TUMOR-NECROSIS-FACTOR C2 MICROSATELLITE ALLELE IS ASSOCIATED WITH THERATE OF HIV DISEASE PROGRESSION

Background: The rate of immunological deterioration and progression to AIDS differs markedly between HIV-positive individuals, and may be in fluenced by cofactors, HIV phenotype and host T-cell response. Tumour necrosis factor (TNF)-alpha and lymphotoxin stimulate HIV replication and may induce apoptosis of HIV-infected and uninfected lymphocytes in vitro, thus accelerating disease progression and CD4 depletion. Varia bility in TNF production between individuals is to a degree geneticall y determined and may be predicted from polymorphisms of microsatellite regions surrounding the human TNF gene locus. Methods: We examined TN F microsatellite polymorphisms in 24 HIV-positive patients with slower disease progression (CD4 count > 400 x 10(6)/l at greater than or equ al to 6 years), 20 HIV-positive patients with faster progression (CD4 count < 200 x 10(6)/l within 5 years) and 109 healthy controls residen t in north-west England. Typing was performed by polymerase chain reac tion amplification of TNF a, b, c and d microsatellites and alleles we re defined using fluorescence-based semi-automated microsatellite mapp ing techniques. Results: No significant differences in TNF a, b and d allele frequencies were observed between faster and slower progressors , or with healthy controls. The frequency of the TNF c2 allele was sig nificantly different between HIV-positive slower (60.9%) and faster (1 5%) progressors (P = 0.002) with an odds ratio of 0.1 (95% confidence interval, 0-0.6). TNF c2 was also less frequent in faster progressors than in healthy controls (45.9%, P = 0.006) with an odds ratio of 0.2 (95% confidence interval 0-0.8). Conclusions: This is the first report demonstrating a strong association between the TNF c2 allele and the rate of HIV progression. Although it is possible that this finding may have arisen as a result of linkage disequilibrium with other alleles within the major histocompatibility complex that exert a more powerful effect upon progression, evidence is mounting to suggest that both TN F-alpha and lymphotoxin are closely involved in HIV disease progressio n and CD4 depletion. Our results serve to highlight the potential impo rtance of genetic polymorphism, particularly of the TNF locus, in infl uencing the progression of HIV infection.