Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual's NRTI-SN risk.

Nucleoside analog-associated sensory neuropathy (NRTI-SN) attributed to stavudine, didanosine, or zalcitabine (the dNRTIs) and distal sensory polyneuropathy (DSP) attributed to HIV are clinically indistinguishable. As inflammatory cytokines are involved in DSP, we addressed a role for inflammation in NRTI-SN by determining the alleles of immune-related genes carried by patients with and without NRTI-SN. Demographic details associated with risk of various neuropathies were included in the analysis. Alleles of 14 polymorphisms in 10 genes were determined in Australian HIV patients with definite NRTI-SN (symptom onset <6 months after first dNRTI exposure, n = 16), NRTI-SN-resistant patients (no neuropathy despite >6 months on dNRTIs, n = 20), patients with late onset NRTI-SN (neuropathy onset after >6 months of dNRTIs, n = 19), and HIV-negative controls. Carriage of TNFA-1031*2 was highest in NRTI-SN patients, suggesting potentiation of NRTI-SN. Carriage of IL12B (3' UTR)*2 was higher in NRTI-SN-resistant patients than controls or NRTI-SN patients, suggesting a protective role. BAT1 (intron 10)*2 was more common in NRTI-SN than resistant patients, but neither group differed from controls. This marks the conserved HLA-A1, B8, DR3 haplotype. Of the demographic details considered, increasing height was associated with NRTI-SN risk. A model including cytokine genotype and height predicted NRTI-SN status (p < 0.0001, R(2) = 0.54). Late onset NRTI-SN patients clustered genetically with NRTI-SN-resistant patients, so these patients may be genetically "protected." In addition to patient height, cytokine genotype influenced NRTI-SN risk following dNRTI exposure, suggesting inflammation contributes to NRTI-SN.

Recovery of CD4+ T Cells in HIV patients with a stable virologic response to antiretroviral therapy is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes.

We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts <300 cells/microL (n = 33) and >400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.012). BAT1*2 uniquely marks the central major histocompatibility complex region of a conserved haplotype (HLA-A1,B8,BAT1*2,TNFA-308*2,DR3,DQ2). There was no association between alleles carried at CCR5Delta32, CCR5 59029, CCR5 59353, CCR2+190 (V64I), SDF1 3'UTR, IL1A+4845, IL1B+3953, IL4-589, IL10-592, IL10-R1+536, IL10-R1+1112, IL12B 3'UTR, TNFA-308, or TNFA-1031 and CD4 T-cell counts. We suggest that immune activation and/or CD4 T-cell apoptosis in HIV patients on effective ART is influenced by genetic factors.