individual monkeys despite their different genetic backgrounds. We are now examining the genetic changes that impart high virulence to molecularly cloned virus strains.

Select Publications

• Chenine AL, Ferrantelli F, Hofmann-Lehmann R, Vangel MG, McClure HM, Ruprecht RM. Older rhesus macaque infants are more susceptible to oral infection with simian-human immunodeficiency virus 89.6P than neonates. J Virol 2005;79:1333-6.
  
  
• Ferrantelli F, Kitabwalla M, Rasmussen RA, Cao C, Chou TC, Katinger H, Stiegler G, Cavacini LM, Bai Y, Cotropia J, Ugen KE, Ruprecht RM. Potent cross-group neutralization of primary human immunodeficiency virus isolates with monoclonal antibodies: implications for acquired immunodeficiency syndrome vaccine. J Infect Dis 2004;189:71-4.
  
  
• Ferrantelli F, Rasmussen RA, Buckley KA, Li PL, 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 2004;189:2167-73.
  
  
• Grisson RD, Chenine AL, Yeh LY, He J, Wood C, Bhat GJ, Xu W, Kankasa C, Ruprecht RM. Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination. J Virol 2004;78:14066-9.
  
  
• Hofmann-Lehmann R, Vlasak J, Williams AL, Chenine AL, McClure HM, Anderson DC, O'Neil S, Ruprecht RM. Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS 2003;17:157-66.
  
  
• Li PL, Wang T, Buckley KA, Chenine AL, Popov S, Ruprecht RM. Phosphorylation of HIV Nef by cAMP-dependent protein kinase. Virology 2005;331:367-74.
  
• Popov S, Chenine AL, Gruber A, Li PL, Ruprecht RM. Long-term productive HIV infection of CD1a-sorted myeloid dendritic cells. J Virol 2005;79:602-8.
  
  
• Whitney JB, Ruprecht RM. Live attenuated HIV vaccines: pitfalls and prospects. Curr Opin Infect Dis 2004;17:17-26.
  
  
• ** Buckley KA, Li PL, 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.
  
  
• Chenine AL, Buckley KA, Li PL, Rasmussen RA, Ong H, Jiang S, Wang T, Augostini P, Secor WE, Ruprecht RM. Schistosoma mansoni infection promotes SHIV clade C replication in rhesus macaques. AIDS 2005;19:1793-7.
  
  

Investigators

• Popov, Sergei, MD, PhD
• Rasmussen, Robert A., PhD
• Mirshahidi, Saied, PhD

Trainees

• Chenine, Agnès-Laurence, PhD
• Li, Pei-Lin, MD
• Wang, Tao, PhD
• Ayash-Rashkovsky, Mila, PhD
• Essono, Sosthène, PhD
• McCann, Chantelle, PhD
• Shai-Kobiler, Ela, PhD
• Song, Ruijiang, PhD
• Whitney, James, PhD