This proposal aims to comprehensively describe host and virus biology associated with HIV-1 subtype C (HIV-1C) mother-to-child transmission (MTCT). We hypothesize that HIV-1 C MTCT is a non-stochastic event mediated by both placenta! and viral determinants. To address this hypothesis, we will: 1) genotype and phenotype vertically transmitted envelope (env) genes, 2) characterize envelope genes isolated from archived placental biopsies, 3) describe the placental environment during MTCT. All experiments will use previously collected samples from a well-characterized cohort of 744 HIV-1 C-infected pregnant Malawian women characterized as nontransmitting (NT), in utero (IU) mother-offspring pairs (MOPs) and intrapartum (IP) MOPs. In a preliminary study, we enumerated HIV-1 C V1/V2 env diversity in 22 MOPs and found that infants had significantly fewer variants than their mothers and confirmed that HIV env diversity is restricted during MTCT. During the mentored portion of this grant (Specific Aim 1), I will test the hypothesis that restriction is facilitated by specific env genotypes. This will be accomplished by cloning full-length envelope genes to: a) compare V1/V2 loop lengths, b) enumerate putative glycosylation sites, c) pseudotype the cloned env genes against CCR5, CxCR4, CD4hi and CD4lo cells. As an independent investigator, I will focus on ID MTCT and test the hypothesis that the placenta is a unique HIV-1 C compartment. Using a heteroduplex tracking assay, I will compare HIV-1 C env genes from matched peripheral blood, placental blood, placental biopsies, and cord blood (Specific Aim 2). Placental specific variants will be characterized using the methods acquired during the mentored phase.
In Specific Aim 3, transmitted and placental specific variants will be psuedotyped against primary placental trophoblasts and Hofbauer cells. Finally, in Specific Aim 4, placental biopsies will be analyzed for HIV-1 C, CCR5, CD4, and CXCR4 expression. The results of this project will provide a comprehensive description of the HIV-1 C envelope genes and the placental environment conducive to in utero HIV-1 C MTCT.
|Handelman, Samuel K; Aaronson, Jacob M; Seweryn, Michal et al. (2015) Cladograms with Path to Event (ClaPTE): a novel algorithm to detect associations between genotypes or phenotypes using phylogenies. Comput Biol Med 58:1-13|
|Mates, Jessica M; Kumar, Surender B; Bazan, Jose et al. (2014) Genotypic and phenotypic heterogeneity in the U3R region of HIV type 1 subtype C. AIDS Res Hum Retroviruses 30:102-12|
|Turner, Abigail Norris; Tabbah, Sammy; Mwapasa, Victor et al. (2013) Severity of maternal HIV-1 disease is associated with adverse birth outcomes in Malawian women: a cohort study. J Acquir Immune Defic Syndr 64:392-9|
|Ackerman 4th, William; Kwiek, Jesse J (2013) Role of the placenta in adverse perinatal outcomes among HIV-1 seropositive women. J Nippon Med Sch 80:90-4|
|Kumar, Surender B; Rice, Cara E; Milner Jr, Danny A et al. (2012) Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission. AIDS 26:685-94|
|Russell, Elizabeth S; Kwiek, Jesse J; Keys, Jessica et al. (2011) The genetic bottleneck in vertical transmission of subtype C HIV-1 is not driven by selection of especially neutralization-resistant virus from the maternal viral population. J Virol 85:8253-62|
|Kumar, Surender B; Handelman, Samuel K; Voronkin, Igor et al. (2011) Different regions of HIV-1 subtype C env are associated with placental localization and in utero mother-to-child transmission. J Virol 85:7142-52|
|Gay, Cynthia L; Mwapasa, Victor; Murdoch, David M et al. (2010) Acute HIV infection among pregnant women in Malawi. Diagn Microbiol Infect Dis 66:356-60|
|Mwapasa, Victor; Cachafeiro, Ada; Makuta, Yohane et al. (2010) Using a simplified human immunodeficiency virus type 1 p24 antigen assay to diagnose pediatric HIV-infection in Malawi. J Clin Virol 49:299-302|
|Kwiek, Jesse J; Mwapasa, Victor; Alker, Alisa P et al. (2008) Socio-demographic characteristics associated with HIV and syphilis seroreactivity among pregnant women in Blantyre, Malawi, 2000-2004. Malawi Med J 20:80-5|
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