In order to develop strategies to interrupt maternal-fetal transmission our goals are to define the """"""""timing"""""""" of maternal fetal transmission as in utero vs. intrapartum using """"""""state of the art"""""""" and relate maternal risk factors to the route of transmission and to define viral and immunological factors of primary infection in the infant associated with both the timing of infection the time to onset of symptoms and the clearance of virus in infants with """"""""transient"""""""" infection. In a prospective study of HIV (+) pregnant women/infants we will explore our hypothesis that both in utero/intrapartum transmission occur as defined by the presence or absence of HIV virus in the infant at birth and that maternal immune mechanisms including the absence of autologous neutralizing antibody will contribute to development of virus with expanded cell tropism, an increased virus load and the emergence of immune escape virus variants that will transmit to the infant. These factors and placental leaks in the maternal fetal barrier, may be relevant to intrauterine transmission whereas local factors presence of virus or absence of HIV IgA antibody in the genital tract at delivery may be important intrapartum transmission. The timing of infection (fetal or neonatal) may be critical to the potential occurrence of accelerated HIV induced (apoptosis) resulting in early T cell dysfunction and early symptoms. This combined with virological factors (virus load, genotype and phenotype) and immune response of neonates may contribute to the infant's prognosis including the clearance of the virus.
The Specific Aims are-to assess the maternal virus burden (quantitive PCR, culture + ICDP24AG) virus cellular tropism, autologous neutralizing antibody and cervical HIV-IGA and HIV-1 secretion at the time of delivery in relation to the risk of in utero/intrapartum transmission. By molecular genetic analysis of maternal/infant and """"""""neutralization antibody escape virus, we will assess whether immune escape variants are passed to the infant. Placentas will be evaluated for inflammation an cofactors. We will assess the sensitivity and specificity of our definition of in utero vs. intrapartum transmission based on detection of HIV virus (PCR/culture/ICPZ4AG) at birth and the virus load/genotype and phenotype and number of apoptotic cells sequentially in infants an correlate this with the onset of symptoms and outcome. These studies will provide essential information to develop strategies of interruption of maternal- fetal transmission including immune therapy antivirals and vaccines.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030629-02
Application #
2202958
Study Section
AIDS and Related Research Study Section 2 (ARRB)
Project Start
1993-05-01
Project End
1998-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Truong, Hong-Ha M; Sim, Myung S; Dillon, Maryanne et al. (2010) Correlation of immune activation during late pregnancy and early postpartum with increases in plasma HIV RNA, CD4/CD8 T cells, and serum activation markers. Clin Vaccine Immunol 17:2024-8
Dickover, Ruth; Garratty, Eileen; Yusim, Karina et al. (2006) Role of maternal autologous neutralizing antibody in selective perinatal transmission of human immunodeficiency virus type 1 escape variants. J Virol 80:6525-33
Tuomala, Ruth E; Shapiro, David E; Mofenson, Lynne M et al. (2002) Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 346:1863-70
Plaeger, S; Bermudez, S; Mikyas, Y et al. (1999) Decreased CD8 cell-mediated viral suppression and other immunologic characteristics of women who transmit human immunodeficiency virus to their infants. J Infect Dis 179:1388-94
Dickover, R E; Herman, S A; Saddiq, K et al. (1998) Optimization of specimen-handling procedures for accurate quantitation of levels of human immunodeficiency virus RNA in plasma by reverse transcriptase PCR. J Clin Microbiol 36:1070-3
Dickover, R E; Dillon, M; Leung, K M et al. (1998) Early prognostic indicators in primary perinatal human immunodeficiency virus type 1 infection: importance of viral RNA and the timing of transmission on long-term outcome. J Infect Dis 178:375-87
Economides, A; Schmid, I; Anisman-Posner, D J et al. (1998) Apoptosis in cord blood T lymphocytes from infants of human immunodeficiency virus-infected mothers. Clin Diagn Lab Immunol 5:230-4
Dickover, R E; Garratty, E M; Herman, S A et al. (1996) Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission. Effect of maternal zidovudine treatment on viral load. JAMA 275:599-605
Nielsen, K; Boyer, P; Dillon, M et al. (1996) Presence of human immunodeficiency virus (HIV) type 1 and HIV-1-specific antibodies in cervicovaginal secretions of infected mothers and in the gastric aspirates of their infants. J Infect Dis 173:1001-4
Nielsen, K; Wei, L S; Sim, M S et al. (1995) Correlation of clinical progression in human immunodeficiency virus-infected children with in vitro zidovudine resistance measured by a direct quantitative peripheral blood lymphocyte assay. J Infect Dis 172:359-64

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