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Viruses
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Mechanisms of Viral Persistence
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Mechanisms of Viral Persistence

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 53315

Special Issue Editors

Dr. Mary Kearney

E-Mail Website
Guest Editor
Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
Interests: HIV translational research; HIV persistence; intra-patient viral genetics; single-cell viral genetics and expression; clonal expansion of HIV-infected cells
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Bill Sugden

E-Mail Website
Guest Editor
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
Interests: EBV-associated tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses of many families can persist in people after an initial phase of infection in chronically lytic and/or latent forms. Viral persistence may be maintained for weeks, months, years, or even for a person’s lifetime. The mechanisms that promote viral persistence in vivo vary across different pathogens and can be imposed by both the virus and the host. Understanding these mechanisms is key to revealing potential targets to be exploited in future strategies to cure these infections. In this Special Issue, we provide original and review articles describing how viruses including HPV, EBV, KSHV, HCV, HIV, and HTLV maintain themselves in proliferating cells and escape immune targeting and elimination. These viruses persist by downregulating host factors, modifying host or viral genetics, and using special mechanisms to maintain latency by affecting host cell survival and proliferation. These articles illustrate the breadth and complexity of the functions used by viral pathogens to persist in their human hosts.

Dr. Mary Kearney
Dr. Bill Sugden
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

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

  • persistence
  • latency
  • immune escape
  • transcriptional modification or silencing
  • eradication
  • remission
  • genome replication
  • genome partitioning

Published Papers (11 papers)

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Research

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12 pages, 2204 KiB  
Article
How Epstein–Barr Virus and Kaposi’s Sarcoma-Associated Herpesvirus Are Maintained Together to Transform the Same B-Cell
by Arthur U. Sugden, Mitch Hayes and Bill Sugden
Viruses 2021, 13(8), 1478; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081478 - 28 Jul 2021
Cited by 3 | Viewed by 2544
Abstract
Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) independently cause human cancers, and both are maintained as plasmids in tumor cells. They differ, however, in their mechanisms of segregation; EBV partitions its genomes quasi-faithfully, while KSHV often clusters its genomes and partitions them [...] Read more.
Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) independently cause human cancers, and both are maintained as plasmids in tumor cells. They differ, however, in their mechanisms of segregation; EBV partitions its genomes quasi-faithfully, while KSHV often clusters its genomes and partitions them randomly. Both viruses can infect the same B-cell to transform it in vitro and to cause primary effusion lymphomas (PELs) in vivo. We have developed simulations based on our measurements of these replicons in B-cells transformed in vitro to elucidate the synthesis and partitioning of these two viral genomes when in the same cell. These simulations successfully capture the biology of EBV and KSHV in PELs. They have revealed that EBV and KSHV replicate and partition independently, that they both contribute selective advantages to their host cell, and that KSHV pays a penalty to cluster its genomes. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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13 pages, 1810 KiB  
Article
Tracking HIV-1-Infected Cell Clones Using Integration Site-Specific qPCR
by Leah D. Brandt, Shuang Guo, Kevin W. Joseph, Jana L. Jacobs, Asma Naqvi, John M. Coffin, Mary F. Kearney, Elias K. Halvas, Xiaolin Wu, Stephen H. Hughes and John W. Mellors
Viruses 2021, 13(7), 1235; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071235 - 25 Jun 2021
Cited by 8 | Viewed by 3379
Abstract
Efforts to cure HIV-1 infection require better quantification of the HIV-1 reservoir, particularly the clones of cells harboring replication-competent (intact) proviruses, termed repliclones. The digital droplet PCR assays commonly used to quantify intact proviruses do not differentiate among specific repliclones, thus the [...] Read more.
Efforts to cure HIV-1 infection require better quantification of the HIV-1 reservoir, particularly the clones of cells harboring replication-competent (intact) proviruses, termed repliclones. The digital droplet PCR assays commonly used to quantify intact proviruses do not differentiate among specific repliclones, thus the dynamics of repliclones are not well defined. The major challenge in tracking repliclones is the relative rarity of the cells carrying specific intact proviruses. To date, detection and accurate quantification of repliclones requires in-depth integration site sequencing. Here, we describe a simplified workflow using integration site-specific qPCR (IS-qPCR) to determine the frequencies of the proviruses integrated in individual repliclones. We designed IS-qPCR to determine the frequencies of repliclones and clones of cells that carry defective proviruses in samples from three donors. Comparing the results of IS-qPCR with deep integration site sequencing data showed that the two methods yielded concordant estimates of clone frequencies (r = 0.838). IS-qPCR is a potentially valuable tool that can be applied to multiple samples and cell types over time to measure the dynamics of individual repliclones and the efficacy of treatments designed to eliminate them. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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16 pages, 1949 KiB  
Article
CpG Methylation Profiles of HIV-1 Proviral DNA in Individuals on ART
by Valerie F. Boltz, Cristina Ceriani, Jason W. Rausch, Wei Shao, Michael J. Bale, Brandon F. Keele, Rebecca Hoh, Jeffrey M. Milush, Steve G. Deeks, Frank Maldarelli, Mary F. Kearney and John M. Coffin
Viruses 2021, 13(5), 799; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050799 - 29 Apr 2021
Cited by 8 | Viewed by 2739
Abstract
The latent HIV-1 reservoir is comprised of stably integrated and intact proviruses with limited to no viral transcription. It has been proposed that latent infection may be maintained by methylation of pro-viral DNA. Here, for the first time, we investigate the cytosine methylation [...] Read more.
The latent HIV-1 reservoir is comprised of stably integrated and intact proviruses with limited to no viral transcription. It has been proposed that latent infection may be maintained by methylation of pro-viral DNA. Here, for the first time, we investigate the cytosine methylation of a replication competent provirus (AMBI-1) found in a T cell clone in a donor on antiretroviral therapy (ART). Methylation profiles of the AMBI-1 provirus were compared to other proviruses in the same donor and in samples from three other individuals on ART, including proviruses isolated from lymph node mononuclear cells (LNMCs) and peripheral blood mononuclear cells (PBMCs). We also evaluated the apparent methylation of cytosines outside of CpG (i.e., CpH) motifs. We found no evidence for methylation in AMBI-1 or any other provirus tested within the 5′ LTR promoter. In contrast, CpG methylation was observed in the env-tat-rev overlapping reading frame. In addition, we found evidence for differential provirus methylation in cells isolated from LNMCs vs. PBMCs in some individuals, possibly from the expansion of infected cell clones. Finally, we determined that apparent low-level methylation of CpH cytosines is consistent with occasional bisulfite reaction failures. In conclusion, our data do not support the proposition that latent HIV infection is associated with methylation of the HIV 5′ LTR promoter. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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Review

