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MBio Dec 2022Human immunodeficiency virus type 1 (HIV-1) can integrate viral DNA into host cell chromosomes to establish a long-term stable latent reservoir, which is a major...
Human immunodeficiency virus type 1 (HIV-1) can integrate viral DNA into host cell chromosomes to establish a long-term stable latent reservoir, which is a major obstacle to cure HIV-1 infection. The characteristics of the HIV-1 latent reservoir have not been fully understood. Here, we identified 126 upregulated plasma membrane proteins in HIV-1 latently infected cells by a label-free liquid chromatography-tandem mass spectrometry analysis. The higher levels of CD98 expression in multiple HIV-1 latently infected cell lines and primary CD4 T cells compared to uninfected cells were further confirmed by quantitative reverse transcription PCR (RT-qPCR) and flow cytometry analyses. In addition, CD98 CD4 T cells displayed hyper-permissiveness to HIV-1 infection and possessed distinct immune phenotypic profiles associated with Th17 and peripheral follicular T helper (pTFH) characteristics. Notably, the CD98 resting memory CD4 T cells harbored significantly higher cell-associated viral RNA and intact provirus than CD98 counterparts in HIV-1-infected individuals receiving combined antiretroviral therapy. Furthermore, CD98 CD4 T cells exhibited a robust proliferative capacity and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. Our study demonstrates that CD98 can be used as a novel biomarker of HIV-1 latently infected cells to indicate the effect of various strategies to reduce the viral reservoir. Identification of cellular biomarkers is the crucial challenge to eradicate the HIV-1 latent reservoir. In our study, we identified CD98 as a novel plasma membrane biomarker for HIV-1 permissiveness and latent infection. Importantly, CD98 CD4 T cells exhibited a hyper-permissiveness to HIV-1 infection and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. CD98 could be targeted to develop therapeutic strategies to reduce the HIV-1 latent reservoir in further research.
Topics: Humans; Biomarkers; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Latent Infection; Permissiveness; Virus Latency; Virus Replication; Fusion Regulatory Protein-1
PubMed: 36214569
DOI: 10.1128/mbio.02496-22 -
Frontiers in Immunology 2021Latent tuberculosis infection (LTBI) poses a major roadblock in the global effort to eradicate tuberculosis (TB). A deep understanding of the host responses involved in... (Meta-Analysis)
Meta-Analysis
Latent tuberculosis infection (LTBI) poses a major roadblock in the global effort to eradicate tuberculosis (TB). A deep understanding of the host responses involved in establishment and maintenance of TB latency is required to propel the development of sensitive methods to detect and treat LTBI. Given that LTBI individuals are typically asymptomatic, it is challenging to differentiate latently infected from uninfected individuals. A major contributor to this problem is that no clear pattern of host response is linked with LTBI, as molecular correlates of latent infection have been hard to identify. In this study, we have analyzed the global perturbations in host response in LTBI individuals as compared to uninfected individuals and particularly the heterogeneity in such response, across LTBI cohorts. For this, we constructed individualized genome-wide host response networks informed by blood transcriptomes for 136 LTBI cases and have used a sensitive network mining algorithm to identify top-ranked host response subnetworks in each case. Our analysis indicates that despite the high heterogeneity in the gene expression profiles among LTBI samples, clear patterns of perturbation are found in the immune response pathways, leading to grouping LTBI samples into 4 different immune-subtypes. Our results suggest that different subnetworks of molecular perturbations are associated with latent tuberculosis.
Topics: Computational Biology; Databases, Genetic; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Latent Tuberculosis; Mycobacterium tuberculosis; Transcriptome; Tuberculosis
PubMed: 33897680
DOI: 10.3389/fimmu.2021.595746 -
Theranostics 2020Epstein-Barr virus (EBV) is found in ~7% of gastric carcinoma cases worldwide, and all tumour cells harbour the clonal EBV genome. EBV can regulate pathways and protein...
