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Viruses
Special Issues
HIV Infection and Spread between T Cells
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HIV Infection and Spread between T Cells

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

Deadline for manuscript submissions: closed (22 December 2021) | Viewed by 22277

Special Issue Editors

Dr. Clare Jolly

E-Mail Website
Guest Editor
Division of Infection and Immunity, University College London, Gower Street, London, UK
Interests: HIV-1; CD4+ T cell; cell-cell spread; innate immunity; pathogenesis; reservoirs
Dr. Philip Tedbury

E-Mail
Guest Editor
Department of Pediatrics, Emory University School of Medicine, Atlanta

Special Issue Information

Dear Colleagues,

HIV-1 predominantly replicates in CD4+ T cells and it is the death and dysfunction of these cells that ultimately drives progression to AIDS. HIV-1 infects CD4+ T cells either by cell-free infection or by cell-to-cell spread. The latter is the dominant mode of HIV-1 spread that drives high-efficient viral replication and evasion of antiviral defences. Importantly, CD4+ T cells also play a key role in HIV-1 persistence by acting as a cellular reservoir of latent virus, presenting a formidable barrier to cure.  Therefore, it is clear that the success of future efforts to eradicate HIV-1 and restore the immune system to normal function will require a greater insight into the biology of HIV-1 infection and spread in CD4+ T cells. Ultimately, we envisage that advancing our understanding of these processes, and the consequences for HIV-1 pathogenesis and persistence, will reveal new opportunities to manipulate them therapeutically.

Historically, studying HIV-1 infection in T cells, particularly primary cells, has proven technically challenging; however, recently we have seen significant new advances in understanding how HIV-1 manipulates CD4+ T cells to regulate successful infection and the consequences thereof for the virus and the host. The aim of this Special Issue of Viruses is to provide an up-to-date view of HIV-1 infection and spread between CD4+ T cells, including new insights into the molecular and cellular biology of HIV-1 - T cell interactions, viral pathogenesis, immune evasion, and HIV-1 reservoirs/latency. We encourage the submission of all types of manuscripts (e.g., reviews, research articles, and short communications) pertaining to HIV-1 replication in T cells from in vitro and in vivo studies, including, but not limited to, the following topics:

  1. Cell biology of HIV-1 infection and replication in T cells
  2. Virus-host interactions that promote and/or restrict HIV-1 infection of T cells
  3. Innate immune sensing and evasion during HIV-1 infection of T cells
  4. New insights into HIV-1 cell-to-cell spread
  5. The establishment, maintenance and clearance of T cell reservoirs and latently infected cells.
  6. New experimental advances for studying HIV-1 infection T cells

Dr. Clare Jolly
Dr. Philip Tedbury
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

  • HIV-1
  • CD4+ T cell
  • cell-cell spread
  • innate immunity
  • pathogenesis
  • reservoirs

Published Papers (7 papers)

