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Viruses
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Cellular Mechanisms Regulating HIV Replication
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Cellular Mechanisms Regulating HIV Replication

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 15 December 2024 | Viewed by 9869

Special Issue Editor

Prof. Dr. Sergei Nekhai

E-Mail Website
Guest Editor
Department of Medicine, Howard University, Washington, DC, USA
Interests: HIV-1; filoviruses; sickle cell disease; proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Curing and eradicating HIV require a deep insight into viral replication mechanisms. Over the past two decades, significant progress has been made in understanding the complex interaction between HIV-1 and host factors that either facilitate or inhibit viral replication. This Special Issue of Viruses will review the latest developments in the HIV-1 field, with a particular focus on host cell factors that participate in various steps of viral replication such as viral entry and capsid nuclear import, as well as uncoating, integration, transcription, viral packaging, and assembly. This collection of comprehensive articles will summarize our current knowledge of the role of host factors in HIV-1 replication, which can help in the future development of novel HIV-1-targeting therapeutics.

Prof. Dr. Sergei Nekhai
Guest Editor

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.

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Published Papers (6 papers)

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Research

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22 pages, 4246 KiB  
Article
Downregulation of miRNA-26a by HIV-1 Enhances CD59 Expression and Packaging, Impacting Virus Susceptibility to Antibody-Dependent Complement-Mediated Lysis
by Nicolas Bellini, Chengyu Ye, Oluwaseun Ajibola, Thomas T. Murooka, Robert Lodge and Éric A. Cohen
Viruses 2024, 16(7), 1076; https://doi.org/10.3390/v16071076 - 4 Jul 2024
Viewed by 1114
Abstract
MicroRNAs (miRNAs) play important roles in the control of HIV-1 infection. Here, we performed RNA-seq profiling of miRNAs and mRNAs expressed in CD4+ T lymphocytes upon HIV-1 infection. Our results reveal significant alterations in miRNA and mRNA expression profiles in infected relative [...] Read more.
MicroRNAs (miRNAs) play important roles in the control of HIV-1 infection. Here, we performed RNA-seq profiling of miRNAs and mRNAs expressed in CD4+ T lymphocytes upon HIV-1 infection. Our results reveal significant alterations in miRNA and mRNA expression profiles in infected relative to uninfected cells. One of the miRNAs markedly downregulated in infected cells is miRNA-26a. Among the putative targets of miRNA-26a are CD59 receptor transcripts, which are significantly upregulated in infected CD4+ T cells. The addition of miRNA-26a mimics to CD4+ T cells reduces CD59 at both the mRNA and surface protein levels, validating CD59 as a miRNA-26a target. Consistent with the reported inhibitory role of CD59 in complement-mediated lysis (CML), knocking out CD59 in CD4+ T cells renders both HIV-1-infected cells and progeny virions more prone to antibody-dependent CML (ADCML). The addition of miRNA-26a mimics to infected cells leads to enhanced sensitivity of progeny virions to ADCML, a condition linked to a reduction in CD59 packaging into released virions. Lastly, HIV-1-mediated downregulation of miRNA-26a expression is shown to be dependent on integrated HIV-1 expression but does not involve viral accessory proteins. Overall, these results highlight a novel mechanism by which HIV-1 limits ADCML by upregulating CD59 expression via miRNA-26a downmodulation. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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14 pages, 2764 KiB  
Article
The Disassociation of A3G-Related HIV-1 cDNA G-to-A Hypermutation to Viral Infectivity
by Joanie Martin, Xin Chen, Xiangxu Jia, Qiujia Shao and Bindong Liu
Viruses 2024, 16(5), 728; https://doi.org/10.3390/v16050728 - 4 May 2024
Viewed by 1391
Abstract
APOBEC3G (A3G) restricts HIV-1 replication primarily by reducing viral cDNA and inducing G-to-A hypermutations in viral cDNA. HIV-1 encodes virion infectivity factor (Vif) to counteract A3G primarily by excluding A3G viral encapsidation. Even though the Vif-induced exclusion is robust, studies suggest that A3G [...] Read more.
