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Identification of TRIM22 single nucleotide polymorphisms associated with loss of inhibition of HIV-1 transcription and advanced HIV-1 disease

Ghezzi, Silviaa; Galli, Laurab; Kajaste-Rudnitski, Annaa; Turrini, Filippoa; Marelli, Saraa; Toniolo, Danielac; Casoli, Claudiod,e; Riva, Agostinod; Poli, Guidof,g; Castagna, Antonellab; Vicenzi, Elisaa

doi: 10.1097/01.aids.0000432474.76873.5f
Basic Science

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.

Design: 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).

Methods: 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.

Results: 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).

Conclusion: TRIM22 genetic diversity affects HIV-1 replication in vitro and it is a potentially novel determinant of HIV-1 disease severity.

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.

Correspondence to Dr Elisa Vicenzi, San Raffaele Scientific Institute, P2/P3 Laboratories, DIBIT-1, Via Olgettina 58, 20132 Milan, Italy. Tel: +39 02 2643 4908; fax: +39 02 2643 4905; e-mail: vicenzi.elisa@hsr.it

Received 9 January, 2013

Revised 10 June, 2013

Accepted 24 June, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.