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Research

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21 pages, 4294 KiB  
Article
A Conserved Tryptophan in the Envelope Cytoplasmic Tail Regulates HIV-1 Assembly and Spread
by Xenia Snetkov, Tafhima Haider, Dejan Mesner, Nicholas Groves, Schuyler B. van Engelenburg and Clare Jolly
Viruses 2022, 14(1), 129; https://doi.org/10.3390/v14010129 - 12 Jan 2022
Cited by 4 | Viewed by 2109
Abstract
The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains within it remain largely [...] Read more.
The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains within it remain largely uncharacterised. Here, we identified a highly conserved tryptophan motif at position 757 (W757) in the LLP-2 alpha helix of the EnvCT as a key determinant for HIV-1 replication and spread between T cells. Alanine substitution at this position potently inhibited HIV-1 cell–cell spread (the dominant mode of HIV-1 dissemination) by preventing recruitment of Env and Gag to sites of cell–cell contact, inhibiting virological synapse (VS) formation and spreading infection. Single-molecule tracking and super-resolution imaging showed that mutation of W757 dysregulates Env diffusion in the plasma membrane and increases Env mobility. Further analysis of Env function revealed that W757 is also required for Env fusion and infectivity, which together with reduced VS formation, result in a potent defect in viral spread. Notably, W757 lies within a region of the EnvCT recently shown to act as a supporting baseplate for Env. Our data support a model in which W757 plays a key role in regulating Env biology, modulating its temporal and spatial recruitment to virus assembly sites and regulating the inherent fusogenicity of the Env ectodomain, thereby supporting efficient HIV-1 replication and spread. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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22 pages, 7988 KiB  
Article
A Replication-Competent HIV Clone Carrying GFP-Env Reveals Rapid Env Recycling at the HIV-1 T Cell Virological Synapse
by Lili Wang, Alice Sandmeyer, Wolfgang Hübner, Hongru Li, Thomas Huser and Benjamin K. Chen
Viruses 2022, 14(1), 38; https://0-doi-org.brum.beds.ac.uk/10.3390/v14010038 - 25 Dec 2021
Cited by 6 | Viewed by 2793
Abstract
HIV-1 infection is enhanced by cell–cell adhesions between infected and uninfected T cells called virological synapses (VS). VS are initiated by the interactions of cell-surface HIV-1 envelope glycoprotein (Env) and CD4 on target cells and act as sites of viral assembly and viral [...] Read more.
HIV-1 infection is enhanced by cell–cell adhesions between infected and uninfected T cells called virological synapses (VS). VS are initiated by the interactions of cell-surface HIV-1 envelope glycoprotein (Env) and CD4 on target cells and act as sites of viral assembly and viral transfer between cells. To study the process that recruits and retains HIV-1 Env at the VS, a replication-competent HIV-1 clone carrying an Env-sfGFP fusion protein was designed to enable live tracking of Env within infected cells. Combined use of surface pulse-labeling of Env and fluorescence recovery after photobleaching (FRAP) studies, enabled the visualization of the targeted accumulation and sustained recycling of Env between endocytic compartments (EC) and the VS. We observed dynamic exchange of Env at the VS, while the viral structural protein, Gag, was largely immobile at the VS. The disparate exchange rates of Gag and Env at the synapse support that the trafficking and/or retention of a majority of Env towards the VS is not maintained by entrapment by a Gag lattice or immobilization by binding to CD4 on the target cell. A FRAP study of an Env endocytosis mutant showed that recycling is not required for accumulation at the VS, but is required for the rapid exchange of Env at the VS. We conclude that the mechanism of Env accumulation at the VS and incorporation into nascent particles involves continuous internalization and targeted secretion rather than irreversible interactions with the budding virus, but that this recycling is largely dispensable for VS formation and viral transfer across the VS. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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20 pages, 4379 KiB  
Article
Endocytic Motif on a Biotin-Tagged HIV-1 Env Modulates the Co-Transfer of Env and Gag during Cell-to-Cell Transmission
by María Inés Barría, Raymond A. Alvarez, Kenneth Law, Deanna L. Wolfson, Thomas Huser and Benjamin K. Chen
Viruses 2021, 13(9), 1729; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091729 - 31 Aug 2021
Cited by 2 | Viewed by 2101
Abstract
During HIV-1 transmission through T cell virological synapses, the recruitment of the envelope (Env) glycoprotein to the site of cell–cell contact is important for adhesion and for packaging onto nascent virus particles which assemble at the site. Live imaging studies in CD4 T [...] Read more.
During HIV-1 transmission through T cell virological synapses, the recruitment of the envelope (Env) glycoprotein to the site of cell–cell contact is important for adhesion and for packaging onto nascent virus particles which assemble at the site. Live imaging studies in CD4 T cells have captured the rapid recruitment of the viral structural protein Gag to VSs. We explored the role of endocytic trafficking of Env initiated by a membrane proximal tyrosine motif during HIV transfer into target cells and examined the factors that allow Gag and Env to be transferred together across the synapse. To facilitate tracking of Env in live cells, we adapted an Env tagging method and introduced a biotin acceptor peptide (BAP) into the V4 loop of Env gp120, enabling sensitive fluorescent tracking of V4-biotinylated Env. The BAP-tagged and biotinylated HIVs were replication-competent in cell-free and cell-to-cell infection assays. Live cell fluorescent imaging experiments showed rapid internalized cell surface Env on infected cells. Cell–cell transfer experiments conducted with the Env endocytosis mutant (Y712A) showed increased transfer of Env. Paradoxically, this increase in Env transfer was associated with significantly reduced Gag transfer into target cells, when compared to viral transfer associated with WT Env. This Y712A Env mutant also exhibited an altered Gag/biotin Env fluorescence ratio during transfer that correlated with decreased productive cell-to-cell infection. These results may suggest that the internalization of Env into recycling pools plays an important role in the coordinated transfer of Gag and Env across the VS, which optimizes productive infection in target cells. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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Review

