Conclusion
High 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.
Methods
Therapy 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.
Results
Genotype 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).