The aim of this revised proposal is to extend the preliminary observation at genes mapping in or near MHC are associated with events regulating the transmission of HIV-l infection from mother to child during pregnancy. The central hypotheses are, one, that certain of the infants born to mothers infected with HIV-1 exhibit a genetically determined state associated with certain MHC alleles that alters the likelihood of becoming infected during pregnancy, and two, that maternal MHC genotype influences the evolution of the HIV infection in the mother such that the probability of viral transmission is affected. The approach involves the study of two independent cohorts of infected mothers and their children, including approximately 13% with multiple sibs. MHC alleles will be identified by direct nucleotide sequence based typing. Preliminary data and the results of typing the smaller MIS cohort will be used to develop specific experimental hypotheses that will be tested in the large WITS cohort in a cross validation design. Conventional association procedures and haplotype(allele relative risk analysis will then be used in the single offspring families in a case control design to determine whether the frequency of alleles differ between infants that become infected and those that do not. The influence of testing for multiple associations will be assessed by computer simulations and diminished by the cross validation design. The location of the genetic effect will attempt to be identified by the strength of associations observed and by linkage studies performed in the multicase families. These may distinguish the direct effect of an HLA allele from linkage disequilibrium with an allele of a polymorphic non-HLA locus. Alternate stratification of mothers and infants according to specific risk factors will be undertaken including whether infants or fetuses suspected of intrauterine infection differ from those more likely to be infected during birth. Special attention will be directed to the contributions made by ethnic differences based on their apparent importance in preliminary studies. Mothers will be studied to address specific hypotheses such as whether maternal genetics influences the transmission frequency and whether vertical transmission is influenced by maternal-fetal histocompatibility. Candidate MHC alleles identified in these studies will be grouped together according to structural features such as shared motifs or common peptide binding pockets for use in further analyses in an attempt to gain insight into potentially novel mechanisms in the host-virus relationship. These data will be provided to the MIS and WITS databases for inclusion in their ongoing multifactorial analysis of transmission.
| Winchester, Robert; Pitt, Jane; Charurat, Manhattan et al. (2004) Mother-to-child transmission of HIV-1: strong association with certain maternal HLA-B alleles independent of viral load implicates innate immune mechanisms. J Acquir Immune Defic Syndr 36:659-70 |
