aViral Pathogens and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases bDepartment of Infectious Diseases cDivision of Genetics and Cell Biology, San Raffaele Scientific Institute dUniversity of Milan eGEMIB srl, Parma fAIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute gUniversità Vita-Salute San Raffaele, School of Medicine, Milan, Italy.
AIDS. 2013 Sep 24;27(15):2335-44. doi: 10.1097/01.aids.0000432474.76873.5f.
OBJECTIVE(S): Tripartite motif-containing 22 (TRIM22) is an interferon-induced protein that inhibits HIV-1 transcription and replication in vitro. Two single nucleotide missense polymorphisms rs7935564A/G (SNP-1) and rs1063303C/G (SNP-2) characterize the coding sequence of human TRIM22 gene. We tested whether these variants affected the inhibitory effect of TRIM22 on HIV-1 replication and transcription and their potential association with HIV-1 disease.
The allelic discrimination was determined in 182 HIV-1-negative and among HIV-1-positive individuals with advanced disease progression (advanced progressors; n = 57), normal progressors (n = 76), and long-term nonprogressors (LTNPs; n = 95).
Renilla luciferase activity was measured after infection of activated peripheral blood mononuclear cells (PBMCs) from an additional group of 61 blood donors with a recombinant HIV-1. HIV-1-long terminal repeat (LTR)-driven luciferase activity was tested in the presence of plasmid expressing TRIM22 variants in 293T cells. The SNP genotyping was determined by TaqMan assay.
HIV-1 replication was more efficient in PBMCs from donors with SNP-1G and SNP-2G than from those with SNP-1A and SNP-2C alleles. Consistently, TRIM22-GG enhanced, whereas TRIM22-AC restricted basal HIV-1 LTR-driven transcription. In vivo, SNP-1G homozygotes and A/G heterozygotes were more frequent in advanced progressors than in LTNPs [odds ratio (OR) = 2.072, P = 0.005] or in normal progressors (OR = 1.809, P = 0.022); in contrast, SNP-2 was not associated with any state of HIV-1 disease progression. Although SNP-2 distribution was similar among the groups, TRIM22-GG haplotype was found more frequently in advanced progressors than in LTNPs (P = 0.02).
TRIM22 genetic diversity affects HIV-1 replication in vitro and it is a potentially novel determinant of HIV-1 disease severity.
三结构域蛋白 22（TRIM22）是一种干扰素诱导蛋白，可在体外抑制 HIV-1 的转录和复制。两个单核苷酸错义多态性 rs7935564A/G（SNP-1）和 rs1063303C/G（SNP-2）是人类 TRIM22 基因编码序列的特征。我们检测了这些变体是否影响了 TRIM22 对 HIV-1 复制和转录的抑制作用及其与 HIV-1 疾病的潜在关联。
在 182 名 HIV-1 阴性个体和 57 名 HIV-1 阳性进展期疾病患者（进展期患者）、76 名正常进展者和 95 名长期非进展者（LTNPs）中确定了等位基因的鉴别。
用重组 HIV-1 感染来自另外 61 名献血者的激活外周血单核细胞（PBMC）后，测定 Renilla 荧光素酶活性。在 293T 细胞中用表达 TRIM22 变体的质粒测试 HIV-1 长末端重复（LTR）驱动的荧光素酶活性。SNP 基因分型通过 TaqMan 法确定。
与 SNP-1A 和 SNP-2C 等位基因相比，SNP-1G 和 SNP-2G 供体的 HIV-1 复制更有效。一致地，TRIM22-GG 增强了基础 HIV-1 LTR 驱动的转录，而 TRIM22-AC 则限制了其转录。在体内，与 LTNPs 相比，SNP-1G 纯合子和 A/G 杂合子在进展期患者中更为常见[比值比（OR）=2.072，P=0.005]或在正常进展者中（OR=1.809，P=0.022）；相反，SNP-2 与 HIV-1 疾病进展的任何状态均无关。尽管 SNP-2 的分布在各组之间相似，但在进展期患者中发现 TRIM22-GG 单体型比 LTNPs 更为常见（P=0.02）。
TRIM22 遗传多样性影响体外 HIV-1 复制，是 HIV-1 疾病严重程度的一个潜在新决定因素。
