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Viruses
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Pathogenesis of Chronic Viral Infections
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Pathogenesis of Chronic Viral Infections

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 28595

Special Issue Editors

Prof. Dr. Shyamasundaran Kottilil

E-Mail Website
Guest Editor
Institute of Human Virology, University of Maryland School of Medicine, 725 W Lombard St., Baltimore, MD 21201, USA
Interests: bench-to-bedside research on pathogenesis and therapeutics for viral infections
Dr. Bhawna Poonia

E-Mail Website
Guest Editor
School of Medicine, University of Maryland, Baltimore, MD, USA
Interests: viral immunology; immune exhaustion; immune modulation; immune therapies; vaccines; HIV; HBV; HCV
Dr. Lydia S.Y. Tang

E-Mail Website
Guest Editor
School of Medicine, University of Maryland, Baltimore, MD, USA
Interests: hepatitis B translational research; clinical trials; hepatitis B cure strategies; hepatitis B treatment; minority community engagement; HIV; immunotherapy; vaccines

Special Issue Information

Dear Colleagues,

Significant human pathogens causing medically important chronic infections include human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV). Eradication of chronic viral infection can be achieved through high uptake of effective prophylaxis such as vaccination, and curative treatment. There is, however, no chronic infection for which both effective prophylaxis and curative treatments are available. Understanding the pathogenesis of viral persistence is crucial for identifying therapeutic targets. Viruses causing chronic infections employ a multitude of mechanisms for viral persistence and have unique pathogen–host interactions, and thus strategies for a cure must reflect this. Still, there is some commonality in their pathogenesis, including viral genome integration into the host genome, virus-specific host immunomodulation, immune exhaustion and immune escape mechanisms. Given the high benchmark of cure as a study outcome, cure research for these infections focuses on viral or immune biomarkers as surrogates for a potential cure. The paucity of data guiding definitions for “successful” changes in these biomarkers is a major impediment for cure research.

In this Special Issue, we will focus on mechanisms of viral persistence, specifically virus–host interactions, immunopathology and novel targets for vaccines and therapeutics.

Prof. Shyamasundaran Kottilil
Dr. Bhawna Poonia
Dr. Lydia S.Y. Tang
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HIV
  • HBV
  • HCV
  • HPV
  • pathology
  • latency
  • cccDNA
  • persistence
  • immune response
  • immune modulators
  • entry inhibitors
  • biomarkers
  • novel drug targets

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Published Papers (10 papers)

