1. Screening low-frequency SNP from genome-wide association study reveals a new risk allele for progression to AIDS.
Le Clerc S, Coulonges C, Delaneau O, Van Manen D, Herbeck JT, Limou S, An P, Martinson JJ, Spadoni JL, Therwath A, Veldink JH, van den Berg LH, Taing L, Labib T, Mellak S, Montes M, Delfraissy JF, Schächter F, Winkler C, Froguel P, Mullins JI, Schuitemaker H, Zagury JF.. Jaids.. 2011 ; 21107268 [PubMed - in process].
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Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance.
2. Multiple-Cohort Genetic Association Study Reveals
CXCR6 as a New Chemokine Receptor Involved
in Long-Term Nonprogression to AIDS
Sophie Limou, Cedric Coulonges, Joshua T. Herbeck, Danielle van Manen, Ping An, Sigrid Le Clerc, Olivier Delaneau, Gora Diop, Lieng Taing, Matthieu Montes, Angelique B. van t Wout, Geoffrey S. Gottlieb, Amu Therwath, Christine Rouzioux, Jean-Francois Delfraissy, Jean-Daniel Lelievre, Yves Levy, Serge Hercberg, Christian Dina, John Phair, Sharyne Donfield, James J. Goedert, Susan Buchbinder, Jerome Estaquier, Francois Schachter, Ivo Gut, Philippe Froguel, James I. Mullins,a Hanneke Schuitemaker,a Cheryl Winkler, and Jean-Francois Zagury. J Infect Dis.. 2010 ; 2010:202(6):908-915. télécharger la publication (version PDF*)
The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. Methods. To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (<100 copies/mL). Results. The rs2234358 polymorphism in the CXCR6 gene was the strongest signal ([Formula: see text]; odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of [Formula: see text][Formula: see text]. This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms. Conclusions. The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.
3. Genomewide Association Study of a Rapid Progression Cohort Identifies New Susceptibility Alleles for AIDS (ANRS Genomewide Association Study 03).
Le Clerc S, Limou S, Coulonges C, Carpentier W, Dina C, Taing L, Delaneau O, Labib T, Sladek R, Group AG, Deveau C, Guillemain H, Ratsimandresy R, Montes M, Spadoni JL, Therwath A, Schächter F, Matsud. J Infect Dis. . 2009 ; 200(8):1194-1201. télécharger la publication (version PDF*)
Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology. Methods. We undertook a case-control GWAS of a unique cohort of 85 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced rapid disease progression, using Illumina HumanHap300 BeadChips. The case group was compared with a control group of 1352 individuals for the 291,119 autosomal single-nucleotide polymorphisms (SNPs) passing the quality control tests, using the false-discovery rate (FDR) statistical method for multitest correction. Results. Novel associations with rapid progression (FDR, 25%) were identified for PRMT6 ([Formula: see text]; odds ratio [OR], 0.24), SOX5 ([Formula: see text]; OR, 0.45), RXRG ([Formula: see text]; OR, 3.29), and TGFBRAP1 ([Formula: see text]; OR, 0.34). The haplotype analysis identified exonic and promoter SNPs potentially important for PRMT6 and TGFBRAP1 function. Conclusions. The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor beta pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets..
4. Genome wide association study on an AIDS non progression cohort emphasizes the role of HLA genes (ANRS Genome wide Association Study 02)
Limou S, Le Clerc S, Coulonges C, Carpentier W, Dina C, Delaneau O, Labib T, ......, Delfraissy JF, Hercberg S, Zagury JF. J Infect Dis.. 2009 ; epub : 28 dec 2008 199:419-426. télécharger la publication (version PDF*)
To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 ([Formula: see text]; odds ratio, 3.47) and was possibly linked to an effect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal ([Formula: see text]) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection..
5. SHAPE-IT : a new rapid and accurate haplotyping software.
Delaneau O, Coulonges C, Zagury JF. . BMC Bioinformatics . 2008 ; 9:540-48 . télécharger la publication (version PDF*)
We have developed a new computational algorithm, Shape-IT, to infer haplotypes under the genetic model of coalescence with recombination developed by Stephens et al. in Phase v2.1. The major algorithmic improvements rely on the use of binary trees to represent the sets of candidate haplotypes for each individual. These binary tree representations : (1) speed up the computations of posterior probabilities of the haplotypes by avoiding the redundant operations made in Phase v2.1, and (2) overcome the exponential aspect of the haplotypes inference problem by the smart exploration of the most plausible pathways (ie. haplotypes) in the binary trees. RESULTS: Our results show that Shape-IT is several orders of magnitude faster than Phase v2.1 while being as accurate. For instance, Shape-IT runs 50 times faster than Phase v2.1 to compute the haplotypes of 200 subjects on 6,000 segments of 50 SNPs extracted from a standard Illumina 300K chip (13 days instead of 630 days). We also compared Shape-IT with other widely used software, Gerbil, PL-EM, Fastphase, 2SNP, and Ishape in various tests: Shape-IT and Phase v2.1 were the most accurate in all cases, followed by Ishape and Fastphase. As a matter of speed, Shape-IT was faster than Ishape and Fastphase for datasets smaller than 100 SNPs, but Fastphase became faster -but still less accurate- to infer haplotypes on larger SNP datasets. CONCLUSION: Shape-IT deserves to be extensively used for regular haplotype inference but also in the context of the new high-throughput genotyping chips since it permits to fit the genetic model of Phase v2.1 on large datasets. This new algorithm based on tree representations could be used in other HMM-based haplotype inference software and may apply more largely to other fields using HMM..
