Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection.
TRIM5alpha acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5alpha on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5alpha 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5alpha 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5alpha R136 protein. The 43Y variant of TRIM5alpha was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts.
Javanbakht
Hassan
H
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
An
Ping
P
Gold
Bert
B
Petersen
Desiree C
DC
O'Huigin
Colm
C
Nelson
George W
GW
O'Brien
Stephen J
SJ
Kirk
Gregory D
GD
Detels
Roger
R
Buchbinder
Susan
S
Donfield
Sharyne
S
Shulenin
Sergey
S
Song
Byeongwoon
B
Perron
Michel J
MJ
Stremlau
Matthew
M
Sodroski
Joseph
J
Dean
Michael
M
Winkler
Cheryl
C
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004198:Disease Susceptibility; D004285:Dogs; D005091:Exons; D005787:Gene Frequency; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D015497:HIV-1 / Q000254:growth & development; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D009052:Leukemia Virus, Murine / Q000254:growth & development; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; D049452:Green Fluorescent Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases