TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients

Joshi, Anjali; Punke, Erin B.; Mehmetoglu-Gurbuz, Tugba; Peralta, Diego P.; Garg, Himanshu

doi:10.1186/s12879-019-3697-9

Cited by 15 publications

(17 citation statements)

References 68 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 81%

“…[ 45 ] The results reporting of the influence of the TLR9 rs352140 on disease progression are contradictory. A study performed in Spain [ 43 ] and American [ 58 ] HIV-infected cohort showed that TLR9 rs352140 is associated with lower CD4 count and higher viral load as rapid progression. In contrast, study in Omani showed that TLR9 rs352140 is associated with high CD4T cell count.…”

Section: Resultsmentioning

confidence: 99%

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

Shi

Sun³

et al. 2020

Medicine

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Background: To find the relationship between toll-like receptor (TLR) gene variants and human immunodeficiency virus (HIV) infection and clinical findings, which could inform clinical decisions and vaccination strategies. Method: Four databases were searched for articles that were published on or before Jul.1, 2020. Review Manager 5.3 software was applied to perform meta-analysis to explore. Results: A total of 10 studies involving 20 genes, 3697 cases, and 6498 controls were included in this systematic review. TLR2 –196 to –174 Ins/Del (odds ratio [OR] = 1.562; P = .002), TLR4 rs4986790 (OR = 2.05; P = .002), TLR3 rs3775291 (OR = 0.25; P = .03), TLR7 rs179008 ( P = .002), TLR7 rs2074109 (OR = 0.27, P = .019) were found associated with HIV infection. TLR2 –196 to –174, TLR4 rs4986790, TLR7 rs179008, TLR8 rs3764880, TLR9 rs352140 were found associated with clinical findings of HIV infection. We identified 5 case-control studies in meta-analysis, involving 695 cases and 729 controls on TLR7 rs179008 polymorphism, totaling 652 cases and 614 controls on TLR9 rs352140 polymorphism. In meta-analysis, we employed various genetic models. The T allele of TLR7 rs179008 was conferred the risk of HIV infection (T vs A: OR = 1.25, P A = .02). An increased risk of HIV infection was found for individuals with the TLR9 rs352140 GG genotype (GG vs AA: OR = 1.50, P A = .04). Conclusions: The systematic review indicated that TLR7 rs179008 T allele provides risk effects for HIV infection. TLR9 rs352140 GG genotype may associate with HIV infection.

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Section: Discussioncontrasting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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

Shi

Sun³

et al. 2020

Medicine

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“…Many of these genes are associated with the cell cycle, apoptosis, lymphocyte migration, or CD4 + T‐cell homeostasis . Conversely, the CCR2 rs1799864‐AG genotypes, HLA‐A68 and HLA‐B15 alleles, TLR9 1635AA genotype, polymorphism rs1385129 in the glut1 gene SLC2A1, and polymorphisms in the IFN‐γ and IL19 genes are linked to poor CD4 + T‐cell recovery in HIV‐1‐infected individuals.…”

Section: Potential Mechanisms Of Incomplete Immune Reconstitutionmentioning

confidence: 99%

“…1635AA genotype, 192 polymorphism rs1385129 in the glut1 gene SLC2A1, 193 and polymorphisms in the IFN-and IL19 genes 194 are linked to poor CD4 + T-cell recovery in HIV-1-infected individuals.…”

Section: Host Genetic Factorsmentioning

confidence: 99%

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

219

214

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The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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“…Sex differences in TLR9 expression has also been reported in mice, where male mice showed higher expression of TLR9 and higher activation of innate immune system with higher numbers of infiltrating neutrophils upon MCMV viral infection but similar viral load between male and female ( Traub et al, 2012 ). Research performed in HIV patients furthermore showed that TLR9 stimulation by viral CpG DNA contributes to HIV immunopathogenesis and the TLR9 polymorphisms 1635A/G and 1486C/T being associated with disease progression ( Joshi et al, 2019 ). Differences in adverse outcome of Covid-19 between ethnic groups may also in part result from genetic predisposition.…”

Section: Multidisciplinary Clues That Reason the Proposed Role For Tlmentioning

confidence: 99%

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

Bezemer

Garssen

2021

Front. Pharmacol.

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By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.

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TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients

Cited by 15 publications

References 68 publications

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

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

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

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