Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection.
BACKGROUND
The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections.


OBJECTIVE
To determine whether single-nucleotide polymorphisms (SNPs) in TLR2-4 and TLR7-9 influenced the natural course of HIV-1 infection.


METHODS
Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation-maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use).


RESULTS
Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7-9.2] for GA versus AA and OR, 4.7 (95% CI,1.9-12.0) for GG versus AA (P = 0.0008).


CONCLUSIONS
Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.
Bochud
Pierre-Yves
PY
Institute for Systems Biology, Seattle, Washington State, USA. pyb@systemsbiology.org
Hersberger
Martin
M
Taffé
Patrick
P
Bochud
Murielle
M
Stein
Catherine M
CM
Rodrigues
Stephanie D
SD
Calandra
Thierry
T
Francioli
Patrick
P
Telenti
Amalio
A
Speck
Roberto F
RF
Aderem
Alan
A
D000328:Adult; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D051217:Toll-Like Receptor 9 / Q000235:genetics*
D051217:Toll-Like Receptor 9