6. Exploration of associations between phospholipase A2 gene family polymorphisms and AIDS progression using the SNPlextrade mark method.
Limou S, Coulonges C, Foglio M, Heath S, Diop G, Leclerc S, Hirtzig T, Spadoni JL, Therwath A, Lambeau G, Gut I, Zagury JF. . Biomed Pharmacother . 2008 ; 62:31-40 . télécharger la publication (version PDF*)
Members of the secreted phospholipase A2 (PLA2) protein family can inhibit HIV-1 virus replication in vitro. To evaluate the impact of PLA2 gene polymorphisms on AIDS disease development, we studied 12 family members using SNPlextrade mark technology that permitted simultaneous typing of 70 tagging Single Nucleotide Polymorphisms (tagSNPs). The study utilized HIV-1 seropositive donors with slow progressor (n=168) or rapid progressor (n=54) status, plus 355 control subjects. All donors were Caucasian (total 577 individuals). Genetic associations yielded mainly 0.01 p 0.05, but lower p-values were obtained for four tagSNPs and seven haplotype alleles. These stronger associations corresponded to both secreted (PLA2G2A, PLA2G2D and PLA2G3) and cytosolic (PLA2G4A and PLA2G6) PLA2 genes, including three (PLA2G2A, PLA2G2D and PLA2G4A) implicated in the pathogenesis of other diseases. Our results suggest that the PLA2 gene family may represent genes of interest for a larger study targeting all the known tagSNPs in the PLA2 genes. The data presented in this study will have to be confirmed in other AIDS cohorts and will also be useful for studies undertaken on the PLA2 gene family in other disease cohorts..
7. ISHAPE : new rapid and accurate software for haplotyping.
Delaneau O, Coulonges C, Boelle PY, Nelson G, Spadoni JL, Zagury JF. . BMC Bioinformatics . 2007 ; 8:205-12 . télécharger la publication (version PDF*)
We have developed a new haplotyping program based on the combination of an iterative multiallelic EM algorithm (IEM), bootstrap resampling and a pseudo Gibbs sampler. The use of the IEM-bootstrap procedure considerably reduces the space of possible haplotype configurations to be explored, greatly reducing computation time, while the adaptation of the Gibbs sampler with a recombination model on this restricted space maintains high accuracy. On large SNP datasets (>30 SNPs), we used a segmented approach based on a specific partition-ligation strategy. We compared this software, Ishape (Iterative Segmented HAPlotyping by Em), with reference programs such as Phase, Fastphase, and PL-EM. Analogously with Phase, there are 2 versions of Ishape: Ishape1 which uses a simple coalescence model for the pseudo Gibbs sampler step, and Ishape2 which uses a recombination model instead. RESULTS: We tested the program on 2 types of real SNP datasets derived from Hapmap: adjacent SNPs (high LD) and SNPs spaced by 5 Kb (lower level of LD). In both cases, we tested 100 replicates for each size: 10, 20, 30, 40, 50, 60, and 80 SNPs. For adjacent SNPs Ishape2 is superior to the other software both in terms of speed and accuracy. For SNPs spaced by 5 Kb, Ishape2 yields similar results to Phase2.1 in terms of accuracy, and both outperform the other software.In terms of speed, Ishape2 runs about 4 times faster than Phase2.1 with 10 SNPs, and about 10 times faster with 80 SNPs. For the case of 5kb-spaced SNPs, Fastphase may run faster with more than 100 SNPs. CONCLUSION: These results show that the Ishape heuristic approach for haplotyping is very competitive in terms of accuracy and speed and deserves to be evaluated extensively for possible future widespread use..
8. A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients.
Vasilescu A, Terashima Y, Enomoto M, Heath S, Poonpiriya V, Gatanaga H, Do H, Diop G, Hirtzig T, Auewarakul P, Lauhakirti D, Sura T, Charneau P, Marullo S, Therwath A, Oka S, Kanegasaki S, Lathrop M, . Proc Natl Acad Sci U S A. . 2007 ; 104:3354-9 . télécharger la publication (version PDF*)
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..
9. Computation of haplotypes on SNPs subsets: advantage of the "global method".
Coulonges C, Delaneau O, Girard M, Do H, Adkins R, Spadoni JL, Zagury J-F. . BMC Genetics. 2006 ; 26;7:50 . télécharger la publication (version PDF*)
Genetic association studies aim at finding correlations between a disease state and genetic variations such as SNPs or combinations of SNPs, termed haplotypes. Some haplotypes have a particular biological meaning such as the ones derived from SNPs located in the promoters, or the ones derived from non synonymous SNPs. All these haplotypes are "subhaplotypes" because they refer only to a part of the SNPs found in the gene. Until now, subhaplotypes were directly computed from the very SNPs chosen to constitute them, without taking into account the rest of the information corresponding to the other SNPs located in the gene. In the present work, we describe an alternative approach, called the "global method", which takes into account all the SNPs known in the region and compare the efficacy of the two "direct" and "global" methods.
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10. Exhaustive genotyping of the Interferon Alpha Receptor 1 (IFNAR1) gene and association of an IFNAR1 protein variant with susceptibility to HIV-1 infection in a French AIDS cohort.