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24 pages, 5556 KiB  
Review
Clonal Expansion of Infected CD4+ T Cells in People Living with HIV
by John M. Coffin and Stephen H. Hughes
Viruses 2021, 13(10), 2078; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102078 - 15 Oct 2021
Cited by 11 | Viewed by 3160
Abstract
HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative [...] Read more.
HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative strategies. The discovery that a large fraction of the persistently infected cells in individuals on suppressive ART are members of large clones greatly changed our view of the reservoir and how it arises. Rather than being the products of infection of resting cells, as was once thought, HIV persistence is largely or entirely a consequence of infection of cells that are either expanding or are destined to expand, primarily due to antigen-driven activation. Although most of the clones carry defective proviruses, some carry intact infectious proviruses; these clones comprise the majority of the reservoir. A large majority of both the defective and the intact infectious proviruses in clones of infected cells are transcriptionally silent; however, a small fraction expresses a few copies of unspliced HIV RNA. A much smaller fraction is responsible for production of low levels of infectious virus, which can rekindle infection when ART is stopped. Further understanding of the reservoir will be needed to clarify the mechanism(s) by which provirus expression is controlled in the clones of cells that constitute the reservoir. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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16 pages, 897 KiB  
Review
New Latency Reversing Agents for HIV-1 Cure: Insights from Nonhuman Primate Models
by Katherine M. Bricker, Ann Chahroudi and Maud Mavigner
Viruses 2021, 13(8), 1560; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081560 - 06 Aug 2021
Cited by 10 | Viewed by 2944
Abstract
Antiretroviral therapy (ART) controls human immunodeficiency virus 1 (HIV-1) replication and prevents disease progression but does not eradicate HIV-1. The persistence of a reservoir of latently infected cells represents the main barrier to a cure. “Shock and kill” is a promising strategy involving [...] Read more.
Antiretroviral therapy (ART) controls human immunodeficiency virus 1 (HIV-1) replication and prevents disease progression but does not eradicate HIV-1. The persistence of a reservoir of latently infected cells represents the main barrier to a cure. “Shock and kill” is a promising strategy involving latency reversing agents (LRAs) to reactivate HIV-1 from latently infected cells, thus exposing the infected cells to killing by the immune system or clearance agents. Here, we review advances to the “shock and kill” strategy made through the nonhuman primate (NHP) model, highlighting recently identified latency reversing agents and approaches such as mimetics of the second mitochondrial activator of caspase (SMACm), experimental CD8+ T cell depletion, immune checkpoint blockade (ICI), and toll-like receptor (TLR) agonists. We also discuss the advantages and limits of the NHP model for HIV cure research and methods developed to evaluate the efficacy of in vivo treatment with LRAs in NHPs. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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15 pages, 1340 KiB  
Review
HIV-1 Persistence in Children during Suppressive ART
by Mary Grace Katusiime, Gert U. Van Zyl, Mark F. Cotton and Mary F. Kearney
Viruses 2021, 13(6), 1134; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061134 - 12 Jun 2021
Cited by 7 | Viewed by 3589
Abstract
There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children [...] Read more.
There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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23 pages, 4133 KiB  
Review
Insights into SARS-CoV-2 Persistence and Its Relevance
by Belete A. Desimmie, Yonas Y. Raru, Hesham M. Awadh, Peimei He, Samson Teka and Kara S. Willenburg
Viruses 2021, 13(6), 1025; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061025 - 29 May 2021
Cited by 34 | Viewed by 7668
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), continues to wreak havoc, threatening the public health services and imposing economic collapse worldwide. Tailoring public health responses to the SARS-CoV-2 pandemic depends on understanding the mechanism of [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), continues to wreak havoc, threatening the public health services and imposing economic collapse worldwide. Tailoring public health responses to the SARS-CoV-2 pandemic depends on understanding the mechanism of viral replication, disease pathogenesis, accurately identifying acute infections, and mapping the spreading risk of hotspots across the globe. However, effective identification and isolation of persons with asymptomatic and mild SARS-CoV-2 infections remain the major obstacles to efforts in controlling the SARS-CoV-2 spread and hence the pandemic. Understanding the mechanism of persistent viral shedding, reinfection, and the post-acute sequalae of SARS-CoV-2 infection (PASC) is crucial in our efforts to combat the pandemic and provide better care and rehabilitation to survivors. Here, we present a living literature review (January 2020 through 15 March 2021) on SARS-CoV-2 viral persistence, reinfection, and PASC. We also highlight potential areas of research to uncover putative links between viral persistence, intra-host evolution, host immune status, and protective immunity to guide and direct future basic science and clinical research priorities. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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25 pages, 1359 KiB  
Review
HIV-1 Natural Antisense Transcription and Its Role in Viral Persistence
by Rui Li, Rachel Sklutuis, Jennifer L. Groebner and Fabio Romerio
Viruses 2021, 13(5), 795; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050795 - 29 Apr 2021
