A Common Polymorphism in TLR3 Confers Natural Resistance to HIV-1 Infection

Abstract

TLR3 recognizes dsRNA and activates antiviral immune responses through the production of inflammatory cytokines and type I IFNs. Genetic association studies have provided evidence concerning the role of a polymorphism in TLR3 (rs3775291, Leu412Phe) in viral infection susceptibility. We genotyped rs3775291 in a population of Spanish HIV-1–exposed seronegative (HESN) individuals who remain HIV seronegative despite repeated exposure through i.v. injection drug use (IDU-HESN individuals) as witnessed by their hepatitis C virus seropositivity. The frequency of individuals carrying at least one 412Phe allele was significantly higher in IDU-HESN individuals compared with that of a matched control sample (odds ratio for a dominant model = 1.87; 95% confidence interval, 1.06–3.34; p = 0.023). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Similar results were obtained: the frequency of individuals carrying at least one 412Phe allele was significantly higher compared with that of a matched control sample (odds ratio, 1.79; 95% confidence interval, 1.05–3.08; p = 0.029). In vitro infection assays showed that in PBMCs carrying the 412Phe allele, HIV-1Ba-L replication was significantly reduced (p = 0.025) compared with that of Leu/Leu homozygous samples and was associated with a higher expression of factors suggestive of a state of immune activation (IL-6, CCL3, CD69). Similarly, stimulation of PBMCs with a TLR3 agonist indicated that the presence of the 412Phe allele results in a significantly increased expression of CD69 and higher production of proinflammatory cytokines including IL-6 and CCL3. The data of this study indicate that a common TLR3 allele confers immunologically mediated protection from HIV-1 and suggest the potential use of TLR3 triggering in HIV-1 immunotherapy.

Toll-like receptor 3 gene polymorphisms are not associated with the risk of hepatitis B and hepatitis C virus infection

“…SNP rs3775291 (1234 C>T) is a nonsynonymous mutation (Leu412Phe) located in the fourth exon and occurs very frequently in HCV carriers who require liver transplantation (6) . In addition, rs3775291 is a risk factor for chronic HBV infection (10) and has been associated with resistance to human immunodefi ciency virus (HIV) infection (11) (12) . Given these reports concerning the influence of the TLR3 gene on infections caused by HCV and HBV, the present study investigated the prevalence of TLR3 SNPs rs5743305 and rs3775291 in hepatitis patients who visited a northern Brazil hospital that is a regional reference for the treatment of hepatic diseases.…”

Functional characterization of genetic variants in the porcine TLR3 gene

“…However, the attenuating TLR signaling plays dual roles in host defense responses. For example, SNP c.1234C>T in the human TLR3, which results in a reduced response to poly(I:C), is associated with susceptibility to recurrent herpes labialis on the one hand (Yang et al, 2012), whereas it confers natural resistance to HIV-1 infection and protects against geographic atrophy, on the other hand (Zhou et al, 2011;Sironi et al, 2012). Therefore, in order to determine to which disease SNP c.933A>G originally provided the carrier resistance, further studies of specific virus infection are needed.…”

HIV induced suppression of host immunity: relevance to <i>Mycobacterium tuberculosis</i> infections

“…Besides HLA polymorphism, polymorphism among cytokines, chemokines, their receptors and PRRs (TLRs etc.) have been studied and demonstrated that few single nucleotide mutations led to low producer of protective cytokines [185][186][187]. Except few, none of the studies conclusively suggest anything.…”