Diop G, Hirtzig T, Do H, Coulonges C, Vasilescu A, Labib T, Spadoni JL, Therwath A, Rappaport J, Lathrop M, Matsuda F, Zagury J-F. . Biomed Pharmacother . 2006 ; 60:569-77 . télécharger la publication (version PDF*)
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..
11. Exhaustive genotyping of the IL-1 family genes and associations with AIDS progression in a French cohort.
Do H, Vasilescu A, Carpentier W, Meyer L, Diop G, Hirtzig T, Coulonges C, Labib T, Spadoni JL, Therwath A, Lathrop M, Matsuda F, Zagury J-F. . J Infect Dis . 2006 ; 1492-504. télécharger la publication (version PDF*)
Interleukin (IL)-1 family members are key players in inflammatory processes but have been the subject of few studies of acquired immunodeficiency syndrome (AIDS). To better evaluate the impact of the IL-1 family on AIDS development, we genotyped the IL1 alpha , IL1 beta , IL1Ra, and IL1R1 genes in 245 slow progressor (SP) and 82 rapid progressor (RP) human immunodeficiency virus type 1-seropositive patients as well as in 446 control subjects, all of whom were of white ethnicity. One hundred sixteen frequent polymorphisms were identified, of which 23 were newly characterized by our study. Many putative associations were found between single-nucleotide polymorphism (SNP) or haplotype alleles and the extreme profiles of progression. Most of them corresponded to weak associations (.01 P .05); however, the SNP IL1Ra_2134 exhibited a consistent association, found at the level of the SNP, haplotypes, and haploblocks, when the SP and control populations were compared (P=.0002). The IL-1-dependent inflammatory response is, thus, likely to play a role in AIDS progression via the regulation of IL-1Ra expression. This association will need to be confirmed in other AIDS cohorts, and experiments will also have to be performed to unravel the biological mechanisms at work. The data presented here will be useful for future genomic studies of the IL-1 family members in other infectious and chronic inflammatory diseases..
12. Associations of the IL2Ra, IL4Ra, IL10Ra, and IFNgR1 cytokine receptor genes with AIDS progression in a French AIDS cohort.
Do H, Vasilescu A, Diop G, Hirtzig T, Coulonges C, Labib T, Heath SC, Spadoni JL, Therwath A, Lathrop M, Matsuda F, Zagury J-F. . Immunogenetics. 2006 Feb 21. 2005 ; 58:89-98 . télécharger la publication (version PDF*)
We have performed an extensive analysis of Th1/Th2 cytokine receptors IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1 gene polymorphisms to evaluate their impact on AIDS progression. The coding regions and promoters of these genes were sequenced in the genetics of resistance to immunodeficiency virus cohort, composed of 327 HIV-1-positive patients with extreme progression phenotypes, slow and rapid progressors, and of 446 healthy control subjects, all of them of Caucasian descent. Overall, 104 single nucleotide polymorphisms and four insertions/deletions with a minor allelic frequency higher than 1% were identified, 21 of them being newly characterized. We observed weak associations for 13 polymorphisms of IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1, and 11 haplotypes of IL2Ralpha, IL4Ralpha, and IFNgammaR1. However, we could not relate these positive signals to any relevant biological information on the gene function. To affirm these putative associations in AIDS, further confirmation on other AIDS cohorts will be needed. This complete catalog of polymorphisms in IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1 cytokine receptor genes should also be useful for investigating associations in other immune-related diseases..
13. Genomic approach of AIDS pathogenesis : exhaustive genotyping of the TNFR1 gene in a French AIDS cohort.
Diop G, Spadoni JL, Do H, Hirtzig T, Coulonges C, Labib T, Issing W, Rappaport J, Therwath A, Lathrop M, Matsuda F, Zagury J-F. . Biomed Pharmacoth. 2005 ; 59(8):474-80. télécharger la publication (version PDF*)
Large-scale genomic studies in cohorts have been made possible for the last few years thanks to the progress of molecular biology and bioinformatics. This systematic approach allows a better understanding of the molecular mechanisms of disease development and as a consequence can contribute to the rational design of new diagnostic and therapeutic tools. We present here the exhaustive genotyping of a candidate gene, tumor necrosis factor receptor 1 (TNFR1), in the genetic of resistance to immunodeficiency virus (GRIV) AIDS cohort. This gene was chosen because it is likely to be involved in the apoptosis pathways of CD4(+) and CD8(+) T-cells during human immunodeficiency virus 1 (HIV-1) infection. Seven frequent polymorphisms were characterized in 319 HIV-1 seropositive patients from the GRIV cohort with extreme disease progression phenotypes, slow progression or rapid progression, and in 427 healthy controls. The TNFR1 gene locus does not appear to be part of any haploblock and contains only a small haploblock of two successive SNPs. One promoter SNP (TNFR1_17444594, position -581) and one intronic SNP (TNFR1_27223241, position +11511) gave weak positive signals of association (resp. P=0.03 and P=0.04) as well as two haplotypes. To our knowledge, this is the first genetic association study dealing with the TNFR1 gene in AIDS and the putative associations identified will need to be validated through other AIDS cohort analyses or by further biological experimentation..
14. Exhaustive genotyping of the CEM15/APOBEC3G gene and absence of association with AIDS progression in a French cohort.