Epstein-Barr virus (EBV) is found in ~7% of gastric carcinoma cases worldwide, and all tumour cells harbour the clonal EBV genome. EBV can regulate pathways and protein expression to induce gastric carcinoma; however, the molecular mechanism underlying EBV-associated gastric carcinoma (EBVaGC) remains elusive. GEO microarray and molecular experiments were performed to compare CXCR4 expression between EBV-positive and EBV-negative gastric carcinoma (EBVnGC). Transfections with LMP2A plasmid or siRNA were carried out to assess the role of LMP2A in CXCR4 expression. The effects and mechanisms of CXCR4 on cell autophagy were analysed using molecular biological and cellular approaches. Additionally, we also determined the regulatory role of CXCR4 in latent EBV infection. CXCR4 expression was significantly upregulated in EBVaGC tissues and cell lines. LMP2A could induce AKT phosphorylation to increase NRF1 expression, thereby binding to the CXCR4 promoter to increase its transcriptional level. Moreover, CXCR4 promoted ZEB1 expression to upregulate ATG7 synthesis, which could then activate autophagy. Moreover, CXCR4 increased the number of cells entering the G2/M phase and inhibited cell apoptosis via the autophagy pathway. Finally, CXCR4 knockdown was associated with elevated BZLF1 expression, but this effect was not influenced by autophagy. Our data suggested new roles for CXCR4 in autophagy and EBV replication in EBVaGC, which further promoted cell survival and persistent latent infection. These new findings can lead to further CXCR4-based anticancer therapy.
Topics: Autophagy; Carcinogenesis; Carcinoma; Cell Line, Tumor; Datasets as Topic; Epstein-Barr Virus Infections; Female; Gastric Mucosa; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Herpesvirus 4, Human; Host Microbial Interactions; Humans; Immunohistochemistry; Latent Infection; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; RNA, Viral; Receptors, CXCR4; Stomach Neoplasms; Up-Regulation; Viral Matrix Proteins
PubMed: 33052232
DOI: 10.7150/thno.44251 -
PloS One 2022Although there have been great advancements in the field of HIV treatment and prevention, there is no cure. There are two types of HIV: HIV-1 and HIV-2. In addition to...
Although there have been great advancements in the field of HIV treatment and prevention, there is no cure. There are two types of HIV: HIV-1 and HIV-2. In addition to genetic differences between the two types of HIV, HIV-2 infection causes a slower disease progression, and the rate of new HIV-2 infections has dramatically decreased since 2003. Like HIV-1, HIV-2 is capable of establishing latent infection in CD4+ T cells, thereby allowing the virus to evade viral cytopathic effects and detection by the immune system. The mechanisms underlying HIV latency are not fully understood, rendering this a significant barrier to development of a cure. Using RT-ddPCR, we previously demonstrated that latent infection with HIV-1 may be due to blocks to HIV transcriptional elongation, distal transcription/polyadenylation, and multiple splicing. In this study, we describe the development of seven highly-specific RT-ddPCR assays for HIV-2 that can be applied to the study of HIV-2 infections and latency. We designed and validated seven assays targeting different HIV-2 RNA regions along the genome that can be used to measure the degree of progression through different blocks to HIV-2 transcription and splicing. Given that HIV-2 is vastly understudied relative to HIV-1 and that it can be considered a model of a less virulent infection, application of these assays to studies of HIV-2 latency may inform new therapies for HIV-2, HIV-1, and other retroviruses.
Topics: HIV Infections; HIV Seropositivity; HIV-1; HIV-2; Humans; Latent Infection; Virus Latency
PubMed: 35476802
DOI: 10.1371/journal.pone.0267402 -
Thorax Nov 2018Lack of a gold standard for latent TB infection has precluded direct measurement of test characteristics of the tuberculin skin test and interferon-γ release assays...
BACKGROUND
Lack of a gold standard for latent TB infection has precluded direct measurement of test characteristics of the tuberculin skin test and interferon-γ release assays (QuantiFERON Gold In-Tube and T-SPOT.TB).
OBJECTIVE
We estimated test sensitivity/specificity and latent TB infection prevalence in a prospective, US-based cohort of 10 740 participants at high risk for latent infection.
METHODS
Bayesian latent class analysis was used to estimate test sensitivity/specificity and latent TB infection prevalence among subgroups based on age, foreign birth outside the USA and HIV infection.
