Our long-range goal is to develop immunoprophylaxis against maternal HIV-1 transmission by active and passive vaccination. Here, we propose to study passive immunoprophylaxis with combinations of human neutralizing monoclonal antibodies (mAbs) directed against different HIV-1 Env epitopes in rhesus macaque models that mimic intrapartum and in utero infection. We will challenge with SHIV-89.6P, a chimeric virus that contains tat, rev, vpu and env of a primary HIV-1 isolate, 89.6, in a simian immunodeficiency virus backbone.
The Specific Aims are to: 1. Determine whether human mAbs that neutralize primary HIV-1 strains inhibit SHIV-89.6P synergistically when used in combination. 2. Perform pharmacokinetic studies with the most potent mAb combination in pregnant macaque dams and in their offspring. Neutralizing mAbs levels will be measured in maternal blood, amniotic fluid, cord blood and in neonatal mucosal secretions after passive therapy of pregnant macaque dams and newborns. 3. Test whether the most potent triple combination of neutralizing mAbs can protect neonatal macaques against intravenous (i.v.) SHIV-89.6P challenge. We will enroll 3 groups of 4 pregnant dams and their offspring. Group 1 animals will not be treated. Group 2 offspring will receive the mAb combination prenatally (by passive therapy of the pregnant dams) as well as after birth; and group 3 offspring will be given mAbs only postnatally. All 12 neonates will be challenged i.v. on day 1 of life with 10 50 percent animal infectious doses (AID50-i.v.) of SHIV-89.6P. 4. Test whether the most potent combination of human neutralizing mAbs can protect neonatal macaques against mucosal SHIV-89.6P challenge. A similar experimental design will be employed as described for Specific Aim #3. Neonates will be challenged orally (po) at birth with cell-free SHIV-89.6P (10 AID50-po). 5. Test whether the most potent combination of human neutralizing mAbs can protect macaque fetuses against intra-amniotic fluid challenge with SHIV-89.6P during the late 3rd trimester. Passive immunoprophylaxis will be given at weekly intervals during gestation; control dams will be left untreated. Cell-free virus will be instilled into the amniotic fluid under ultrasound guidance. The proposed experiments are highly significant because they allow a direct evaluation of human neutralizing mAbs directed against primary HIV-1 strains in primates. Data generated from this work can be translated into human clinical trials aimed at preventing maternal HIV-1 transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI034266-04
Application #
2543342
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Robinson, Jerry
Project Start
1997-12-01
Project End
2002-03-31
Budget Start
1998-04-15
Budget End
1999-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
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
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
Ferrantelli, Flavia; Rasmussen, Robert A; Hofmann-Lehmann, Regina et al. (2002) Do not underestimate the power of antibodies--lessons from adoptive transfer of antibodies against HIV. Vaccine 20 Suppl 4:A61-5

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