Do H, Vasilescu A, Diop G, Hirtzig T, Heath SC, Therwath A, Coulonges C, Rappaport J, Lathrop M, Matsuda F, Zagury J-F. . J Infect Dis. 2005 ; 191 :159-63. télécharger la publication (version PDF*)
CEM15 (or APOBEC3G) has recently been identified as an inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. To evaluate the impact of its genetic variations on the progression of acquired immunodeficiency syndrome (AIDS), we have performed an extensive genetic analysis of CEM15. We have sequenced CEM15 in a cohort of 327 HIV-1-seropositive patients with extreme disease progression phenotypes--either slow progression or rapid progression--and in 446 healthy control subjects, all of white descent. We have identified 29 polymorphisms with allele frequencies >1%, 14 of which were newly characterized. There were no significant associations between the polymorphisms or haplotypes of CEM15 and a disease progression phenotype in our cohort..
15. Genomic analysis of Fas and FasL genes and absence of correlation with disease progression in AIDS.
Vasilescu A, Heath SC, Diop G, Do H, Hirtzig T, Hendel H, Bertin-Maghit S, Rappaport J, Therwath A, Lathrop GM, Matsuda F, Zagury J-F. . Immunogenetics. 2004 ; 56:56-60. télécharger la publication (version PDF*)
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..
16. Dominant effects of the CCR5 polymorphisms in AIDS disease progression.
Winkler C, Hendel H, Carrington M, Smith M, Nelson G, Rappaport J, Haumont P, Bertin-Maghit S, Lu W, Andrieu JM, Therwath A, Zagury J-F. . J Acquir Immune Defic Syndr. 2004 ; 37:1534-38. télécharger la publication (version PDF*)
Three haplotypes for the CCR2-CCR5 region previously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contributions to AIDS progression of CCR2 64I, CCR5 Delta32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included patients representing the extremes of the distribution for AIDS progression: rapid progressors (RP) who developed CD4 T-cell counts of <300/ mm within 3 years after the last HIV-1-seronegative test and slow progressors (SP) who were HIV-1 infected for > or =8 years with CD4 T-cell counts of >500/mm. Comparing the RP with a seroconverter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 Delta32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the intermediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progression; the tendency towards a disproportionately early effect was significant for CCR5 Delta32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype distribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression..
17. Analysis of IgG and IgG4 in HIV-1 seropositive subjects and correlation with biological and genetic markers
Abbas A, Vasilescu A, Do H, Hendel H, Maachi M, Goutalier FX, Rappaport J, Matsuda F, Therwath A, Aucouturier P, Zagury J-F. . Biomed Pharmacother. 2005 ; 59:38-46. télécharger la publication (version PDF*)
We have compared the levels of immunoglobulins G (IgG) and G4 (IgG4) in extreme seropositive patients from the GRIV cohort consisting of 168 patients with slow progression (SP) and 60 with rapid progression (RP) as well as in 173 healthy controls. IgG levels were significantly higher in SP patients than in RP patients (P = 0.008), both higher than in seronegative individuals. IgG4 levels were significantly lower in SP patients than in RP patients (P = 0.001), both lower than in seronegative individuals. We tried to correlate these levels with biological parameters (CD4(+) and CD8(+) cells, total lymphocytes, white blood cell counts, percentage of CD4(+) cells, and viral load) as well as with genetic markers from Th1/Th2 cytokines (IL2, IL4, IL6, IL10, IL13, and IFNgamma). IgG levels were correlated with the percentage of CD4(+) cells in SP while IgG4 levels were correlated with CD8(+) cell count in SP and with percentage of CD4(+) cells in RP patients. Among the parameters measured in SP patients at the time of inclusion in the study, the best predictor of progression towards AIDS was the viral load, the best predictor for stability was CD4(+) cell count, but overall, the best predictor for SP evolution (stability vs. progression) appeared to be the percentage of CD4(+) cells. Interestingly, correlations between the levels of IgG or IgG4 and the cytokine gene polymorphisms were found, notably in the IL10 gene..
18. Specificity and effect on apoptosis of Tat antibodies from vaccinated and SHIV-infected rhesus macaques and HIV-infected individuals.
Belliard G, Romieu A, Zagury J-F, Dali H, Chaloin O, Le Grand R, Loret E, Briand JP, Roques B, Desgranges C, Muller S. . Vaccine. 2003 ; 21:3186-99. télécharger la publication (version PDF*)
Recent contributions have demonstrated that actively secreted Tat protein plays an important functional role in human immunodeficiency virus-1 (HIV-1) infection and that Tat antibodies might interfere with disease progression by blocking the protein extracellularly. In this context we have studied the recognition of several Tat mutants as well as various synthetic Tat fragments by anti-Tat monoclonal antibodies and by IgG antibodies from a large collection of slow and fast-progressor infected individuals. We have also tested the sera from simian/human immunodeficiency virus (SHIV)-infected macaques with these Tat peptides. Important differences were found between long-term non-progressors and fast-progressors, and between human and monkey sera in terms of antibody specificity. Rabbits and macaques were immunised with several Tat peptides and we found that certain antibody subsets from immunised animals recognised the cognate protein Tat and had the capacity to inhibit Tat-induced apoptosis of T cells. Such antibodies might be important for controlling Tat-induced death in cells uninfected by HIV-1..
