Background
Acquired immune deficiency syndrome (AIDS) is a condition caused by human immunodeficiency virus (HIV), a virus that progressively destroys the immune system. This remains a major worldwide public health problem. There were 1.7 million new HIV-infected patients worldwide, and 0.69 million died from AIDS-related illnesses in 2019 [
1]. New HIV infections have declined by 23% compared to 2010 [
1]. In 2019, 67% of all people living with HIV were receiving antiretroviral therapy. It is well known that the risk of acquiring HIV is higher among certain populations: men who have sex with men, people who inject drugs, sex workers and transgender people [
1]. Currently, host genomics has attracted much attention, and considerable evidence has demonstrated that genetic factors play an essential role in HIV infection [
2,
3].
Data on host genetics have broadened our understanding of host factors’ importance in susceptibility to HIV infection [
2,
3]. Recent studies have indicated that several important host polymorphisms play a vital role in HIV infection and the progression to AIDS [
2‐
5]. Human leukocyte antigen (HLA) type is a widely studied example of host factors in the course of HIV [
4,
5]. Another important host factor polymorphism is the CCR5 deletion mutation CCR532, which is the only genotype that has been consistently identified as protective against HIV infection [
4,
6]. Researchers have also found that the toll-interacting protein (
TOLLIP) and mannose-binding lectin 2 (
MBL2) genes may also play a vital role in HIV infection and the progression to AIDS [
7‐
10].
The
TOLLIP gene encodes a ubiquitin-binding protein that interacts with several Toll-like receptor (TLR) signaling cascade components. TLR signaling has been widely suggested to inhibit HIV and other retrovirus infections [
11‐
13]. A previous study found that the rs5743867 polymorphism is significantly associated with protection from sepsis [
14], and the GG genotype of rs5743867 was associated with increased risks for pulmonary tuberculosis [
15]. In a case-population study in Vietnam, researchers found that SNPs rs5743899 and rs3750920 in the
TOLLIP gene were associated with susceptibility to tuberculosis, which demonstrates that
TOLLIP deficiency is associated with an increased risk of infectious disease [
16]. In addition, rs3750920 was associated with decreased levels of
TOLLIP mRNA expression, and rs5743899 was associated with increased IL-6 production [
16]. The host factor
TOLLIP gene, which is involved in TLR signaling, may play an important role in HIV infection. Researchers found that the
TOLLIP gene plays a crucial role in inhibiting HIV infection and regulating the incubation period of the virus [
7]. Others found that the
TOLLIP gene suppressed NF-κB-dependent HIV-1 TLR-driven transcription, which indicates the potential role of the genetic factor
TOLLIP in maintaining viral persistence [
17].
The
MBL2 protein can recognize and bind to mannose and N-acetylglucosamine on many microorganisms, including bacteria, yeast, and viruses such as influenza and HIV virus [
18]. Therefore, polymorphisms of the
MBL2 gene may be related to susceptibility to autoimmune and infectious diseases. When compared with healthy controls, a meta-analysis found that
MBL2 exon 1 polymorphisms were associated with host susceptibility to HIV-1 infection in three genetic models (dominant, recessive and allelic model) (
P < 0.05), and the
MBL2 0/0 mutant allele has also been previously associated with an increased risk for HIV infection (
p < 0.00001) [
19]. Subgroup analysis by ethnicity showed that significantly elevated risks were found in Caucasians in the recessive model but not in Asians [
19]. In addition, variants in the
MBL2 gene have also been shown to be related to disease progression to AIDS and death [
20,
21]. When comparing the frequency of
MBL2 promoter polymorphisms with healthy individuals, the X/X genotype of rs7096206 was significantly higher in HIV-positive patients [
21]. Sheng et al. found a higher prevalence of the heterozygous genotype with the B variant (rs1800450) in HIV-1-infected patients than in healthy controls, indicating that individuals with the B variant are more susceptible to HIV-1 infection [
22].
However, such studies addressing host genetic susceptibility to HIV infection are limited. This study aimed to investigate the relationship of single nucleotide polymorphisms (SNPs) of the TOLLIP and MBL2 genes with HIV infection in the Chinese Han population.
Discussion
Few data have evaluated the relationship between
TOLLIP gene polymorphisms and susceptibility to HIV infection [
7,
17]. Moreover, previous results were basic cell experiments and lacked extensive population-based sample genetic association studies. In the present study, two SNPs [rs5743899(T > C) and rs5743867(A > G)] in the
TOLLIP gene were found to be significantly associated with HIV infection in the Chinese Han population. Further analysis showed that rs5743899 was not independently associated with HIV infection. We also observed an association of the
TOLLIP haplotype with HIV infection. The CCG haplotype showed an increased risk for HIV infection in our study populations.
