All ETDs from UAB

Advisory Committee Chair

Richard A Kaslow

Advisory Committee Members

Jeffery C Edberg

Sadeep Shrestha

Jianming Tang

S Louis Bridges

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Host factors including genes and their variants are important to HIV-1 acquisition, transmission and disease progression. In particular, chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have multiple variants of interest. We first investigated the impact of CCR2-CCR5 haplotypes on several outcomes among 567 HIV-1 discordant Zambian couples. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta=-0.58 log10 P=0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta=0.54, log10 P=0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by the HIV-1 exposed seronegatives (HESN) (HR=2.0, 95% CI=1.20-3.43, P=0.008), after adjustments for index partner VL and the presence of genital ulcer or inflammation in either partner in Cox multivariable models. CC-motif chemokine ligands (CCLs) can block HIV-1 binding sites on CCR5 and inhibit viral entry. We studied single nucleotide polymorphisms (SNPs) in genes encoding three CCR5 ligands [CCL3 (MIP-1α), CCL4 (MIP-1ß), and CCL5 (RANTES)] along with an adjacent gene encoding a CCR2 ligand [CCL2 (MCP-1)] on HIV-1 VL and heterosexual transmission in Zambia cohort. We found that rs5029410 C allele (in CCL3 intron 2) was associated with lower VL in seroconverters, adjusted for gender and age (regression beta=-0.57 log10, P=4x10-6). In addition, rs34171309 A allele in CCL3 exon 3 was associated with increased risk of HIV-1 acquisition in HESNs (hazard ratio=1.52, P=0.006) when adjusted for donor VL and genital ulcer/inflammation. We further screened variants in CCR5 gene and untranslated regions (UTRs) of CCR2 gene in order to rule out the potential confounding by population-specific variants not reported in the literature. Among 27 SNPs found in 109 Zambian samples with representative CCR2-CCR5 diplotypes, 5 are within the CCR5 coding region. Genotyping for the entire Zambian cohort (567 couples) revealed that allele T for CCR5 SNP rs1800944 (encoding alanine to valine change) was associated with slightly higher viral load in donor partners, after adjusting for age and gender (beta=0.24 log10, P=0.026). Analyses for other outcomes and other SNPs were not conclusive. Overall, our data favor the hypothesis that host genetic variants within several C-C-motif chemokine ligand and receptor genes can mediate HIV-1 acquisition and control of infection in our study population. Future investigation may need to focus on a) functional relevance of CCL and CCR variants; b) the potential interaction of CCL and CCR gene variants and other HIV-1-related host factors; and c) viral evolution attributable to CCR and CCL gene variants. Such efforts will be essential to producing a clear picture about the innate and adaptive immunity to HIV-1 infection.

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