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


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


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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