19. T-cell receptor excision circles (TREC) and maintenance of long-term non-progression status in HIV-1 infection.
Richardson MW, Sverstiuk AE, Gracely EJ, Hendel H, Khalili K, Zagury J-F, Rappaport J. . AIDS. 2003 ; 17:915-7. télécharger la publication (version PDF*)
Les TRECs sont des marqueurs du degré de réplication des lymphocytes T matures. Plus ils se répliquent moins on en trouve. En analysant les sujets infectés enrôlés comme progresseurs lents, ceux qui restent stables avaient au départ plus de TRECs que ceux qui progressent vers la maladie. Ce travail montre que les TRECs sont des bons marqueurs prédictifs d'évolution, et suggère que l'évolution vers le SIDA pourrait être associée à un plus haut taux de réplication lymphocytaire.
20. Genomic analysis of Th1-Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes and their association to the disease progression
Vasilescu A, Heath SC, Ivanova R, Hendel H, Do H, Mazoyer A, Khadivpour E, Goutalier FX, Khalili K, Rappaport J, Lathrop GM, Matsuda F and Zagury J-F. . Genes Immunity. 2003 ; 4:441-449. télécharger la publication (version PDF*)
Polymorphisms of Th1-Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNgamma. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1-Th2 cytokines in AIDS and other immune-related.
21. Associations of MHC ancestral haplotypes with resistance/susceptibility to AIDS disease development
Flores-Villanueva P, Hendel H, Caillat-Zucman S, Rappaport J, Burgos-Tiburcio A, Bertin-Maghit S, Ruiz-Morales JA, Teran ME, Rodriguez-Tafur J, Zagury J-F. . J Immunol. 2003 ; 170:1925-29. télécharger la publication (version PDF*)
We tested the association of MHC ancestral haplotypes with rapid or slow progression to AIDS by comparing their frequencies in the French genetics of resistance/susceptibility to immunodeficiency virus cohort with that reported in a control French population. Seven ancestral haplotypes were identified in the genetics of resistance/susceptibility to immunodeficiency virus cohort with a frequency >1%. The 8.1 (odds ratio (OR) = 3, p = 0.006), 35.1 (OR = 5.7, p = 0.001), and 44.2 (OR = 3.4, p = 0.007) ancestral haplotypes were associated with rapid progression, whereas the 35.2 (OR = 3.6, p = 0.001), 44.1 (OR = 5.4, p < 10(-4)), and 57.1 (OR = 5.8, p < 10(-4)) ancestral haplotypes were associated with slow progression to AIDS. Although the frequency of each ancestral haplotype is low in the population, the OR were quite higher than those previously obtained for single HLA allele associations, with some p values as low as 10(-4). The analysis of the recombinant fragments of these haplotypes allowed the identification of the MHC regions in the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression to AIDS and the MHC regions of the 44.1 and 57.1 haplotypes associated with slow progression to AIDS. Previous studies have identified single HLA alleles associated with disease progression. Our results on recombinant fragments confirm the direct role of HLA-B35 in rapid progression. Associations with HLA-A29 and -B57 might be due to linkage disequilibrium with other causative genes within the MHC region..
22. Genomic studies in AIDSÂ : problems and answers. Development of a statistical model integrating both longitudinal cohort studies and transversal observations of extreme cases.
Huber C, Pons H, Hendel H, Jacquemin L, Tamim S, Zagury J-F. . Biomed Pharmacother . 2003 ; 57:25-33. . télécharger la publication (version PDF*)
Genomic studies developed to understand HIV-1 infection and pathogenesis have often lead to conflicting results. This is linked to various factors, including differences in cohort design and selection, the numbers of patients involved, the influence of population substructure, the ethnic origins of the participants, and phenotypic definition. These difficulties in the interpretation of results are examined through published studies on the role of polymorphisms in HLA and the chemokine receptors genes in AIDS. Our analysis suggests that the use of haplotypes will strengthen the results obtained in a given cohort, and meta-analysis including multiple cohorts to gather large-enough numbers of patients should also allow clarification of the genetic associations observed. A P-value of 0.001 appears to be a good compromise for significance on candidate genes in a genetic study. Due to the generally limited size of available cohorts, results will have to be validated in other cohorts.We developed a model to fit transversal case studies (extreme case-control studies) with longitudinal cohorts (all-stages patients) for observations on two gene polymorphisms of CCR5 and NQO1. Interestingly, we observe a protective effect for the CCR5-Delta32 mutant allele in 95% of the simulations based on that model when using a population of 600 subjects; however, when using populations of 250 subjects we find a significant protection in only 59% of the simulations. Our model gives thus an explanation for the discrepancies observed in the various genomic studies published in AIDS on CCR5-Delta32 and other gene polymorphisms: they result from statistical fluctuations due to a lack of power. The sizes of most seroconverter cohorts presently available seem thus insufficient since they include less than a few hundred subjects. This result underlines the power and usefulness of the transversal studies involving extreme patients and their complementarity to longitudinal studies involving seroconverter cohorts. The transposition approach of extreme case-control data into longitudinal analysis should prove useful not only in AIDS but also in other diseases induced by chronic exposure to a foreign agent or with chronic clinical manifestations..
23. Antibodies to Tat and Vpr in the GRIV cohort: differential association with maintenance of long-term non-progression status in HIV-1 infection.
