Exhaustive genotyping of the interferon alpha receptor 1 (IFNAR1) gene and association of an IFNAR1 protein variant with AIDS progression or susceptibility to HIV-1 infection in a French AIDS cohort.

We have undertaken a systematic genomic approach in order to explore the role of the interferon alpha (IFN-alpha) pathway in AIDS disease development. As it is very difficult to genotype the IFN-alpha gene itself since it has many pseudo-genes, we have focused our interest on the genetic polymorphisms of the IFN-alpha receptor 1 (IFNAR1). We genotyped the Genetics of Resistance to Immunodeficiency Virus (GRIV) cohort composed of patients with extreme profiles of progression to AIDS, slow progressors (SP) and rapid progressors (RP), as well as seronegative controls (CTR). We identified 19 single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) greater than 1% among which two were newly characterized by our study. We found putative associations with AIDS disease development for four SNP alleles and for three haplotypes. The most interesting signals were found for two SNPs in linkage disequilibrium, the SNP IFNAR1_18339 corresponding to a Val168Leu mutation in the extracellular domain of the protein and the intronic SNP, IFNAR1_30127. The intronic SNP IFNAR1_30127 yielded a strong signal both when comparing SP with CTR (P=0.002) and RP with CTR (P=0.005) while IFNAR1_18339 yielded a smaller signal because less patients were analyzed; these SNPs could thus be involved in AIDS progression or in susceptibility to human immunodeficiency virus 1 (HIV-1) infection. Interestingly, two independent studies have previously pointed out the SNP IFNAR1_18339 in susceptibility to multiple sclerosis and to malaria. This is the first work investigating the polymorphisms of the IFNAR1 gene in AIDS. Our results which point out a possible role for the IFN-alpha pathway in susceptibility to HIV-1 infection or progression to AIDS need a necessary confirmation by genomic studies in other AIDS cohorts.

[Profiles of IgG responses against CSP, GLURP and LSA-3NR2 in urban malaria (Dakar): relations with haemoglobin levels and parasite densities]. / Profils des réponses IgG dirigées contre CSP, GLURP et LSA-3NR2 dans le paludisme urbain à Dakar : influence sur l'hémoglobinémie et les parasitémies circulantes.

Malaria remains a major health problem in sub- Saharan African countries despite substantial decreases in morbidity and mortality due to sustained control programs. Vaccines candidates were mainly tested in rural endemic setting; however increasing proportion of the population is living in urban area. Evaluation of the qualitative or quantitative immune responses to key targets of anti-Plasmodium immunity requires further investigation in urban area. In a cohort of 144 patients with mild malaria living in Dakar, we analyzed IgG responses against target antigens of P. falciparum: CSP, LSA-3NR2 and GLURP by ELISA. A mean age of 15 yrs (4-65 yrs) was found and patients were separated in 59 adults (<15yrs) and 85 children (≤15 yrs). Parasites densities (0,01-15%) did not differ between the two age groups. In contrast, haemoglobin levels appeared lower in children (4.5-16.6 g/dl) (p<0.01). For the immune results, the most recognized antigens were GLURP and CSP compared to LSA-3NR2. Levels of IgG against these antigens were significantly different between the two age groups and they were positively correlated (rho = 0.32; p<0.001). In addition, levels of IgG anti-GLURP were associated with low parasitemia (≤1%) and absence of anemia (≥11g/dl), particularly in adults (p<0.001). In a multiple regression analysis, no significant relationship was found between parasite densities and IgG responses against all the tested antigens. Our study shows the implication of IgG anti-GLURP in humoral immune response against the parasite. The present work contributes to determine IgG levels that can be used as relevant immunologic biomarkers in urban clinical malaria.

[IgG responses to candidate malaria vaccine antigens in the urban area of Dakar (Senegal): evolution according to age and parasitemia in patients with mild symptoms]. / Analyses des réponses IgG dirigées contre des antigènes candidats vaccins dans le paludisme urbain non aggravé à Dakar (Sénégal): variations suivant l'âge et les densités parasitaires.