RESULTS
Latent TB infection prevalence varied from 4.0% among foreign-born, HIV-seronegative persons aged <5 years to 34.0% among foreign-born, HIV-seronegative persons aged ≥5 years. Test sensitivity ranged from 45.8% for the T-SPOT.TB among foreign-born, HIV-seropositive persons aged ≥5 years to 80.7% for the tuberculin skin test among foreign-born, HIV-seronegative persons aged ≥5 years. The skin test was less specific than either interferon-γ release assay, particularly among foreign-born populations (eg, the skin test had 70.0% specificity among foreign-born, HIV-seronegative persons aged ≥5 years vs 98.5% and 99.3% specificity for the QuantiFERON and T-SPOT.TB, respectively). The tuberculin skin test's positive predictive value ranged from 10.0% among foreign-born children aged <5 years to 69.2% among foreign-born, HIV-seropositive persons aged ≥5 years; the positive predictive values of the QuantiFERON (41.4%) and T-SPOT.TB (77.5%) were also low among US-born, HIV-seropositive persons aged ≥5 years.
CONCLUSIONS
These data reinforce guidelines preferring interferon-γ release assays for foreign-born populations and recommending against screening populations at low risk for latent TB infection.
TRIAL REGISTRATION NUMBER
NCT01622140.
Topics: Adolescent; Adult; Bayes Theorem; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Incidence; Latent Class Analysis; Latent Tuberculosis; Male; Mass Screening; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Reproducibility of Results; Tuberculin Test; United States; Young Adult
PubMed: 29982223
DOI: 10.1136/thoraxjnl-2018-211715 -
PLoS Pathogens Oct 2023Even though gammaherpesvirus and parasitic infections are endemic in parts of the world, there is a lack of understanding about the outcome of coinfection. In humans,...
Even though gammaherpesvirus and parasitic infections are endemic in parts of the world, there is a lack of understanding about the outcome of coinfection. In humans, coinfections usually occur sequentially, with fluctuating order and timing in different hosts. However, experimental studies in mice generally do not address the variables of order and timing of coinfections. We sought to examine the variable of coinfection order in a system of gammaherpesvirus-helminth coinfection. Our previous work demonstrated that infection with the intestinal parasite, Heligmosomoides polygyrus, induced transient reactivation from latency of murine gammaherpesvirus-68 (MHV68). In this report, we reverse the order of coinfection, infecting with H. polygyrus first, followed by MHV68, and examined the effects of preexisting parasite infection on MHV68 acute and latent infection. We found that preexisting parasite infection increased the propensity of MHV68 to reactivate from latency. However, when we examined the mechanism for reactivation, we found that preexisting parasite infection increased the ability of MHV68 to reactivate in a vitamin A dependent manner, a distinct mechanism to what we found previously with parasite-induced reactivation after latency establishment. We determined that H. polygyrus infection increased both acute and latent MHV68 infection in a population of tissue resident macrophages, called large peritoneal macrophages. We demonstrate that this population of macrophages and vitamin A are required for increased acute and latent infection during parasite coinfection.
Topics: Humans; Animals; Mice; Virus Activation; Coinfection; Virus Latency; Vitamin A; B-Lymphocytes; Herpesviridae Infections; Gammaherpesvirinae; Macrophages; Latent Infection; Helminths; Parasitic Diseases; Mice, Inbred C57BL
PubMed: 37847677
DOI: 10.1371/journal.ppat.1011691 -
Frontiers in Immunology 2023We aimed to evaluate the indeterminate rate of interferon gamma release assays (IGRAs) in the detection of latent tuberculosis infection (LTBI). (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We aimed to evaluate the indeterminate rate of interferon gamma release assays (IGRAs) in the detection of latent tuberculosis infection (LTBI).
METHODS
On 15 November 2022, we searched the PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), and Cochrane Library databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators independently extracted the study data and assessed their quality using a modified quality assessment of diagnostic accuracy studies (i.e., QUADAS-2) tool. A random-effects model was used to calculate pooled results.
RESULTS
We included 403 studies involving 486,886 individuals and found that the pooled indeterminate rate was 3.9% (95% CI 3.5%-4.2%). The pooled indeterminate rate for QuantiFERON®-TB (QFT) was similar to that for T-SPOT®.TB (T-SPOT) [odds ratio (OR) = 0.88, 95% CI 0.59-1.32]; however, the indeterminate rate for a new generation of QFT (QFT-plus) was lower than that of T-SPOT (OR = 0.24, 95% CI 0.16-0.35). The indeterminate rate in the immunocompromised population was significantly higher than that in healthy controls (OR = 3.51, 95% CI 2.11-5.82), and it increased with the reduction of CD4+ cell count in HIV-positive patients. Children's pooled indeterminate rates (OR = 2.56, 95% CI 1.79-3.57) were significantly higher than those of adults, and the rates increased as the children's age decreased.
