Abstract
IntroductionThe natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals. Host genetic factors may be one of the possible reasons for variable HIV-1 disease progression. Single nucleotide polymorphisms (SNPs) in the promoter region of TNF-α gene can influence its production. The aim of the present study was to determine the association of functional TNF-α SNPs and its associated parameters related to apoptosis that may influence the rate of HIV-1 disease progression.MethodsTherapy naive, 100 HIV slow progressors (SPs), 100 HIV fast progressors (FPs), 50 HIV exposed but seronegative individuals (ESNs) and 260 healthy controls from same ethnic origin were recruited. Genotyping of TNF-α variants (−863C/A, -308G/A and -238G/A) was done using PCR-RFLP. CD4 counts were determined by flow cytometry. Plasma viral load was estimated by COBAS AMPLICOR HIV-1 monitor test. Plasma TNF-α concentration was estimated by Human CBA Th1/Th2 cytokine kit. The lymphocyte mitochondrial membrane potential was measured by JC-1 dye by flow cytometry.ResultsGenotype and allele frequency of TNF-α -238G/A and -863C/A was not significantly different in HIV-1-infected patients when compared to controls, while that of TNF-α -308G/A variant (high TNF-α producer) was significantly higher in FPs compared to SPs (p<0.01, OR = 3.43). Haplotype analyses also showed that carriers of high TNF-α producing haplotype CAG was significantly more common among FPs compared to SPs (p<0.01, OR = 3). The circulating TNF-α levels in blood also correlated well with genotypes. The lymphocyte mitochondrial membrane potential of FPs having CAG haplotype was significantly low as compared to wild type (CGG) haplotype (417±22 vs 571±28, p<0.01).ConclusionHigh producer haplotype, CAG of TNF-α gene associates with enhanced apoptosis of lymphocytes in HIV-1 infected individuals, hence faster progression to AIDS. However, further functional studies are needed to confirm this association and this knowledge may help clinicians to better understand the disease outcome.
Highlights
The natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals
Genotype and allele frequency of tumor necrosis factor-alpha (TNF-a) -238G/A and -863C/A was not significantly different in HIV-1-infected patients when compared to controls, while that of TNF-a -308G/A variant was significantly higher in fast progressors (FPs) compared to slow progressor (SPs) (p,0.01, Odds ratio (OR) = 3.43)
Haplotype analyses showed that carriers of high TNF-a producing haplotype CAG was significantly more common among FPs compared to SPs (p,0.01, OR = 3)
Summary
The natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals. Single nucleotide polymorphisms (SNPs) in the promoter region of TNF-a gene can influence its production. The aim of the present study was to determine the association of functional TNF-a SNPs and its associated parameters related to apoptosis that may influence the rate of HIV-1 disease progression. Single nucleotide polymorphisms (SNPs) in the promoter region of cytokine genes may affect the quality of the immune response against a pathogen [2]. The impact of such SNPs on the course of HIV-1 infection has not been seriously investigated in Indian population. Few case-control studies have assessed the influence of TNF-a gene-polymorphism on HIV-1 disease progression in infected patients [12] [11]. There is a lack of comparative data on the influence of TNF-a SNPs on various clinical cohorts of HIV-1 infections like fast progressors, elite controllers, long-term non-progressors and exposed but seronegative individuals
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