APOBEC3G (A3G) restricts HIV-1 replication primarily by reducing viral cDNA and inducing G-to-A hypermutations in viral cDNA. HIV-1 encodes virion infectivity factor (Vif) to counteract A3G primarily by excluding A3G viral encapsidation. Even though the Vif-induced exclusion is robust, studies suggest that A3G is still detectable in the virion. The impact of encapsidated A3G in the HIV-1 replication is unclear. Using a highly sensitive next-generation sequencing (NGS)-based G-to-A hypermutation detecting assay, we found that wild-type HIV-1 produced from A3G-expressing T-cells induced higher G-to-A hypermutation frequency in viral cDNA than HIV-1 from non-A3G-expressing T-cells. Interestingly, although the virus produced from A3G-expressing T-cells induced higher hypermutation frequency, there was no significant difference in viral infectivity, revealing a disassociation of cDNA G-to-A hypermutation to viral infectivity. We also measured G-to-A hypermutation in the viral RNA genome. Surprisingly, our data showed that hypermutation frequency in the viral RNA genome was significantly lower than in the integrated DNA, suggesting a mechanism exists to preferentially select intact genomic RNA for viral packing. This study revealed a new insight into the mechanism of HIV-1 counteracting A3G antiviral function and might lay a foundation for new antiviral strategies. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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22 pages, 2173 KiB  
Article
Schlafen14 Impairs HIV-1 Expression in a Codon Usage-Dependent Manner
by Carlos Valenzuela, Sergio Saucedo and Manuel Llano
Viruses 2024, 16(4), 502; https://doi.org/10.3390/v16040502 - 25 Mar 2024
Cited by 1 | Viewed by 1762
Abstract
Schlafen (SLFN) is a family of proteins upregulated by type I interferons with a regulatory role in translation. Intriguingly, SLFN14 associates with the ribosome and can degrade rRNA, tRNA, and mRNA in vitro, but a role in translation is still unknown. Ribosomes are [...] Read more.
Schlafen (SLFN) is a family of proteins upregulated by type I interferons with a regulatory role in translation. Intriguingly, SLFN14 associates with the ribosome and can degrade rRNA, tRNA, and mRNA in vitro, but a role in translation is still unknown. Ribosomes are important regulatory hubs during translation elongation of mRNAs rich in rare codons. Therefore, we evaluated the potential role of SLFN14 in the expression of mRNAs enriched in rare codons, using HIV-1 genes as a model. We found that, in a variety of cell types, including primary immune cells, SLFN14 regulates the expression of HIV-1 and non-viral genes based on their codon adaptation index, a measurement of the synonymous codon usage bias; consequently, SLFN14 inhibits the replication of HIV-1. The potent inhibitory effect of SLFN14 on the expression of the rare codon-rich transcript HIV-1 Gag was minimized by codon optimization. Mechanistically, we found that the endoribonuclease activity of SLFN14 is required, and that ribosomal RNA degradation is involved. Therefore, we propose that SLFN14 impairs the expression of HIV-1 transcripts rich in rare codons, in a catalytic-dependent manner. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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12 pages, 1349 KiB  
Article
PTEN Mediates the Silencing of Unintegrated HIV-1 DNA
by An Thanh Phan and Yiping Zhu
Viruses 2024, 16(2), 291; https://doi.org/10.3390/v16020291 - 14 Feb 2024
Cited by 1 | Viewed by 1606
Abstract
The integration of viral DNA into a host genome is an important step in HIV-1 replication. However, due to the high failure rate of integration, the majority of viral DNA exists in an unintegrated state during HIV-1 infection. In contrast to the robust [...] Read more.
The integration of viral DNA into a host genome is an important step in HIV-1 replication. However, due to the high failure rate of integration, the majority of viral DNA exists in an unintegrated state during HIV-1 infection. In contrast to the robust expression from integrated viral DNA, unintegrated HIV-1 DNA is very poorly transcribed in infected cells, but the molecular machinery responsible for the silencing of unintegrated HIV-1 DNA remains poorly characterized. In this study, we sought to characterize new host factors for the inhibition of expression from unintegrated HIV-1 DNA. A genome-wide CRISPR-Cas9 knockout screening revealed the essential role of phosphatase and tensin homolog (PTEN) in the silencing of unintegrated HIV-1 DNA. PTEN’s phosphatase activity negatively regulates the PI3K-Akt pathway to inhibit the transcription from unintegrated HIV-1 DNA. The knockout (KO) of PTEN or inhibition of PTEN’s phosphatase activity by point mutagenesis activates Akt by phosphorylation and enhances the transcription from unintegrated HIV-1 DNA. Inhibition of the PI3K-Akt pathway by Akt inhibitor in PTEN-KO cells restores the silencing of unintegrated HIV-1 DNA. Transcriptional factors (NF-κB, Sp1, and AP-1) are important for the activation of unintegrated HIV-1 DNA in PTEN-KO cells. Finally, the knockout of PTEN increases the levels of active epigenetic marks (H3ac and H3K4me3) and the recruitment of PolII on unintegrated HIV-1 DNA chromatin. Our experiments reveal that PTEN targets transcription factors (NF-κB, Sp1, and AP-1) by negatively regulating the PI3K-Akt pathway to promote the silencing of unintegrated HIV-1 DNA. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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Review

