Abstract

Using ultrasound (US)-guided inoculation of the amniotic fluid with the simian immunodeficiency virus (SIV), we have achieved a 86% fetal infection rate in rhesus monkeys (Macaca mulatta). However, neutralizing antibodies developed against HIV-1 cannot be evaluated in this system. Thus, we propose to establish a fetal infection model in macaques using a chimeric virus based on the infectious molecular clone SlVmac239 in which the tat, rev and env sequences of SIV were replaced by homologous sequences of HIV, and into which the vpu sequences of HIV were inserted as welL The resulting chimeric virus, SHIV-vpu+, is infectious in rhesus monkeys.
The Specific Aims for this proposal are to: 1. Titrate the dose of SHIV-vpu+ required for reproducible fetal infection via the amniotic fluid. using 8 pregnant M. mulatta late in gestation. The mother/infant pairs will be followed for viremia and disease. 2. Examine a panel of neutralizing human anti-HIV-1 Env monoclonal antibodies (mAbs) for their ability to neutralize SHIV-vpu+. Human mAbs directed against the CD4 binding domain or against the V3 loop will be examined for their activity against SHIV-vpu+ in vitro, singly and in combination regimens. 3. Determine the pharmacokinetics of human mAbs during gestation by weekly injections into pregnant, uninfected macaques. Neutralizing titers in serum, amniotic fluid, cord blood, placental tissues and milk will be determined. Mothers and infants will be examined carefully for signs of toxicity. 4. Test passive immunoprophylaxis with the optimal combination regimen of human anti-HIV mAbs (as determined in Specific Aim #2) during gestation. We anticipate that a combination of mAbs directed against the CD4 binding domain and the V3 loop will be used. Pregnant controls will be treated with irrelevant human mAbs. After pre-treatment, all animals will be challenged with SHIV-vpu + via the amniotic fluid. Moab therapy will be continued until Cesarean section. Mother/infant pairs will be followed for development of viremia and disease. The proposed work is highly significant because it allows in vivo analysis of neutralizing human Moab's directed against the HIV-1 envelope glycoprotein.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI034266-03S1
Application #
2436183
Study Section
Special Emphasis Panel (ZRG5-AAR (01))
Project Start
1994-04-01
Project End
1998-03-31
Budget Start
1997-07-01
Budget End
1998-03-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Sholukh, Anton M; Watkins, Jennifer D; Vyas, Hemant K et al. (2015) Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge. Vaccine 33:2086-95
Lakhashe, Samir K; Silvestri, Guido; Ruprecht, Ruth M (2011) No acquisition: a new ambition for HIV vaccine development? Curr Opin Virol 1:246-53
Ferrantelli, Flavia; Buckley, Kathleen A; Rasmussen, Robert A et al. (2007) Time dependence of protective post-exposure prophylaxis with human monoclonal antibodies against pathogenic SHIV challenge in newborn macaques. Virology 358:69-78
Zhang, Hong; Hoffmann, Federico; He, Jun et al. (2005) Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant. Retrovirology 2:67
Chenine, Agnes-Laurence; Ferrantelli, Flavia; Hofmann-Lehmann, Regina et al. (2005) Older rhesus macaque infants are more susceptible to oral infection with simian-human immunodeficiency virus 89.6P than neonates. J Virol 79:1333-6
Ferrantelli, Flavia; Kitabwalla, Moiz; Rasmussen, Robert A et al. (2004) Potent cross-group neutralization of primary human immunodeficiency virus isolates with monoclonal antibodies--implications for acquired immunodeficiency syndrome vaccine. J Infect Dis 189:71-4
Ferrantelli, Flavia; Rasmussen, Robert A; Buckley, Kathleen A et al. (2004) Complete protection of neonatal rhesus macaques against oral exposure to pathogenic simian-human immunodeficiency virus by human anti-HIV monoclonal antibodies. J Infect Dis 189:2167-73
Kitabwalla, Moiz; Ferrantelli, Flavia; Wang, Tao et al. (2003) Primary African HIV clade A and D isolates: effective cross-clade neutralization with a quadruple combination of human monoclonal antibodies raised against clade B. AIDS Res Hum Retroviruses 19:125-31
Ferrantelli, Flavia; Hofmann-Lehmann, Regina; Rasmussen, Robert A et al. (2003) Post-exposure prophylaxis with human monoclonal antibodies prevented SHIV89.6P infection or disease in neonatal macaques. AIDS 17:301-9
Hofmann-Lehmann, Regina; Vlasak, Josef; Chenine, Agnes-Laurence et al. (2002) Molecular evolution of human immunodeficiency virus env in humans and monkeys: similar patterns occur during natural disease progression or rapid virus passage. J Virol 76:5278-84

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