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15 pages, 726 KiB  
Review
HIV Infection and Spread between Th17 Cells
by Janet P. Zayas and João I. Mamede
Viruses 2022, 14(2), 404; https://0-doi-org.brum.beds.ac.uk/10.3390/v14020404 - 16 Feb 2022
Cited by 8 | Viewed by 3182
Abstract
HIV mainly targets CD4+ T cells, from which Th17 cells represent a major cell type, permissive, and are capable of supporting intracellular replication at mucosal sites. Th17 cells possess well-described dual roles, while being central to maintaining gut integrity, these [...] Read more.
HIV mainly targets CD4+ T cells, from which Th17 cells represent a major cell type, permissive, and are capable of supporting intracellular replication at mucosal sites. Th17 cells possess well-described dual roles, while being central to maintaining gut integrity, these may induce inflammation and contribute to autoimmune disorders; however, Th17 cells’ antiviral function in HIV infection is not completely understood. Th17 cells are star players to HIV-1 pathogenesis and a potential target to prevent or decrease HIV transmission. HIV-1 can be spread among permissive cells via direct cell-to-cell and/or cell-free infection. The debate on which mode of transmission is more efficient is still ongoing without a concrete conclusion yet. Most assessments of virus transmission analyzing either cell-to-cell or cell-free modes use in vitro systems; however, the actual interactions and conditions in vivo are not fully understood. The fact that infected breast milk, semen, and vaginal secretions contain a mix of both cell-free viral particles and infected cells presents an argument for the probability of HIV taking advantage of both modes of transmission to spread. Here, we review important insights and recent findings about the role of Th17 cells during HIV pathogenesis in mucosal surfaces, and the mechanisms of HIV-1 infection spread among T cells in tissues. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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12 pages, 1044 KiB  
Review
Roles of Virion-Incorporated CD162 (PSGL-1), CD43, and CD44 in HIV-1 Infection of T Cells
by Tomoyuki Murakami and Akira Ono
Viruses 2021, 13(10), 1935; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101935 - 26 Sep 2021
Cited by 3 | Viewed by 2687
Abstract
Nascent HIV-1 particles incorporate the viral envelope glycoprotein and multiple host transmembrane proteins during assembly at the plasma membrane. At least some of these host transmembrane proteins on the surface of virions are reported as pro-viral factors that enhance virus attachment to target [...] Read more.
Nascent HIV-1 particles incorporate the viral envelope glycoprotein and multiple host transmembrane proteins during assembly at the plasma membrane. At least some of these host transmembrane proteins on the surface of virions are reported as pro-viral factors that enhance virus attachment to target cells or facilitate trans-infection of CD4+ T cells via interactions with non-T cells. In addition to the pro-viral factors, anti-viral transmembrane proteins are incorporated into progeny virions. These virion-incorporated transmembrane proteins inhibit HIV-1 entry at the point of attachment and fusion. In infected polarized CD4+ T cells, HIV-1 Gag localizes to a rear-end protrusion known as the uropod. Regardless of cell polarization, Gag colocalizes with and promotes the virion incorporation of a subset of uropod-directed host transmembrane proteins, including CD162, CD43, and CD44. Until recently, the functions of these virion-incorporated proteins had not been clear. Here, we review the recent findings about the roles played by virion-incorporated CD162, CD43, and CD44 in HIV-1 spread to CD4+ T cells. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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19 pages, 5219 KiB  
Review
The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 Persistence
by Yang-Hui Jimmy Yeh, Kerui Yang, Anya Razmi and Ya-Chi Ho
Viruses 2021, 13(9), 1858; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091858 - 17 Sep 2021
Cited by 15 | Viewed by 3973
Abstract
More than 50% of the HIV-1 latent reservoir is maintained by clonal expansion. The clonally expanded HIV-1-infected cells can contribute to persistent nonsuppressible low-level viremia and viral rebound. HIV-1 integration site and proviral genome landscape profiling reveals the clonal expansion dynamics of HIV-1-infected [...] Read more.
More than 50% of the HIV-1 latent reservoir is maintained by clonal expansion. The clonally expanded HIV-1-infected cells can contribute to persistent nonsuppressible low-level viremia and viral rebound. HIV-1 integration site and proviral genome landscape profiling reveals the clonal expansion dynamics of HIV-1-infected cells. In individuals under long-term suppressive antiretroviral therapy (ART), HIV-1 integration sites are enriched in specific locations in certain cancer-related genes in the same orientation as the host transcription unit. Single-cell transcriptome analysis revealed that HIV-1 drives aberrant cancer-related gene expression through HIV-1-to-host RNA splicing. Furthermore, the HIV-1 promoter dominates over the host gene promoter and drives high levels of cancer-related gene expression. When HIV-1 integrates into cancer-related genes and causes gain of function of oncogenes or loss of function of tumor suppressor genes, HIV-1 insertional mutagenesis drives the proliferation of HIV-1-infected cells and may cause cancer in rare cases. HIV-1-driven aberrant cancer-related gene expression at the integration site can be suppressed by CRISPR-mediated inhibition of the HIV-1 promoter or by HIV-1 suppressing agents. Given that ART does not suppress HIV-1 promoter activity, therapeutic agents that suppress HIV-1 transcription and halt the clonal expansion of HIV-1-infected cells should be explored to block the clonal expansion of the HIV-1 latent reservoir. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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17 pages, 759 KiB  
Review
The Unknown Unknowns: Recovering Gamma-Delta T Cells for Control of Human Immunodeficiency Virus (HIV)
by Shivkumar Biradar, Michael T. Lotze and Robbie B. Mailliard
Viruses 2020, 12(12), 1455; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121455 - 17 Dec 2020
Cited by 3 | Viewed by 4398
Abstract
Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 [...] Read more.
Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential. Full article
(This article belongs to the Special Issue HIV Infection and Spread between T Cells)
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