Association of toll-like receptor polymorphisms with acquisition of HIV infection and clinical findings

1. Introduction

Acquired immunodeficiency syndrome (AIDS) is a contagious and potentially fatal disease caused by the human immunodeficiency virus (HIV). It is now recognized that chronic, generalized immune activation is a major driving force for CD4+ T cell depletion and AIDS progression.^[1] With similar risk exposure levels, the course of HIV-1 infection varies widely among individuals.^[2–4] In addition, different AIDS patients whose rate of progression to immunodeficiency and associated complications exhibited a high differences. Without antiretroviral treatment, most HIV-positive patients develop AIDS within 10 years, but some infected persons progress to AIDS within 1 to 5 years and others may remain asymptomatic for over 20 years.^[5–8] There is extensive heterogeneity among individuals in susceptibility to infection and the time to develop AIDS-defining diseases. Therefore, the genetic background of an individual might play an important role in acquisition of HIV and disease progression after HIV infection.^[9] Using a combination of analyses is including genome-wide association studies (GWAS) have identified a number of common host genetic polymorphisms involved in HIV immunopathogenesis,^[10–13] such as toll-like receptors (TLRs), interferon regulatory factor-3 (IRF-3) and tripartite motif 5a (TRIM5a) gene family.^[14]

TLRs belong to the family of pattern recognition receptors and are important pathogen recognition receptors (PRRs).^[15] They can recognize pathogen-associated molecular patterns and initiate signaling pathways that lead to the activation of the innate immune response, cytokines, and formation of the adaptive immune response.^[16] To date, about 13 TLRs recognizing different pathogen-associated molecular patterns have been discovered,^[17] 11 including in human.^[18] Different TLRs have different structurally characterized, TLR1, 2,4, 5, 6, 10, and 11 are expressed on the cell surface while TLR3, 7, 8, and 9 reside in the endosomal compartments.^[19] The TLRs on the cell surface sense conserved molecular motifs from a variety of organisms, primarily recognize bacteria, fungi parasites, and viruses.^[15,20,21] Similarly, through the intracellular domains, TLRs function primarily to detect nucleic acids.^[22] As innate immune sensors, TLRs are integral to resisting chronic and opportunistic infections. Mounting evidence implicates shows that single-nucleotide polymorphisms (SNPs) in TLRs link to various infectious diseases, such as tuberculosis (TLR2),^[23] cytomegalovirus infection (TLR3, TLR9),^[24] meningococcaemia (TLR4),^[25] also including HIV infection.

Immune activation is a major determinant for AIDS, the stimulation of TLRs implicate a wide array of innate immune responses and inflammation and play an important role in controlling the pathogenesis of infections and their control.^[26,27] They can trigger a complex cascade of signaling pathways in several cell types including dendritic cells, monocytes, macrophages neutrophils, and CD4 T lymphocytes, which are the target cells of HIV. There are now many evidences demonstrated the role of TLRs in HIV infection. Some studies provided TLR1,^[28] TLR2,^[29–32] TLR3,^[31,33,34] TLR4,^[29–33,35] TLR6,^[31] TLR7/8,^{[31,33,36–38]} and TLR9^[33] have a functional role in HIV infection and disease. In addition, SNPs in TLR2,^[39–43] TLR3,^[39–42] TLR4,^[39–43] TLR7,^[39–41,44] TLR8,^[39–41,45] and TLR9^[39–43,46] have been evaluated for their effects on HIV acquisition and disease progression in various populations under a variety of study designs. However, some research samples are too small, the research focus is not the same, and even some research results are contradictory. Up to now, there is no systematic review on this aspect. Thus, to better assess the potential associations between TLR gene polymorphisms and HIV infection and clinical findings, we performed a systematic review of all relevant studies.

2. Materials and methods

3. Results

4. Discussion

It is well known that HIV can attack the human immune system and then cause chronic activation of the immune system in association with dysfunction of cellular and humoral immune responses and failure to effectively control virus replication.^[59,60] Considerable variability exists among individuals in their susceptibility to HIV infection and subsequent clinical findings. Genetic variants of TLRs may influence susceptibility of HIV infection and disease outcome. To better understand the relationship between TLRs and HIV infection, we performed this systematic review.

In the present study, we totally pooled 10 articles, some of which have been proved TLR polymorphisms associated with HIV infection and clinical findings. For example, Vidyant et al has successive reported TLR2 –196 to –174 Ins/Del (Del mutant genotype, allele) and TLR4 rs4986790 (heterozygous genotype and the mutant allele G) were associated with HIV infection.^[51,52] A study performed on an Indian cohort study showed that TLR7 rs2074109 may have role in association with HIV infection.^[54] Meanwhile, in this Indian cohort study also reported TLR7 rs179008 were not associated with HIV infection, which is the opposite of the conclusion of the Germany cohort.^[44] The reason for this contradictory result may be due to the different ethnicity. In our study, we found TLR7 rs179008 polymorphism may be associated with increased HIV infection, which is consistent with a previous study.^[44] We found TLR7 rs179008 on T allele was the risk factor for HIV infection. Subsequently, significant association of TLR7 rs179008 polymorphism with HIV infection was identified in the dominant model and heterozygote model. Although the relationship between TLR9 rs352140 and HIV infection has not been studied in these articles, we found the TLR9 rs352140 GG genotype was a risk factor for HIV infection by meta-analysis. The authenticity of our meta-analysis results was verified by TSA and FPRP.