Richardson MW, Mirchandani J, Duong J, Grimaldo S, Kocieda V, Hendel H, Khalili K, Zagury J-F, Rappaport J. . Biomed Pharmacother. 2003 ; 57:4-14. télécharger la publication (version PDF*)
The HIV-1 regulatory protein Tat and the accessory protein Vpr are thought to stimulate viral replication and contribute to viral pathogenesis as extracellular proteins. Humoral immune responses to these early viral proteins may therefore be beneficial. We examined serum anti-Tat and anti-Vpr IgG by ELISA in the GRIV cohort of HIV-1 seropositive slow/non-progressors (NP) and fast-progressors (FP), and in seronegative controls. Based on information obtained during a brief follow-up period (median = 20 months), NPs were sub-grouped as those maintaining non-progression status and therefore stable (NP-S), and those showing signs of disease progression (NP-P). As the primary comparison, initial serum anti-Tat and anti-Vpr IgG (prior to follow-up) were analyzed in the NP sub-groups and in FPs. Anti-Tat IgG was significantly higher in stable NP-S compared to unstable NP-P (P = 0.047) and FPs (P < 0.0005); the predictive value of higher anti-Tat IgG for maintenance of non-progression status was 92% (P = 0.029). In contrast, no-difference was observed in anti-Vpr IgG between NP-S and NP-P, although both were significantly higher than FPs (P
24. The interferon antagonist sarcolectin in the progress of HIV-1 infection and in AIDS
Kaba A, Ilunga AJ, Achour A, Zagury J-F, Chany C. . Interferon Cytokine Res. 2002 ; 22:305-10. télécharger la publication (version PDF*)
Sarcolectin (SCL) is a nonspecific stimulator of cellular DNA synthesis that was found in all animal sera tested to date. It inhibits the established interferon (IFN)-dependent antiviral state, restoring cells to their normal status. In this study, we examined the excretion/secretion of the IFN antagonist SCL in sera from healthy donors and in sera collected during different periods of human immunodeficiency virus type 1 (HIV-1) infection. We followed HIV-1-infected patients during all stages of development (seroconversion, initial and advanced phases of AIDS) and found a significant increase in SCL in sera of HIV-infected patients compared with seronegative subjects used as controls. This increase was established during seroconversion, and then the titers leveled off. In the final stage of the disease, the SCL titer increased again very significantly. We attribute this rapid rise to the virus-dependent destruction of T cells that can no longer be repaired. The high SCL level observed at this final stage, which is most predictive of the disease's progression, suggests that the action, rather than the production, of IFN is impaired..
25. Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data
Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL, Buchbinder SP, Coutinho RA, Eugen-Olsen J, Gallart T, Katzenstein TL, Kostrikis LG, Kuipers H, Louie LG, Mallal SA, Margolick JB, Martin. Ann Intern Med. 2001 ; 135:782-795. télécharger la publication (version PDF*)
Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection..
26. Validation of genetic case-control studies in AIDS and application to the CX3CR1 polymorphism
Hendel H, Winkler C, Nelson G, Haumont P, O’Brien S, Khalili K, Zagury D, Rappaport J, Zagury J-F. . Acquir Immune Defic Syndr. 2001 ; 26:507-11. télécharger la publication (version PDF*)
New polymorphisms have been recently identified in CX3CR1, a coreceptor for some HIV-1 strains, one of which was associated with a strong acceleration of HIV disease progression. This effect was observed both by a case-control study involving 63 nonprogressors (NP) from the asymptomatic long-term (ALT) cohort and Kaplan-Meier analysis of 426 French seroconverters (SEROCO cohort).These results prompted us to analyze these polymorphisms in 244 nonprogressors (NPs) and 80 rapid progressors (RPs) from the largest case-control cohort known to date, the GRIV cohort. Surprisingly, the genetic frequencies found were identical for both groups under all genetic models (p >.8). The discrepancy with the previous work stemmed only from the difference between GRIV NPs versus ALT NPs. We hypothesized this might be due to the limited number of NPs in ALT (n = 63) and in this line we reanalyzed the data previously collected on GRIV for over 100 different genetic polymorphisms: we effectively observed that the genetic frequencies of some polymorphisms could vary by as much as 10% (absolute percentage) when computing them on the first 50 NP subjects enrolled, on the first 100, or on all the NPs tested (240 study subjects). This observation emphasizes the need for caution in case-control studies involving small numbers of subjects: p values should be low or other control groups should be used.However, the association of the CX3CR1 polymorphism with progression seems quite significant in the Kaplan-Meier analysis of the SEROCO cohort (426 individuals), and the difference observed with GRIV might be explained by a delayed effect of the polymorphism on disease. Further studies on other seroconverter cohorts are needed to confirm the reported association with disease progression..
27. Auto-antibodies to TNFa in HIV infection : prospects for anti-cytokine vaccine therapy
Capini CJ, Richardson, MW, Sverstiuk AE, Mirchandani J, Regulier EG, Khalili K, Zagury J-F, and Rappaport J.. Biomed Pharmacoth. 2001 ; 55:1-9. télécharger la publication (version PDF*)
Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine principally involved in the activation of lymphocytes in response to viral infection. TNFalpha also stimulates the production of other cytokines, activates NK cells and potentiates cell death and/or lysis in certain models of viral infection. Although TNFalpha might be expected to be a protective component of an antiviral immune response, several lines of evidence suggest that TNFalpha and other virally-induced cytokines actually may contribute to the pathogenesis of HIV infection. Based on the activation of HIV replication in response to TNFalpha, HIV appears to have evolved to take advantage of host cytokine activation pathways. Antibodies to TNFalpha are present in the serum of normal individuals as well as in certain autoimmune disorders, and may modulate disease progression in the setting of HIV infection. We examined TNFalpha-specific antibodies in HIV-infected non-progressors and healthy seronegatives; anti-TNFalpha antibody levels are significantly higher in GRIV seropositive slow/non-progressors (N = 120, mean = 0.24), compared to seronegative controls (N= 12, mean = 0.11). TNFalpha antibodies correlated positively with viral load, (P = 0.013, r = 0.282), and CD8+ cell count (P = 0.03, r = 0.258), and inversely with CD4+ cell count (P = 0.003, r = - 0.246), percent CD4+ cells (P = 0.008, r = -0.306), and CD4 :CD8 ratio (P = 0.033, r = - 0.251). TNFalpha antibodies also correlated positively with antibodies to peptides corresponding to the CD4 binding site of gp160 (P = 0.001, r = 0.384), the CD4 identity region (P = 0.016, r = 0.29), the V3 loop (P = 0.005, r = 0.34), and the amino terminus of Tat (P = 0.001, r = 0.395); TNFalpha antibodies also correlated positively with antibodies to Nef protein (P = 0.008, r = 0.302). The production of anti-TNFalpha antibodies appears to be an adaptive response to HIV infection and suggests the potential utility of modified cytokine vaccines in the treatment of HIV infections as well as AIDS-related and unrelated autoimmune and CNS disorders..
28. Expression of sarcolectin in sera from HIV-1 infected patients during progression of the disease.
Ilunga AG, Kaba A, Achour A, Zagury J-F, Chany C. . AIDS. 2000 ; 14:2206-7. télécharger la publication (version PDF*)
Ce travail examine la présence de sarcolectine, une lectine antagoniste à la fonction de l'interféron, avec l'avancée de la maladie. Paradoxalement, la concentration sérique des 2 molécules croît avec l'avancée de la maladie..
29. Analysis of telomere length and thymic output in fast and slow/non-progressors with HIV infection.
Richardson MW, Sverstiuk A, Hendel H, Cheung TW, Zagury J-F, Rappaport J. . Biomed Pharmacoth. 2000 ; 54:21-31. télécharger la publication (version PDF*)
There are two models for CD4+ T-cell depletion leading to AIDS: a kinetic model and an immune suppression model. In the kinetic model, direct cell killing due to viral replication results in a continuous demand for CD4+ T-cells, which eventually exhausts their capacity for renewal by proliferative mechanisms. In the immune suppression model, CD4+ T-cell decline is due to an indirect global inhibitory effect of the virus on uninfected immune cell function. In order to address differences in the two models, we investigated proliferative history and thymic output in PBMC from the GRIV cohort of fast (FP) and slow/non-progressors (S/NP), and uninfected controls. Proliferative history and thymic output were assessed by measurement of mean telomeric restriction fragment (TRF) length and T-cell receptor Rearrangement Excision Circles (TREC) levels, respectively. Mean TRF lengths were significantly shorter in S/NP (n = 93, 7.59 +/- 0.11 kb) and FP (n = 42, 7.25 +/- 0.15 kb) compared to controls (n = 35, 9.17 +/- 0.19 kb). Mean TRF length in PBMC (n = 9, 7.32 +/- 0.31 kb) and CD4+ enriched fractions (n = 9, 7.41 +/- 0.30 kb) from a subset of non-GRIV HIV-1 infected samples were also significantly smaller than PBMC (n = 8, 9.77 +/- 0.33 kb) and CD4+ fractions (n = 8, 9.41 +/- 0.32 kb) from uninfected controls. Rates of telomeric shortening, however, were similar among S/NP (n = 93, -45 +/- 20 bp/yr), FP (n = 42, -41 +/- 14 bp/yr) and controls (-29 +/- 17 bp/yr). Paralleling differences observed in mean TRF length, TREC levels were significantly reduced in S/NP (n = 10, 3,433 +/- 843 mol/mu and FP (n = 8, 1,193 +/- 413) compared to controls (n = 15, 22,706 +/- 5,089), indicative of a defect in thymopoiesis in HIV-1 infection. When evaluated in the context of reduced thymopoiesis, the difference in mean TRF length between S/NP and controls (1.58 +/- 0.30 kb) is similar to that observed between memory and naïve T-cells (1.4 +/- 0.1 kb), and may reflect perturbations in the peripheral T-cell population due to a decline in thymic output of naïve T-cells rather than increased turnover. Based on the different clinical criteria used to select S/NP and FP, the sight difference in TREC between these two groups suggests the threshold for pathogenesis as a result of naïve T-cell depletion may be quite low, and incremental increases in thymic output may yield substantial clinical results. Future studies regarding therapeutic vaccination, specifically with HIV-1 Tat targeted anti-immunosuppressive vaccines, should address the defect in thymic output in HIV-1 infection by using TREC analysis as a rapid method for biological evaluation..
30. New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS.
Hendel H, Caillat-Zucman S, Le Buanec H, Carrington M, O’Brien S, Andrieu JM, Schachter F, Zagury D, Rappaport J, Winkler C, Nelson G & Zagury J-F. . J Immunol. 1999 ; 162:6942-46. télécharger la publication (version PDF*)
The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-Delta32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development..
31. Distinctive effects of CCR5, CCR2 and SDF1 genetic polymorphisms
Hendel H, Henon N, Lebuanec H, Lachgar A, Poncelet H, Caillat-Zucman S, Winkler C, Smith MW, Kenefic L, O’Brien SJ, Lu W, Andrieu JM, Zagury D, Schächter F, Rappaport J, Zagury J-F . J Acquir Immune Defic Syndr. 1998 ; 19:381-86. télécharger l'abstract (version PDF*)
The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = . 12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (64I) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is >8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects..
32. Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: A rationale for the use of Tat Toxoid as an HIV-1 vaccine.
Zagury J-F, Sill A, Blattner W, Lachgar A, Le Buanec H, Richardson M, Rappaport J, Hendel H, Bizzini B, Gringeri A, Carcagno M, Criscuolo M, Burny A, Gallo RC & Zagury D. . J Hum Virol. 1998 ; 1:282-92. télécharger l'abstract (version PDF*)
To investigate which immune parameters, such as antibodies against HIV-1 specificities, or viral parameters, such as p24 antigenemia, are predictive of disease progression. STUDY DESIGN: We performed studies on serum collected from individuals exhibiting two extremes of disease evolution--67 fast progressors (FP) and 182 nonprogressors (NP)--at their enrollment. After a 1- to 2-year clinical follow-up of 104 nonprogressors after their enrollment, we could determine the best serologic predictors for disease progression. METHODS: We investigated levels of antibodies to tetanus toxoid and to HIV antigens including Env, Gag, Nef, and Tat proteins, as well as p24 antigenemia, viremia, CD4 cell count, and interferon-alpha (IFN-alpha) titers in FPs and NPs, and we correlated these data with clinical and biologic signs of progression. RESULTS: p24 Antigenemia, a marker of viral replication, and anti-Tat antibodies were highly and inversely correlated in both groups (P < .001). Furthermore, anti-p24 antibodies and low serum IFN-alpha levels were correlated to the NP versus the FP cohort. Finally, among NPs, only antibodies to Tat and not to the other HIV specificities (Env, Nef, Gag) were significantly predictive of clinical stability during their follow-up. CONCLUSION: Antibodies toward HIV-1 Tat, which are inversely correlated to p24 antigenemia, appear as a critical marker for a lack of disease progression. This study strongly suggests that rising anti-Tat antibodies through active immunization may be beneficial in AIDS vaccine development to control viral replication..
33. Interferon and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS
Zagury D, Lachgar A, Chams V, Fall LS, Bernard J, Zagury J-F, Bizzini B, Gringeri A, Santagostino E, Rappaport J, Feldman M, O’BriEn SJ, Burny A & Gallo RC. . Proc Natl Acad Sci USA. 1998 ; 95:3851-3856. télécharger la publication (version PDF*)
HIV type 1 (HIV-1) not only directly kills infected CD4(+) T cells but also induces immunosuppression of uninfected T cells. Two immunosuppressive proteins, interferon alpha (IFNalpha) and extracellular Tat, mediate this process because specific antibodies against these proteins prevent generation of suppressor cells in HIV-1-infected peripheral blood mononuclear cell cultures. Furthermore, the production of C-C chemokines in response to immune cell activation, initially enhanced by IFNalpha and Tat, ultimately is inhibited by these proteins in parallel with their induction of immunosuppression. The clinical corollary is the immunosuppression of uninfected T cells and the decline in C-C chemokine release found at advanced stages of HIV-1 infection paralleling rising levels of IFNalpha and extracellular Tat. We, therefore, suggest that IFNalpha and Tat may be critical targets for anti-AIDS strategies..
34. The 32 bp CCR-5 gene deletion confers resistance to fast progression among HIV-1 infected heterozygous individuals
Rappaport J, Cho Y-Y, Hendel H, Schwartz EJ, Schächter F, Zagury J-F . The Lancet. 1997 ; 349:922-23. télécharger la publication (version PDF*)
Chemokine and AIDS research fields are converging. CCR-5 and fusin are receptors for chemokines which have been recently identified as co-receptors for HIV-1 infection. The CC-chemokines MIP-1?, MIP-1?, and Rantes bind to the CCR-5 receptor and can inhibit infection of target cells by HIV-1 monocytotropic strains.1 A previous term32next term base-pair deletion in the CCR-5 gene (?32) is present in approximately 18% of white people, but virtually absent in black and Asian people. People homozygous for the ?32 deletion are resistant to HIV infection.2, 3 and 4 Among heterozygotes, this deletion does not seem to confer resistance to HIV-1 infection. The role of the mutant CCR-5 allele in late disease progression is not yet clear.4.
35. Contribution of cohort studies in understanding HIV pathogenesis: introduction of the GRIV cohort and preliminary results
Hendel H, Cho Y-Y, Gauthier N, Rappaport J, Schachter F, Zagury J-F. . Biomed Pharmacoth. 1996 ; 50:480-87. télécharger la publication (version PDF*)
In the present paper we review studies performed on HIV-infected patients previous termcohortsnext term in order to understand AIDS disease development. The interplay between diverse factors such as the HIV envelope proteins, cellular co-receptors, the immune response with chemokines and cytokines production define the viral tropisrn, cytopathicity and progression of HIV disease. We present the trends of the research particularly in the domain concerning host genetics. In this context, we describe the GRIV previous termcohortnext term of fast and slow/non-progressors, and its use for understanding basic features of the yet unknown HIV pathogenesis mechanisms..
