Background:  AIDS dementia complex (ADC) affects only approximately 20% of advanced HIV disease patients without ART. Both viral and host factors affect the development of ADC. Candidate host factors associated with increased cytokine synthesis may predispose patients to ADC, given that the best marker of ADC severity is the degree of microglial activation, which in turn is related to excess cytokines. We hypothesized that polymorphisms in genes encoding the cytokines tumor necrosis factor-a (TNFa), interleukin (IL)-1a, IL-1β, and IL-12p40 may be associated with ADC. We examined the relationship between ADC and ApoE4, as there have been conflicting results from previous studies.

Methods:  Genomic DNA was isolated from cryopreserved peripheral blood mononuclear cell from 56 HIV⁺ ADC patients (mean age 36 years), 112 to 203 patients with HIV disease without ADC and 60 to 204 patients without HIV disease. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) assays were used to determine the alleles carried at TNFA-308, IL1A-889, IL1B+3953, IL12B-3’UTR, and ApoE. Alleles carried at BAT1(intron 10) in the central MHC were included as a marker of a conserved MHC haplotype associated with multiple immunopathological diseases (HLA-A1, B8, BAT1 [intron 10]*2, TNFA-308*2, DR3, DQ2). Fisher’s exact test was used to evaluate differences in allelic carriage.

Results:  Carriage of TNFA-308*(2,2) with BAT1(intron 10)*(2,x) was significantly more common in the ADC patients than in either control group (p = 0.005 for HIV⁺ controls and p = 0.024 for HIV^­ controls). Carriage of the other polymorphisms was similar in the ADC patients and control groups.

Conclusions:  Previously 2 studies (one clinically based, the other pathology based) reported contradictory findings in relation to TNFA-308 and ADC. The present study is the largest thus far, so we suggest that the association is pathogenetically important. Indeed the association is of the same magnitude as that of the MCP-1 polymorphism. The lack of association with ApoE4 status may be related to the younger age of the ADC patients in our study. Presently the genetic risk signature for ADC appears to be TNFA-308*(2,2) with BAT1(inton10)*(2,x), MCP1*2578G, and ApoE (4,4), the latter being important in older patients. Other yet-to-be-determined genetic risk factors may be important. The elucidation of the genetic signature will allow the identification of patients who will require more intensive monitoring and perhaps the earlier introduction of HAART.