Much of the data comes from genetic analysis of populations that have an extreme phenotype in the clinical findings of HIV-1 infection, including viral load, CD4/CD8 cell counts, and disease progression. During the course of immune activation, activated T cells are produced as viral targets, further driving viral replication, and CD4 cell depletion. Immune activation and the above clinical findings are closely related in HIV-infected subjects. Genetic variants of the TLR gene are thought to regulate immune activation in HIV infection. Vidyant et al found that TLR2 Del homozygous genotypes were lower in low CD4 T-cell counts as compared to high CD4 T-cell counts and is associated with reduced risk of HIV-1 disease progression.^[51] The TLR7 rs179008 and TLR9 rs352140 polymorphism are the most frequently studied in clinical findings of HIV infection. TLR7 rs179008, TLR9 rs352140 were linked to the high viral loads and lower CD4 T-cell counts in Germany, Spanish, American cohort respectively.^[43,44,58] However, above results were in contrast to findings of Said et al.^[57] These inconsistent findings may be due to ethnicity, sample size, or sampling error. Therefore, we need more research to expand the sample size for meta-analysis and ethnicity subgroup analysis to get more reliable conclusions.

HIV pathogenesis is a multifactorial and complex phenomenon and the large portion of variability in the natural history of HIV remains unexplained and influence disease outcome are still largely unknown. For example, we all know that AIDS patients with low immunity often tend to have tumors. HIV-AIDS is the most common cause of acquired immune deficiency syndrome and the most important risk factor for the malignant lymphoma. The majority of HIV-related lymphomas originate from germinal center B cells or postgerminal center B cells.^[61] In the last years, experimental and clinical studies have shown that chronic inflammation, immune stimulation/deregulation, and oxidative stress are involved in the lymphomagenesis/lymphoproliferative disorders. The chronic inflammation transcription factor NF-kB activation - inflammatory cytokines release -ROS generation -oxidative stress - genomic instability -clonal volution link.^[62] The results of Amelia Maria Gaman et al suggest that oxidative stress may be associated with the stage of advanced diffuse large B cell lymphoma.^[63] Oxidative stress is involved in a variety of human diseases and disorders, including apoptosis and carcinogenesis. The antioxidant capacity of the human body decreases with age.^[64] Therefore, the link between the HIV infection and lymphomagenesis/lymphoproliferative disorders can also be mediated by chronic inflammation and oxidative stress. It may also be related to the pathogenic properties of the virus itself, environmental factors, rare genetic variants, and other immune factors. The differences between studies may also reflect the variable nature of HIV infection among genetically different individuals. It is clear that the function and impact of genetic polymorphisms differ according to race and ethnicity. The risk of transmission and progression depends on multiple interactions between virus and host, and no single genetic variant is a crucial factor in HIV pathogenesis.

As per our knowledge, this is the first and the most comprehensive systematic review about TLR polymorphisms association with HIV infection. Moreover, most of included studies had acceptable quality and had no significant heterogeneity. However, there were also some limitations in our study that should be considered when explaining the present results. First, because only a relatively small number of studies have investigated the roles of TLR polymorphisms in HIV infection, the number of studies included in the systematic review lacked of sufficient data to detect associations within ethnic groups. Future research with diverse demographic and clinical characteristics is necessary in ethnically diverse populations. Second, analysis was only based on genotyping data. It is impossible for only single genetic polymorphism to significantly contribute to the occurrence and development of this disease. Lastly, limiting the study to English language articles may have potentially led to a language bias.

5. Conclusions

In summary, this systematic review aimed to summarize the effects of the most commonly investigated TLR SNPs in relation to HIV infection. Our results suggested that TLR7 rs179008 T allele is the risk of HIV infection. TLR9 rs352140 GG genotype may associate with increasing HIV infection. Our study may have implications for the individual risk assessment of patients infected with HIV, meanwhile, this results is benefit to identify new targets for HIV preventative and therapeutic interventions.

Acknowledgments

The authors would like to acknowledge all people who consented to participate in this study.

Author contributions

Formal analysis: Han Shi, Hongyan He.

Methodology: Yunjian Sheng.

Writing – original draft: Han Shi.

Writing – review & editing: Hongyan He, Changfeng Sun, Juan Fu, Dipritu Ghosh, Cunliang Deng, Yunjian Sheng.

Supplementary Material