Polymorphism in the Interleukin-4 Promoter Affects Acquisition of Human Immunodeficiency Virus Type 1 Syncytium-Inducing Phenotype

Abstract

The emergence of syncytium-inducing (SI) variants of human immunodeficiency virus type 1 (HIV-1) in infected individuals is an indicator of poor prognosis and is often correlated with faster CD4؉ cell depletion and rapid disease progression. Interleukin-4 (IL-4) is a pleiotropic cytokine with various immune-modulating functions including induction of immunoglobulin E (IgE) production in B cells, down-regulation of CCR5 (a coreceptor for HIV-1 non-SI [NSI] strains), and up-regulation of CXCR4 (a coreceptor for HIV-1 SI variants).Here we show that homozygosity of a polymorphism in the IL-4 promoter region, IL-4 ؊589T, is correlated with increased rates of SI variant acquisition in HIV-1-infected individuals in Japan. This mutation was also shown to be associated with elevated serum IgE levels in HIV-1-infected individuals, especially in those at advanced stages of disease. In contrast, neither a triallele polymorphism in IL-10, another Th2 cytokine, nor a biallele polymorphism in the RANTES promoter affected acquisition of the SI phenotype. This finding suggested that IL-4-589T increases IL-4 production in the human body and thus accelerates the phenotypic switch of HIV-1 from NSI to SI and possibly disease progression of AIDS.

Identification of Three Immunologic Correlates for HIV Type 1 Pathogenesis in Youth

“…In particular, an elevated interleukin (IL)-4:interferon (IFN)-g ratio has been correlated with high plasma viral load and rapid loss of CD4 þ T cells, 6 while increases in IL-4 and IL-4-induced IgE production appear to coincide with the emergence of syncytium-inducing viruses. 10,11 Emerging consensus findings point to circulating IL-7, IL-10, IL-15, IL-18, and tumor growth factor (TGF)-b1 as probable predictors or biomarkers of HIV-1-related outcomes that range from infection to disease progression and response to therapy. [12][13][14][15][16][17][18][19] Analyses of other immune activation markers such as soluble CD30 (tumor necrosis factor receptor superfamily, member 8) can be equally informative.…”

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study

“…[24][25][26][27] Molecular genetic epidemiological studies have identified polymorphisms in more than 20 human genes, including several chemokines and their receptors, that are associated with HIV-1 infection and/or AIDS disease pathogenesis. [28][29][30][31][32][33][34][35][36][37][38][39][40] Given the importance of SDF-1 in various metabolic and developmental activities, we examined the allele frequencies and haplotype structure of nine SNPs in and around the SDF-1 gene. In addition, given the important role played by SDF-1 and CXCR4 in HIV-1/AIDS, we looked for the influence of genetic variation in these SNPs and haplotypes on disease in over 3000 subjects enrolled in five USA-based natural history HIV-1/AIDS cohorts.…”

Mother-to-infant transmission of HIV-1: the placenta fights back

“…IL-4 is of particular interest because in vitro it promotes the growth of syncytium-inducing (SI) virus by increasing CXCR4 expression on CD4 + lymphocytes and decreasing CCR5 expression, and by stimulating replication of HIV-1 isolates via transcriptional activation (19). Moreover, recent data suggest that homozygosity of a polymorphism in the IL-4 promoter region, IL-4 589T, is correlated with increased rates of SI variant acquisition in HIV-1-infected individuals (20). Thus, polymorphisms in the IL-4 gene resulting in increased levels of IL-4 place pressure on virus to become SI, CXCR4-using strains that are least likely to be transmitted from mother to infant.…”