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Research

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16 pages, 2650 KiB  
Article
Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy
by Antonio Solis-Leal, Summer Siddiqui, Fei Wu, Mahesh Mohan, Wenhui Hu, Lara A. Doyle-Meyers, Jason P. Dufour and Binhua Ling
Viruses 2022, 14(1), 139; https://doi.org/10.3390/v14010139 - 13 Jan 2022
Cited by 5 | Viewed by 2777
Abstract
The central nervous system (CNS) HIV reservoir is an obstacle to achieving an HIV cure. The basal ganglia harbor a higher frequency of SIV than other brain regions in the SIV-infected rhesus macaques of Chinese-origin (chRMs) even on suppressive combination antiretroviral therapy (ART). [...] Read more.
The central nervous system (CNS) HIV reservoir is an obstacle to achieving an HIV cure. The basal ganglia harbor a higher frequency of SIV than other brain regions in the SIV-infected rhesus macaques of Chinese-origin (chRMs) even on suppressive combination antiretroviral therapy (ART). Since residual HIV/SIV reservoir is associated with inflammation, we characterized the neuroinflammation by gene expression and systemic levels of inflammatory molecules in healthy controls and SIV-infected chRMs with or without ART. CCL2, IL-6, and IFN-γ were significantly reduced in the cerebrospinal fluid (CSF) of animals receiving ART. Moreover, there was a correlation between levels of CCL2 in plasma and CSF, suggesting the potential use of plasma CCL2 as a neuroinflammation biomarker. With higher SIV frequency, the basal ganglia of untreated SIV-infected chRMs showed an upregulation of secreted phosphoprotein 1 (SPP1), which could be an indicator of ongoing neuroinflammation. While ART greatly reduced neuroinflammation in general, proinflammatory genes, such as IL-9, were still significantly upregulated. These results expand our understanding of neuroinflammation and signaling in SIV-infected chRMs on ART, an excellent model to study HIV/SIV persistence in the CNS. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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17 pages, 5007 KiB  
Article
Hepatitis C Virus Core Protein Down-Regulates Expression of Src-Homology 2 Domain Containing Protein Tyrosine Phosphatase by Modulating Promoter DNA Methylation
by Priya Devi, Seisuke Ota, Tanel Punga and Anders Bergqvist
Viruses 2021, 13(12), 2514; https://doi.org/10.3390/v13122514 - 15 Dec 2021
Cited by 5 | Viewed by 3122
Abstract
Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The main virion component, the core (C) protein, has been implicated in several aspects of HCV pathology including oncogenesis and immune subversion. Here we show that expression [...] Read more.
Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The main virion component, the core (C) protein, has been implicated in several aspects of HCV pathology including oncogenesis and immune subversion. Here we show that expression of the C protein induced specific tyrosine phosphorylation of the TCR-related signaling proteins ZAP-70, LAT and PLC-γ in the T cells. Stable expression of the C protein specifically reduced Src homology domain 2-containing protein tyrosine phosphatase 1 (SHP-1) mRNA and protein accumulation. Quantitative CpG methylation analysis revealed a distinct CpG methylation pattern at the SHP-1 gene promoter in the C protein expressing cells that included specific hypermethylation of the binding site for Sp1 transcription factor. Collectively, our results suggest that HCV may suppress immune responses and facilitate its own persistence by deregulating phosphotyrosine signaling via repressive epigenetic CpG modification at the SHP-1 promoter in the T cells. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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15 pages, 5959 KiB  
Article
Oral Selective TLR8 Agonist Selgantolimod Induces Multiple Immune Cell Responses in Humans
by Natarajan Ayithan, Alip Ghosh, Ankit Dwivedi, Jeffrey J. Wallin, Susanna K. Tan, Diana Chen, Shyam Kottilil and Bhawna Poonia
Viruses 2021, 13(12), 2400; https://doi.org/10.3390/v13122400 - 30 Nov 2021
Cited by 8 | Viewed by 3138
Abstract
TLR8 agonists have the potential for use as immunomodulatory components in therapeutic modalities for viral infections such as chronic HBV (CHB) and HIV. In this study, using peripheral blood samples from a phase 1a clinical trial, we examined the acute effects of a [...] Read more.
TLR8 agonists have the potential for use as immunomodulatory components in therapeutic modalities for viral infections such as chronic HBV (CHB) and HIV. In this study, using peripheral blood samples from a phase 1a clinical trial, we examined the acute effects of a single oral administration of a selective TLR8 agonist on immune cell phenotypes. Administration of the TLR8 agonist selgantolimod (SLGN) in healthy individuals resulted in alteration in frequencies of peripheral blood monocytes, pDCs, mDCs and MAIT cells. Frequencies of mDCs and lymphoid cells significantly reduced after 8 h of SLGN administration, whereas pDC frequencies significantly increased, with changes possibly reflecting migration of different cell types between peripheral and tissue compartments in response to the agonist. Myeloid cell activation was evident by an upregulated expression of co-stimulatory molecules CD40 and CD86 accompanied by the production of IL-6 and IL-18 from these cells. Concomitantly, there was induction of the early activation marker CD69 on innate and adaptive lymphoid cells, including MAIT and NK cell subsets. Further, these activated lymphoid cells had enhanced expression of the effector molecules granzyme B and perforin. Microarray analysis of isolated lymphocytes and monocytes from baseline and post-SLGN treatment revealed changes in expression of genes involved in cellular response to cytokine stimulus, innate immune response, myeloid cell differentiation and antigen receptor-mediated signaling pathway. In a preliminary analysis of samples from CHB patients treated with selgantolimod, activation of innate and adaptive lymphocytes was evident. In conclusion, this first in-human study shows that selgantolimod administration in humans results in activation of multiple immune cell responses with antiviral potential. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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8 pages, 1066 KiB  
Article
Systemic and Intestinal Viral Reservoirs in CD4+ T Cell Subsets in Primary SIV Infection
by Xiaolei Wang, Widade Ziani, Ronald S. Veazey and Huanbin Xu
Viruses 2021, 13(12), 2398; https://doi.org/10.3390/v13122398 - 30 Nov 2021
Cited by 1 | Viewed by 1963
Abstract
The HIV reservoir size in target CD4+ T cells during primary infection remains unknown. Here, we sorted peripheral and intestinal CD4+ T cells and quantified the levels of cell-associated SIV RNA and DNA in rhesus macaques within days of SIVmac251 inoculation. As a [...] Read more.
