Background Co-infection with the flavivirus GB virus C is frequent in patients suffering from human immunodeficiency virus (HIV) due to shared routes of transmission. GBV-C co-infection has been proposed to exert a beneficial influence on HIV infection. In vitro studies demonstrated down-regulation of CCR5 as a potential mechanism of GBV-C to modulate HIV disease progression. We therefore studied surface expression of the two major HIV co-receptors, CCR5 and CXCR4, on CD4+ and CD8+ T-cells in 128 HIV patients stratified with respect to their GBV-C status, immune function and HAART in vivo. Methods GBV-C infection was studied in 128 HIV patients by nested RT-PCR. FACS analysis was used to measure CCR5 and CXCR4 surface expression on CD4+ and CD8+ T cells. Results GBV-C RNA replication was detected in 30% (38/128) of patients. In HIV patients with advanced immunodeficiency, we found up-regulation of CCR5 surface expression on CD4+ T cells. However, in patients with GBV-C co-infection, no up-regulation of CCR5 CD4+ T cells was detected. Furthermore, CXCR4 surface expression was reduced in GBV-C co-infected patients. These findings were independent of HAART and HIV viral load. HIV co-receptor expression on CD8+ T cells was not altered in patients with GBV-C co-infection. Conclusion Thus, GBV-C co-infection in HIV disease leads to reduced expression of the two major HIV co-receptors, CCR5 and CXCR4, on CD4+ T cells in patients with advanced stage of immunodeficiency providing a possible molecular explanation for the clinical benefit of GBV-C co-infection in late stage HIV disease.
Multiple genotypes of GB virus C (GBV-C) – a non-pathogenic flavivirus – have been identified to date, although they are not uniformly distributed worldwide. It has also been suggested that GBV-C genotype may play a role in modulating HIV disease; however, the prevalence and genotype distribution of GBV-C has not been adequately studied in most countries. Among 408 HIV positive subjects in Germany, 97 (23.8%) had detectable GBV-C RNA. Based on sequencing of the 5′ untranslated region (5′UTR), the GBV-C genotypes were 1 (n = 8; 8.2%), 2 (n = 81; 83.5%), and 3 (n = 2; 2.1%), as well as a unique genotype not previously reported (n = 6; 6.2%). Among 17 samples also sequenced in the envelope 2 (E2) region, 14 had concordant genotype results when comparing the 5′UTR and E2, while evidence of intergenotypic recombination was observed among E2 sequences from 3 individuals. These results suggest that genotypic diversity and viral recombination contribute to the overall genetic variability of GB virus C.
The inbred BD rat strains constitute a model system for analysis of the genetic basis of susceptibility or resistance to the development of neural tumors, as they exhibit distinct strain-specific differences regarding the sensitivity to tumor induction by the alkylating carcinogen N-ethyl-N-nitrosourea (EtNU). Among the different BD strains, BDIX and BDIV rats, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced malignant schwannomas of the peripheral nervous system (PNS), predominantly of the trigeminal nerves. We have previously mapped one locus associated with susceptibility/resistance to schwannoma induction to the telomeric third of chromosome 10 (Mss1) in segregating (BDIX 3 BDIV) crosses. We report on the genetic mapping of 6 further loci controlling tumor incidence or survival time on chromosomes 1 (Mss2), 3 (Mss3), 6 (Mss4), 13 (Mss5) and 15 (Mss6) as well as on chromosome 10 (Mss7) close to the centromere. Interestingly, most of these loci mediate gender-specific effects of variable strength ranging from minor influences on tumor development to complete tumor resistance. The gender specificity is reflected by the fact that male (BDIX 3 BDIV) F 2 rats exhibit a 2-fold higher incidence of EtNUinduced schwannomas than females as well as a shorter survival time. A number of human nervous system tumors too arise with a marked gender bias. Genes mediating gender-specific predisposition of developing malignant schwannomas in the rat may be relevant for the human individual risk of developing nervous system tumors. ' 2005 Wiley-Liss, Inc.
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