Maternal transmission of HlV-1 is a growing problem worldwide. We will test two key issues in congenital HIV-1 infection in primate models: the mechanism of neonatal infection across intact mucosa, and the fate of mucosal Langerhans cells (LC) during disease progression. Our group is uniquely qualified to conduct this work. First, by inoculating simian immunodeficiency virus (SlV) into amniotic fluid, we created a primate model for in utero infection. Second, by exposing neonatal macaques orally to SIV following C-section, we created a primate model which mimics intrapartum mucosal transmission. For both models, high infection rates were achieved. Using oral infection at birth with SIVdelta3, which is deleted in nef, vpr and NRE, and which is attenuated in adult macaques after intravenous (i.v.) infection, we made a startling finding: SIVdelta3 replicated to high levels and caused AIDS in infants. This led us to hypothesize that a) mucosal LC play a pivotal role in the early dissemination of SlV across neonatal mucosal surfaces; b) that these steps require neither Nef nor Vpr; and c) that infection of LC may play a key role in the pathogenesis of primate immunodeficiency virus infection in neonates.
The Specific Aims are to: 1. Compare the susceptibility of cultured neonatal LC to lentiviral infection with that of adult cells and investigate the mechanism(s) of virus dissemination from acutely infected LC; compare the rate of virus production by LC exposed to isogenic HIV-1 and SIV differing only in nef or vpr. 2. Determine the portal of virus entry (using wild-type SIVmac251) initial target cells and pattern of virus spread following oral or i.v. infection of neonates. Are IC the earliest cells infected after oral infection? Do LC, and dendritic cells in general, undergo apoptosis in infected neonates? 3. Determine the infection rate and fate of LC during the clinically asymptomatic period after seroconversion following oral or i.v. neonatal infection, and after full-blown AIDS has developed. 4. Determine infection rate and fate of LC after in utero infection; test whether viral load, number or phenotype of apoptotic cells, or the rate of disease progression differ in neonates infected before and after acquiring the capability to mount immune responses. 5. Test whether immune activation precipitates wide-spread apoptosis in SIV-infected infant macaques. Are LC, and dendritic cells in general, lost as a consequence? The proposed work, which is based on our prior accomplishments, is highly significant because it will yield new insights into lentiviral pathogenesis during ontogeny.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032330-08
Application #
2672110
Study Section
Special Emphasis Panel (SRC (55))
Project Start
1991-09-30
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
8
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
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

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