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Inhibition of and Selection against Vertical HIV-1 Transmission by the Placenta B. K. PATTERSON1*, H. BEHBAHANI2, D. MATHUI3, S. BRODIE3, J. ANDERSSON2, A. LANDAY4, Z. BURKI1, P. GARCIA1, and E. POPEK5. 1Northwestern Univ Med. Sch./Children’s Mem. Hosp., Chicago, IL; 2Karolinska Inst., Stockholm, Sweden; 3Univ. of Washington, Seattle; 4Rush Med. Coll., Chicago, IL; and 5Baylor Coll. of Med., Houston, TX Recent data on the use of caesarian section indicates that maternal fetal transmission of HIV may be more likely to occur around the time of birth which suggests that the placenta may protect against vertical transmission. To determine the role of the placenta in preventing vertical transmission, we studied 29 placentas including 5 from transmitting women (TT), 13 from non-transmitting women (TNT), 6 from normal women, and 5 pre-term products of conception (POC). All but two placentas were from women not on AZT therapy. Using gene expression arrays (GEAS) and sequencing of the C2-V5 region of mother, placenta, and baby HIV-1 env DNA, we found distinct immunologic and molecular differences in TT placentas compared to TNT placentas. Using total RNA extracted from placentas in our GEAS, we found that IL-10, CXCR4, TNF-a, and FasL were all elevated in TNT compared to TT (all p<0.02) placentas but not significantly elevated compared to placentas from HIV seronegative mothers. Using neighbor joining and phylogenetic trees of at least 7 clones per sample, analysis of env DNA revealed distinct clusters of TT sequences versus TNT sequences. Further, HIV env DNA sequences from baby PBMCs were variants of the mother sequences but not the placental sequences in 1 of 2 TT placentas. Last, V3 sequences from TT placentas were predominantly R5, NSI while V3 sequences from TNT were predominantly X4, SI. In summary, the immunologic milieu of the placenta from normal and TNT women increases the CXCR4/CCR5 mRNA and protein expression ratio and, in TNT placentas, selects for X4, SI HIV-1 isolates that were not transmitted in our cohort. Upregulation of FasL has been shown in mice to inhibit the migration of activated T-lymphocytes into the placenta and in humans may prevent HIV-infected cells from entering the placenta. Baby HIV-1 isolates were either a variant of the mother isolate but not of the placental isolate supporting acquisition of HIV-1 at the time of birth or a variant of the NSI isolate found in the paired TT placenta. Key Words: gene sequence, placenta, transmission |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |