Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV-1-infected individuals.
Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV-1-infected individuals.
复制标题
DOI：
10.1371/journal.ppat.1000781
复制
发表时间：
2010-02-26
期刊：
影响因子：
6.7
通讯作者：
Center for HIV/AIDS Vaccine Immunology
中科院分区：
文献类型：
--
作者：
Rotger M;Dang KK;Fellay J;Heinzen EL;Feng S;Descombes P;Shianna KV;Ge D;Günthard HF;Goldstein DB;Telenti A;Swiss HIV Cohort Study;Center for HIV/AIDS Vaccine Immunology
There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control. There has been recent progress in understanding the genetic factors that modulate susceptibility to HIV-1 infection. Genetic variation explains to a certain extent differences in disease progression among individuals. Less is known regarding the contribution of differences in gene expression to viral control. The present study evaluated, genome-wide, gene expression levels in CD4+ T cell, the main target of HIV-1. Thereafter, it searched for genetic variants that would modify gene expression. Specific expression profiles associated with high levels of viremia—in particular, the upregulation of genes of the antiviral defense. In contrast, no expression profile associated with effective viral control. Multiple genetic variants modulated gene expression in CD4+ T cells; however, none had a strong influence on viral control. This integrated genome-wide assessment suggests that viral replication drives gene expression rather than expression pointing to mechanisms of viral control.
登录
查看更多内容
剪接的组织特异性遗传控制：对复杂性状的研究的影响。
影响因子：
9.8
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
3.3
作者：
Imbeault, Michael;Ouellet, Michel;Tremblay, Michel J.
通讯作者：
Tremblay, Michel J.
影响因子：
3.8
作者：
Fink J;Gu F;Ling L;Tolfvenstam T;Olfat F;Chin KC;Aw P;George J;Kuznetsov VA;Schreiber M;Vasudevan SG;Hibberd ML
通讯作者：
Hibberd ML
抗病毒 2′,5′-寡腺苷酸合成酶（2′5′AS）酶活性的变化受 OAS1 基因中剪接接受位点单核苷酸多态性的控制
影响因子：
9.8
作者：
Bonnevie-Nielsen, V;Field, LL;Pociot, F
通讯作者：
Pociot, F
影响因子：
4.5
作者：
Fellay J;Ge D;Shianna KV;Colombo S;Ledergerber B;Cirulli ET;Urban TJ;Zhang K;Gumbs CE;Smith JP;Castagna A;Cozzi-Lepri A;De Luca A;Easterbrook P;Günthard HF;Mallal S;Mussini C;Dalmau J;Martinez-Picado J;Miro JM;Obel N;Wolinsky SM;Martinson JJ;Detels R;Margolick JB;Jacobson LP;Descombes P;Antonarakis SE;Beckmann JS;O'Brien SJ;Letvin NL;McMichael AJ;Haynes BF;Carrington M;Feng S;Telenti A;Goldstein DB;NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
通讯作者：
NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)