The HIV reservoir size in target CD4+ T cells during primary infection remains unknown. Here, we sorted peripheral and intestinal CD4+ T cells and quantified the levels of cell-associated SIV RNA and DNA in rhesus macaques within days of SIVmac251 inoculation. As a major target cell of HIV/SIV, CD4+ T cells in both tissues contained a large amount of SIV RNA and DNA at day 8–13 post-SIV infection, in which productive SIV RNA highly correlated with the levels of cell-associated SIV DNA. Memory CD4+ T cells had much higher viral RNA and DNA than naïve subsets, yet memory CD4+ T cells co-expressing CCR5 had no significant reservoir size compared with those that were CCR5-negative in blood and intestine. Collectively, memory CD4+ T cells appear to be the major targets for primary infection, and viral reservoirs are equally distributed in systemic and lymphoid compartments in acutely SIV-infected macaques. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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16 pages, 7995 KiB  
Article
A Combination of M50I and V151I Polymorphic Mutations in HIV-1 Subtype B Integrase Results in Defects in Autoprocessing
by Jun Yang, Ming Hao, Muhammad A. Khan, Muhammad T. Rehman, Helene C. Highbarger, Qian Chen, Suranjana Goswami, Brad T. Sherman, Catherine A. Rehm, Robin L. Dewar, Weizhong Chang and Tomozumi Imamichi
Viruses 2021, 13(11), 2331; https://doi.org/10.3390/v13112331 - 22 Nov 2021
Cited by 2 | Viewed by 2048
Abstract
We have recently reported that a recombinant HIV-1NL4.3 containing Met-to-Ile change at codon 50 of integrase (IN) (IN:M50I) exhibits suppression of the virus release below 0.5% of WT HIV, and the released viral particles are replication-incompetent due to defects in Gag/GagPol processing by [...] Read more.
We have recently reported that a recombinant HIV-1NL4.3 containing Met-to-Ile change at codon 50 of integrase (IN) (IN:M50I) exhibits suppression of the virus release below 0.5% of WT HIV, and the released viral particles are replication-incompetent due to defects in Gag/GagPol processing by inhibition of the initiation of autoprocessing of GagPol polyproteins in the virions and leads to replication-incompetent viruses. The coexisting Ser-to-Asn change at codon 17 of IN or Asn-to-Ser mutation at codon 79 of RNaseH (RH) compensated the defective IN:M50I phenotype, suggesting that both IN and RH regulate an HIV infectability. In the current study, to elucidate a distribution of the three mutations during anti-retroviral therapy among patients, we performed a population analysis using 529 plasma virus RNA sequences obtained through the MiSeq. The result demonstrated that 14 plasma HIVs contained IN:M50I without the compensatory mutations. Comparing the sequences of the 14 viruses with that of the defective virus illustrated that only Val-to-Ile change at codon 151 of IN (IN:V151I) existed in the recombinant virus. This IN:V151I is known as a polymorphic mutation and was derived from HIVNL4.3 backbone. A back-mutation at 151 from Ile-to-Val in the defective virus recovered HIV replication capability, and Western Blotting assay displayed that the back-mutation restored Gag/GagPol processing in viral particles. These results demonstrate that a combination of IN:M50I and IN:V151I mutations, but not IN:M50I alone, produces a defective virus. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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12 pages, 3242 KiB  
Article
CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV/HCV-Coinfected Patients
by Shikha Shrivastava, Shyam Kottilil, Kenneth E. Sherman, Henry Masur and Lydia Tang
Viruses 2021, 13(10), 2074; https://doi.org/10.3390/v13102074 - 14 Oct 2021
Cited by 1 | Viewed by 3342
Abstract
Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to [...] Read more.
Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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9 pages, 521 KiB  
Article
Outcomes in Hepatitis C Positive Liver Transplantation: Timing of Direct-Acting Antiviral Treatment and Impact on Graft Fibrosis
by Jennifer Wellington, Andrew Ma, Shyam Kottilil, Bharath Ravichandran, Jennifer Husson, David Bruno and Eleanor Wilson
Viruses 2021, 13(9), 1831; https://doi.org/10.3390/v13091831 - 14 Sep 2021
Cited by 3 | Viewed by 1902
Abstract
Liver transplantation for hepatitis C virus (HCV)-related disease has the lowest five-year graft survival among all liver transplant recipients. Graft failure due to accelerated fibrosis from unrestrained HCV replication is common. Optimal timing of HCV treatment with direct-acting antiviral agents remains unknown. We [...] Read more.
Liver transplantation for hepatitis C virus (HCV)-related disease has the lowest five-year graft survival among all liver transplant recipients. Graft failure due to accelerated fibrosis from unrestrained HCV replication is common. Optimal timing of HCV treatment with direct-acting antiviral agents remains unknown. We compared HCV liver transplant recipients successfully treated for HCV before transplant to those treated within 1 year of transplant to determine if graft fibrosis, measured by Fib-4 scores, differs with timing of treatment. Fib-4 scores less than or equal to 1.45 defined minimal fibrosis and greater than 1.45 defined greater than minimal fibrosis. We identified 117 liver transplant recipients: 52 treated before transplantation and 65 treated within 1 year of transplantation. Overall, 34% of recipients had minimal fibrosis, and the likelihood of having minimal fibrosis following treatment and liver transplantation did not differ by timing of treatment. The odds ratio of having greater than minimal fibrosis was 0.65 (95% CI 0.30, 1.42) among those treated within 1 year after transplantation compared to those treated before transplantation (p-value 0.28). Importantly, nearly 2/3 of these patients had evidence of fibrosis progression one year after sustained virologic response, supporting recommendations for early antiviral-based treatment to prevent accumulation of HCV-related disease. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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10 pages, 244 KiB  
Article
Hepatitis C Virus Infection in Persons Who Inject Drugs in the Middle East and North Africa: Intervention Strategies
by Jag H. Khalsa and Poonam Mathur
Viruses 2021, 13(7), 1363; https://doi.org/10.3390/v13071363 - 14 Jul 2021
Cited by 5 | Viewed by 2322
Abstract
There is a high incidence and prevalence of hepatitis C viral infection in persons with or without substance use disorders (SUDs) in the Middle East and North Africa (MENA) region, but only a small number receive comprehensive care. Highly effective direct-acting antiviral (DAA) [...] Read more.
There is a high incidence and prevalence of hepatitis C viral infection in persons with or without substance use disorders (SUDs) in the Middle East and North Africa (MENA) region, but only a small number receive comprehensive care. Highly effective direct-acting antiviral (DAA) medications are available at substantially lower costs; however, complete elimination of the hepatitis C virus (HCV) can only be achieved if integrated care strategies target those at highest risk for HCV infection and transmission and improve access to care. Due to the high prevalence of SUD in the MENA region, strategies to eliminate HCV must focus on integrated healthcare across multiple subspecialties, including addiction medicine, psychiatry, infectious diseases, hepatology, and social work. In this invited manuscript, we review the epidemiology of HCV in the MENA region and highlight intervention strategies to attain the WHO’s goal of HCV eradication by 2030. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)