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38 pages, 4518 KiB  
Review
CRL4-DCAF1 Ubiquitin Ligase Dependent Functions of HIV Viral Protein R and Viral Protein X
by Ashley Dobransky, Mary Root, Nicholas Hafner, Matty Marcum and H. John Sharifi
Viruses 2024, 16(8), 1313; https://doi.org/10.3390/v16081313 - 17 Aug 2024
Viewed by 1520
Abstract
The Human Immunodeficiency Virus (HIV) encodes several proteins that contort the host cell environment to promote viral replication and spread. This is often accomplished through the hijacking of cellular ubiquitin ligases. These reprogrammed complexes initiate or enhance the ubiquitination of cellular proteins that [...] Read more.
The Human Immunodeficiency Virus (HIV) encodes several proteins that contort the host cell environment to promote viral replication and spread. This is often accomplished through the hijacking of cellular ubiquitin ligases. These reprogrammed complexes initiate or enhance the ubiquitination of cellular proteins that may otherwise act to restrain viral replication. Ubiquitination of target proteins may alter protein function or initiate proteasome-dependent destruction. HIV Viral Protein R (Vpr) and the related HIV-2 Viral Protein X (Vpx), engage the CRL4-DCAF1 ubiquitin ligase complex to target numerous cellular proteins. In this review we describe the CRL4-DCAF1 ubiquitin ligase complex and its interactions with HIV Vpr and Vpx. We additionally summarize the cellular proteins targeted by this association as well as the observed or hypothesized impact on HIV. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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46 pages, 2259 KiB  
Review
Help or Hinder: Protein Host Factors That Impact HIV-1 Replication
by Michael Rameen Moezpoor and Mario Stevenson
Viruses 2024, 16(8), 1281; https://doi.org/10.3390/v16081281 - 10 Aug 2024
Cited by 1 | Viewed by 1727
Abstract
Interactions between human immunodeficiency virus type 1 (HIV-1) and the host factors or restriction factors of its target cells determine the cell’s susceptibility to, and outcome of, infection. Factors intrinsic to the cell are involved at every step of the HIV-1 replication cycle, [...] Read more.
Interactions between human immunodeficiency virus type 1 (HIV-1) and the host factors or restriction factors of its target cells determine the cell’s susceptibility to, and outcome of, infection. Factors intrinsic to the cell are involved at every step of the HIV-1 replication cycle, contributing to productive infection and replication, or severely attenuating the chances of success. Furthermore, factors unique to certain cell types contribute to the differences in infection between these cell types. Understanding the involvement of these factors in HIV-1 infection is a key requirement for the development of anti-HIV-1 therapies. As the list of factors grows, and the dynamic interactions between these factors and the virus are elucidated, comprehensive and up-to-date summaries that recount the knowledge gathered after decades of research are beneficial to the field, displaying what is known so that researchers can build off the groundwork of others to investigate what is unknown. Herein, we aim to provide a review focusing on protein host factors, both well-known and relatively new, that impact HIV-1 replication in a positive or negative manner at each stage of the replication cycle, highlighting factors unique to the various HIV-1 target cell types where appropriate. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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