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


METHODS
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).


CONCLUSIONS
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.
Silvia
S
Ghezzi
Laura
L
Galli
Anna
A
Kajaste-Rudnitski
Filippo
F
Turrini
Sara
S
Marelli
Daniela
D
Toniolo
Claudio
C
Casoli
Agostino
A
Riva
Guido
G
Poli
Antonella
A
Castagna
Elisa
E
Vicenzi
D000328:Adult; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D014779:Virus Replication
D015778:Minor Histocompatibility Antigens; D012097:Repressor Proteins; C094314:TRIM22 protein, human; D000070584:Tripartite Motif Proteins