To our knowledge, this is the first report that provides evidence that
TOLLIP gene polymorphisms are associated with susceptibility to HIV infection in Chinese Han populations. We found that two SNPs [rs5743899(T > C) and rs5743867(A > G)] in the
TOLLIP gene were found to be significantly associated with HIV infection, while rs3750920 was not. Our results show that the rs5743899 and rs5743867 SNPs in the
TOLLIP gene are in almost perfect LD in these populations. When adjusted in the dominant model for rs5743867, age and sex, we found that rs5743899 was not independently associated with HIV infection. That is, the association between rs5743899 and susceptibility to HIV infection may be due to its LD and rs5743867. A significant association with HIV infection was observed with the
TOLLIP gene intron polymorphism rs5743867. A previous study found that the rs5743867 polymorphism is significantly associated with protection from sepsis in a Chinese Han population [
14]. It has also been reported that the GG genotype of rs5743867 was associated with increased risks for pulmonary tuberculosis in the Chinese Han population [
15]. The minor allele frequency of SNP rs5743867 was 0.409 in the control group in this study, which is similar to two previous studies conducted among the Chinese Han population; 0.39.5 in Song’s study [
14], and 0.38 in Wu’s study [
15]. Another SNP, rs3793964, in the
TOLLIP gene was associated with an increased risk for leprosy and increased skin expression of
TOLLIP and IL-1R antagonist [
26]. Taken together, these studies demonstrated that polymorphisms in the
TOLLIP gene were related to infectious diseases. It has been reported that rs5743867 in the
TOLLIP gene is significantly associated with the levels of TNF-α and IL-6 [
14], and rs5743899 is associated with increased IL-6 production [
16]. This result indicated that the
TOLLIP gene may affect mRNA expression. As an endogenous negative regulator of TLR signaling in the inflammatory response,
TOLLIP can prevent cell signaling mediated by TLR2 and TLR4 by directly binding to TLRs or blocking IL-1 receptor-related receptor kinases [
27]. Yang et al. proved that
TOLLIP could inhibit HIV-LTR-driven gene expression by inhibiting the activation of NF-κB [
17]. In addition, their results also indicate that
TOLLIP plays a role in maintaining viral latency [
17]. Li et al. found that
TOLLIP can inhibit the activity of LTRs from multiple HIV-1 subtypes, and
TOLLIP knockout in primary CD+ T cells can promote the activation of HIV from latent infection [
7].
The MBL protein is encoded by the
MBL2 gene, which is a key molecule of the innate immune system and a Ca2 + −dependent C-type serum lectin mainly produced by the liver [
28]. Early in vitro experiments showed that MBL could inhibit HIV infection by binding to HIV-1 gp120 glycoprotein [
29]. MBL can also selectively bind to HIV-1-infected cells and inhibit viral infection of CD4+ T cell lines [
30]. Variations in the
MBL2 gene encoding MBL may affect human susceptibility to HIV infection. Many genetic epidemiological studies have explored the relationship between
MBL2 gene mutation and HIV-1 infection, but the results are controversial and inconclusive [
8,
9,
20‐
22,
31‐
33]. Tan et al. demonstrated a significant association between
MBL2 genotypes and MBL serum levels, suggesting an increased susceptibility to HIV-1 infection and disease progression with
MBL2 polymorphisms [
32]. A statistical relationship was observed between
MBL2 gene polymorphisms and HIV-1 infection in the South Brazilian [
21], Italian [
20], and Chinese Han [
22] populations. Boniotto et al. found that a 6 bp deletion at position − 328 was correlated with HIV-1 infection [
20]. The frequency of the X/X genotype of rs7096206 was significantly higher in HIV-positive patients in South Brazil than in healthy individuals [
21]. Another study found that the prevalence of the heterozygous genotype with the B variant (rs1800450) was higher in HIV-1-infected patients than in controls [
22]. Other researchers did not find this association in Zambian [
31], Chinese Han [
8], Colombian [
33], or white Spanish patients [
10]. Consistent with Li et al. [
8], our results in Chinese populations failed to find a significant association between
MBL2 gene polymorphisms and susceptibility to HIV infection, which indicated that gene polymorphisms in the
MBL2 gene might not be associated with HIV infection among this population. Considering the positive results in some other studies, there may be other variants not studied that may be associated with HIV infection. Further large-scale genome-wide association studies are needed.
Our research has some limitations. First, as a retrospective study, we lacked follow-up data, which may have limited our ability to analyze the association of TOLLIP gene SNPs with disease progression and outcome. Further prospective studies are needed. Second, this study included HIV uninfected healthy people as the control group, but we were unaware of their HIV exposure risk. As a result, we cannot analyze the genetic susceptibility of HIV infection in people who are also at risk of HIV exposure. Third, only two SNPs in MBL2 were genotyped, and other potential functional variations may have been ignored. A large-scale genome-wide association study is needed in the future. Finally, the ethnic uniformity of this study was another limitation. This study only included the Chinese Han population. However, considering that there may be differences in SNP alleles and genotypes frequency of different ethnic groups, the conclusions of this data are only drawn to the Chinese Han population, and conclusions should be made cautiously when interpreting in other ethnic groups.
This study found that two SNPs (rs5743867 and rs5743899) in the TOLLIP gene associated with susceptibility to HIV infection were observed in the Chinese Han population, suggesting a potential role for the TOLLIP gene in susceptibility to HIV infection.
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