Cited by 10 | Viewed by 3109
Abstract
Natural antisense transcripts (NATs) represent a class of RNA molecules that are transcribed from the opposite strand of a protein-coding gene, and that have the ability to regulate the expression of their cognate protein-coding gene via multiple mechanisms. NATs have been described in [...] Read more.
Natural antisense transcripts (NATs) represent a class of RNA molecules that are transcribed from the opposite strand of a protein-coding gene, and that have the ability to regulate the expression of their cognate protein-coding gene via multiple mechanisms. NATs have been described in many prokaryotic and eukaryotic systems, as well as in the viruses that infect them. The human immunodeficiency virus (HIV-1) is no exception, and produces one or more NAT from a promoter within the 3’ long terminal repeat. HIV-1 antisense transcripts have been the focus of several studies spanning over 30 years. However, a complete appreciation of the role that these transcripts play in the virus lifecycle is still lacking. In this review, we cover the current knowledge about HIV-1 NATs, discuss some of the questions that are still open and identify possible areas of future research. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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15 pages, 719 KiB  
Review
Residual Proviral Reservoirs: A High Risk for HIV Persistence and Driving Forces for Viral Rebound after Analytical Treatment Interruption
by Xiaolei Wang and Huanbin Xu
Viruses 2021, 13(2), 335; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020335 - 21 Feb 2021
Cited by 6 | Viewed by 2706
Abstract
Antiretroviral therapy (ART) has dramatically suppressed human immunodeficiency virus (HIV) replication and become undetectable viremia. However, a small number of residual replication-competent HIV proviruses can still persist in a latent state even with lifelong ART, fueling viral rebound in HIV-infected patient subjects after [...] Read more.
Antiretroviral therapy (ART) has dramatically suppressed human immunodeficiency virus (HIV) replication and become undetectable viremia. However, a small number of residual replication-competent HIV proviruses can still persist in a latent state even with lifelong ART, fueling viral rebound in HIV-infected patient subjects after treatment interruption. Therefore, the proviral reservoirs distributed in tissues in the body represent a major obstacle to a cure for HIV infection. Given unavailable HIV vaccine and a failure to eradicate HIV proviral reservoirs by current treatment, it is crucial to develop new therapeutic strategies to eliminate proviral reservoirs for ART-free HIV remission (functional cure), including a sterilizing cure (eradication of HIV reservoirs). This review highlights recent advances in the establishment and persistence of HIV proviral reservoirs, their detection, and potential eradication strategies. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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16 pages, 2711 KiB  
Review
Persistent Human Papillomavirus Infection
by Ashley N. Della Fera, Alix Warburton, Tami L. Coursey, Simran Khurana and Alison A. McBride
Viruses 2021, 13(2), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020321 - 20 Feb 2021
Cited by 72 | Viewed by 10277
Abstract
Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of [...] Read more.
Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of a lesion, while progeny viral genomes are amplified to large numbers in differentiated superficial cells. The viral E1 and E2 proteins initiate viral DNA replication and maintain and partition viral genomes, in concert with the cellular replication machinery. Additionally, the E5, E6, and E7 proteins are required to evade host immune responses and to produce a cellular environment that supports viral DNA replication. An unfortunate consequence of the manipulation of cellular proliferation and differentiation is that cells become at high risk for carcinogenesis. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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17 pages, 1350 KiB  
Review
Persistent Detection and Infectious Potential of SARS-CoV-2 Virus in Clinical Specimens from COVID-19 Patients
by Michael Zapor
Viruses 2020, 12(12), 1384; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121384 - 03 Dec 2020
Cited by 43 | Viewed by 7897
Abstract
The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) that emerged in December 2019 as the causative agent of Coronavirus 2019 (COVID-19) and was declared a pandemic by the World Health Organization in March 2020 has several distinctive features, including extensive multiorgan involvement with a [...] Read more.
The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) that emerged in December 2019 as the causative agent of Coronavirus 2019 (COVID-19) and was declared a pandemic by the World Health Organization in March 2020 has several distinctive features, including extensive multiorgan involvement with a robust systemic inflammatory response, significant associated morbidity and mortality, and prolonged persistence of viral RNA in the clinical specimens of infected individuals as detected by Reverse Transcription Polymerase Chain Reaction (RT-PCR) amplification. This review begins with an overview of SARS-CoV-2 morphology and replication and summarizes what is known to date about the detection of the virus in nasal, oropharyngeal, and fecal specimens of patients who have recovered from COVID-19, with a focus on the factors thought to contribute to prolonged detection. This review also provides a discussion on the infective potential of this material from asymptomatic, pre-symptomatic, and convalescing individuals, to include a discussion of the relative persistence and infectious potential of virus in clinical specimens recovered from pediatric COVID-19 patients. Full article
(This article belongs to the Special Issue Mechanisms of Viral Persistence)
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