Malaria remains a major problem in African countries despite substantial decreases in morbidity and mortality due to sustained control programs. Studies for the evaluation of qualitative or quantitative Ab responses to key targets of anti-plasmodium immunity were mostly done in rural endemic setting compared to urban area. In a cohort of 200 patients with mild malaria and living in Dakar, we analyze total and subclasses IgG responses to a panel of P. falciparum blood stage antigens: MSP1p19, MSP3, EB200, GST-5 and R23. A mean age of 15 yrs (4 to 56 yrs) and parasitemia between 0.1 to 17% were found. Levels of IgG anti-MSP3 were higher in patients with low parasitemia (≤1%) and appear negatively correlated to parasite densities (Rho =. 0.54; p= 0.021). This correlation is more significant in children (≤ 15 yrs). In addition, an increase of IgG responses against MSP1p19 is highly observed in adults having a parasitemia less than 1%. In those patients, we find that IgG1 subclasses were predominant (p <0.01). Our study shows an association between Ab responses and parasitemia. This association is dependant to IgG anti-MSP3 in children and IgG anti-MSP1p19 in adults living in urban area.

Lack of association between peripheral neuropathy and HTLV-I infection in west Africa. Epidemiological, serological and nerve biopsy study.

Patients (n = 1166) with various neurological disorders hospitalized in Dakar, Abidjan, Lomé and Ouagadougou were examined prospectively over a 42-month period. Seropositivity for HTLV-I alone was found to be 1.8%, which is comparable to that estimated for the general population in Africa. Eighteen of the patients with TSP and only 5 with PN were HTLV-I positive, but co-infections were found in 30-40% of cases. Discrete and unspecific lesions were observed on light and electron microscopic examination of peripheral nerve biopsies from 11 patients. Since spastic paraparesis emerges as the disorder containing the largest number of HTLV-I-positive individuals, it may be premature to conclude that HTLV-I is a causal agent in PN. Nevertheless, their rarity and the frequency of retroviral co-infections distinguish these cases of African HTLV-I-associated myelopathy from comparable cases observed in other parts of the world.

A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients.

Chemokines and their receptors are key factors in the onset and progression of AIDS. Among them, accumulating evidence strongly indicates the involvement of IL-8 and its receptors, CXCR1 and CXCR2, in AIDS-related conditions. Through extensive investigation of genetic variations of the human CXCR1-CXCR2 locus, we identified a haplotype of the CXCR1 gene (CXCR1-Ha) carrying two nonsynonymous single nucleotide polymorphisms, CXCR1_300 (Met to Arg) in the N terminus extracellular domain and CXCR1_142 (Arg to Cys) in the C terminus intracellular domain. Transfection experiments with CXCR1 cDNAs corresponding to the CXCR1-Ha and the alternative CXCR1-HA haplotype showed reduced expression of CD4 and CXCR4 in CXCR1-Ha cells in human osteosarcoma cells as well as in Jurkat and CEM human T lymphocytes. Furthermore, the efficiency of X4-tropic HIV-1(NL4-3) infection was significantly lower in CXCR1-Ha cells than in CXCR1-HA cells. The results were further confirmed by a series of experiments using six HIV-1 clinical isolates from AIDS patients. A genetic association study was performed by using an HIV-1(+) patient cohort consisting of two subpopulations of AIDS with extreme phenotypes of rapid and slow progression of the disease. The frequency of the CXCR1-Ha allele is markedly less frequent in patients with rapid disease onset than those with slow progression (P = 0.0003). These results provide strong evidence of a protective role of the CXCR1-Ha allele on disease progression in AIDS, probably acting through modulation of CD4 and CXCR4 expression.

Genomic analysis of Fas and FasL genes and absence of correlation with disease progression in AIDS.

Apoptosis has been suggested as a major mechanism for the CD4(+) T-lymphocyte depletion observed in patients infected with human immunodeficiency virus 1 (HIV-1). To evaluate the impact of genetic variations to apoptosis during progression of acquired immunodeficiency syndrome (AIDS), we have performed an extensive genetic analysis of Fas and Fas ligand ( FasL) genes. The coding regions and promoters of these genes were resequenced in a cohort of 212 HIV-1-seropositive patients presenting extreme disease phenotypes and 155 healthy controls of Caucasian origin. Overall, 33 single nucleotide polymorphisms (SNPs) with an allele frequency >1% were identified and evaluated for their association with disease progression. Among them, 14 polymorphisms were newly characterized. We did not find any statistically significant association of Fas and FasL polymorphisms and haplotypes with AIDS progression.