Review

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10 pages, 1264 KiB  
Review
Variable Normalization of Naïve CD4+ Lymphopenia and Markers of Monocyte and T Cell Activation over the Course of Direct-Acting Anti-Viral Treatment of Chronic Hepatitis C Virus Infection
by Ann W. N. Auma, Carey L. Shive, Lenche Kostadinova and Donald D. Anthony
Viruses 2022, 14(1), 50; https://doi.org/10.3390/v14010050 - 29 Dec 2021
Cited by 5 | Viewed by 2312
Abstract
Chronic hepatitis C virus (HCV) infection is associated with naïve CD4+ T cell lymphopenia and long-standing/persistent elevation of cellular and soluble immune activation parameters, the latter heightened in the setting of HIV co-infection. The underlying mechanisms are not completely understood. However, we recently [...] Read more.
Chronic hepatitis C virus (HCV) infection is associated with naïve CD4+ T cell lymphopenia and long-standing/persistent elevation of cellular and soluble immune activation parameters, the latter heightened in the setting of HIV co-infection. The underlying mechanisms are not completely understood. However, we recently reported that accelerated peripheral cell death may contribute to naïve CD4+ T cell loss and that mechanistic relationships between monocyte activation, T cell activation, and soluble inflammatory mediators may also contribute. Chronic HCV infection can be cured by direct-acting anti-viral (DAA) therapy, and success is defined as sustained virological response (SVR, undetectable HCV RNA (ribonucleic acid) at 12 weeks after DAA treatment completion). However, there is no general consensus on the short-term and long-term immunological outcomes of DAA therapy. Here, we consolidate previous reports on the partial normalization of naïve CD4+ lymphopenia and T cell immune activation and the apparent irreversibility of monocyte activation following DAA therapy in HCV infected and HCV/HIV co-infected individuals. Further, advanced age and cirrhosis are associated with delayed or abrogation of immune reconstitution after DAA therapy, an indication that non-viral factors also likely contribute to host immune dysregulation in HCV infection. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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17 pages, 765 KiB  
Review
Drugs of Abuse and Their Impact on Viral Pathogenesis
by Jason T. Blackard and Kenneth E. Sherman
Viruses 2021, 13(12), 2387; https://doi.org/10.3390/v13122387 - 29 Nov 2021
Cited by 10 | Viewed by 3959
Abstract
Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), [...] Read more.
Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). This review focuses on the myriad of mechanisms by which drugs of abuse impact viral replication and disease progression. Virus–drug interactions can accelerate viral disease progression and lead to increased risk of virus transmission. Full article
(This article belongs to the Special Issue Pathogenesis of Chronic Viral Infections)
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