The AIDS epidemic involves increasing numbers of children, most of whom are infected with the human immunodeficiency virus type 1 (HIV-1) by their mothers. Presently, no effective therapy exists to prevent maternal transmission of HIV-1. The overall goal of this proposal is to develop a primate model for pediatric AIDS, using the simian immunodeficiency virus (SIV). Because maternal SIV infection occurs only rarely, if ever, in infected pregnant rhesus monkeys, we propose to use ultrasound-guided inoculation of fetal compartments.
The specific aims are to: 1. Define the minimal infectious dose of SIV(mac251) required for fetal infection following ultrasound-guided inoculation of amniotic fluid. Our data indicate that cell-free SIV given by this route in the 3rd trimester infects the fetus successfully. Virus entry is thought to occur via skin or mucous membrane contact when the fetus swallows SIV+ amniotic fluid. A similar mode of infection may occur naturally during birth. We plan to find an SIV inoculum that will reliably result in infected, live-born offspring. 2. Define the pathogenicity of SIV(mac251) when the fetus is infected at various time points during gestation. Will early prenatal infection lead to a more aggressive course of disease? Does the incidence of nervous system involvement rise or is tissue distribution of SIV altered as fetuses are infected at earlier time points? Does fetal infection during the first trimester lead to abortion? 3. Define the immune response to SIV i rhesus monkeys infected in utero at different times. Can fetuses infected late in gestation mount cytotoxic T-cell responses against SIV gag-expressing cells? Do they develop neutralizing antibodies? Does early in utero exposure to SIV lead to tolerance? 4. Test whether antiviral drugs administered to pregnant rhesus monkeys can protect their fetuses against subsequent intrauterine SIV challenge. Efficacy, toxicity and teratogenicity will be monitored in parallel. 5. Compare the pathogenicity of SIV if the route of infection is altered, or if infection occurs through infected maternal peripheral blood mononuclear cells. To mimic maternal virus passage across the placenta, which results in SIV entry into the fetal circulation, we plan to use ultrasound-guided transabdominal injection of the umbilical vain and compare the outcome with amniotic fluid infection. Is transplacental antiviral drug prophylaxis equally effective against cell-free versus cell-associated virus? The proposed work is highly significant for establishing a primate model system for fetal and neonatal lentiviral infection. Because it emphasizes high infection rates, such a model system will be cost effective for evaluating viral pathogenesis during ontogeny as well as prophylaxis. Our proposed experiments may yield important information for planning 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 #
5R01AI032330-04
Application #
2067197
Study Section
AIDS and Related Research Study Section 2 (ARRB)
Project Start
1991-09-30
Project End
1995-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Pion, M; Liska, V; Chenine, A L et al. (2001) Extensively deleted simian immunodeficiency virus (SIV) DNA in macaques inoculated with supercoiled plasmid DNA encoding full-length SIVmac239. Virology 289:103-13
Liska, V; Hofmann-Lehmann, R; Ruprecht, R M (2001) Infectivity of lentiviral DNA in animals. Dev Biol (Basel) 106:291-7; discussion 297-8, 317-29
Baba, T W; Liska, V; Hofmann-Lehmann, R et al. (2000) Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med 6:200-6
Ruprecht, R M; Baba, T W; Liska, V et al. (1999) Oral transmission of primate lentiviruses. J Infect Dis 179 Suppl 3:S408-12
Ruprecht, R M (1999) Live attenuated AIDS viruses as vaccines: promise or peril? Immunol Rev 170:135-49
Liska, V; Khimani, A H; Hofmann-Lehmann, R et al. (1999) Viremia and AIDS in rhesus macaques after intramuscular inoculation of plasmid DNA encoding full-length SIVmac239. AIDS Res Hum Retroviruses 15:445-50
Liska, V; Ruprecht, R M (1999) Isolation of high-molecular-weight genomic DNA from intact biohazardous mammalian tissues. Biotechniques 26:62-4, 66
Baba, T W; Liska, V; Khimani, A H et al. (1999) Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med 5:194-203
Ruprecht, R M; Baba, T W; Liska, V et al. (1998) Oral SIV, SHIV, and HIV type 1 infection. AIDS Res Hum Retroviruses 14 Suppl 1:S97-103
Ayehunie, S; Garcia-Zepeda, E A; Hoxie, J A et al. (1997) Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors. Blood 90:1379-86

Showing the most recent 10 out of 20 publications