CONCLUSION
On average, 1 in 26 tests yields indeterminate IGRA results in LTBI screening. The use of advanced versions of the QuantiFERON-TB assay (QFT-plus), may potentially reduce the occurrence of an indeterminate result. Our study emphasizes the high risk of immunosuppression and young age in relation to indeterminate IGRA, which should receive more attention in the management of LTBI.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020211363, CRD42020211363.
Topics: United States; Child; Adult; Humans; Interferon-gamma Release Tests; Latent Tuberculosis; Mass Screening; HIV Seropositivity; Immunocompromised Host
PubMed: 37256138
DOI: 10.3389/fimmu.2023.1170579 -
Clinical & Developmental Immunology 2011Phagocytosis of tubercle bacilli by antigen-presenting cells in human lung alveoli initiates a complex infection process by Mycobacterium tuberculosis and a potentially... (Review)
Review
Phagocytosis of tubercle bacilli by antigen-presenting cells in human lung alveoli initiates a complex infection process by Mycobacterium tuberculosis and a potentially protective immune response by the host. M. tuberculosis has devoted a large part of its genome towards functions that allow it to successfully establish latent or progressive infection in the majority of infected individuals. The failure of immune-mediated clearance is due to multiple strategies adopted by M. tuberculosis that blunt the microbicidal mechanisms of infected immune cells and formation of distinct granulomatous lesions that differ in their ability to support or suppress the persistence of viable M. tuberculosis. In this paper, current understanding of various immune processes that lead to the establishment of latent M. tuberculosis infection, bacterial spreading, persistence, reactivation, and waning or elimination of latent infection as well as new diagnostic approaches being used for identification of latently infected individuals for possible control of tuberculosis epidemic are described.
Topics: Animals; Humans; Latent Tuberculosis; Mice; Mycobacterium tuberculosis; Tuberculosis, Pulmonary
PubMed: 21234341
DOI: 10.1155/2011/814943 -
Topics in Antiviral Medicine 2022Tuberculosis (TB) remains the leading cause of death among people with HIV, and annual risk of progression from latent TB infection to active disease in this population...
Tuberculosis (TB) remains the leading cause of death among people with HIV, and annual risk of progression from latent TB infection to active disease in this population is 10%. Diagnostic tests for latent and active TB remain suboptimal for people with HIV who have a CD4+ count below 200 cells/μL, and there is an urgent need for assays that predict progression from latent to active disease, monitor treatment response, and test for cure after latent and active TB treatment. Traditional treatment duration for latent infection and active TB disease has been onerous for patients; however, shorter-course regimens are increasingly available across the spectrum of TB, including for drug-resistant TB. Simultaneous treatment of HIV and TB is complicated by drug-drug interactions, although trials are ongoing to better understand the magnitude of these interactions and guide clinicians in how to use short-course regimens, particularly for people with HIV.
Topics: Humans; HIV Infections; Latent Tuberculosis; Tuberculosis; CD4 Lymphocyte Count
PubMed: 36346703
DOI: No ID Found -
Emerging Infectious Diseases Mar 2011To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide,... (Meta-Analysis)
Meta-Analysis Review
To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide, and the population-attributable fraction of TB to exposure of HCWs in their work settings, we reviewed the literature. Stratified pooled estimates for the LTBI rate for countries with low (<50 cases/100,000 population), intermediate (50-100/100,000 population), and high (>100/100,000 population) TB incidence were 3.8% (95% confidence interval [CI] 3.0%-4.6%), 6.9% (95% CI 3.4%-10.3%), and 8.4% (95% CI 2.7%-14.0%), respectively. For TB, estimated incident rate ratios were 2.4 (95% CI 1.2-3.6), 2.4 (95% CI 1.0-3.8), and 3.7 (95% CI 2.9-4.5), respectively. Median estimated population-attributable fraction for TB was as high as 0.4%. HCWs are at higher than average risk for TB. Sound TB infection control measures should be implemented in all health care facilities with patients suspected of having infectious TB.
Topics: Health Personnel; Humans; Incidence; Infection Control; Infectious Disease Transmission, Patient-to-Professional; Latent Tuberculosis; Occupational Diseases; Risk Factors; Tuberculosis
PubMed: 21392441
DOI: 10.3201/eid1703.100947