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Viruses
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CAR-T Cell Therapy for HIV Cure 2023
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CAR-T Cell Therapy for HIV Cure 2023

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 22980

Special Issue Editor

Dr. Maria Salgado

E-Mail Website
Guest Editor
AIDS Research Institute, IrsiCaixa, 08916 Badalona, Barcelona, Spain
Interests: HIV; reservoirs; eradication; control

Special Issue Information

Dear Colleagues,

The latent reservoir of HIV-1 is considered the major barrier to achieving the eradication of the disease, although some evidence indicates that curing HIV-1 is a feasible goal. Different immunotherapy-based strategies have been proven to be able to kill HIV-infected cells. Therapeutic vaccination has obtained interesting results with regard to increasing HIV-1 specific immune responses, with a limited reduction in the HIV reservoirs. Additionally, inhibitory receptors, also called immune checkpoint inhibitors (ICIs), can exert their influence on T-cell responses, but with only marginal results so far. To date, chimeric antigen receptor (CAR) T cell therapy appears to be the most suitable strategy for enhancing the T cell responses to levels that can mimic the alloreactivity of the allo-HSCT.

Previous investigations have focused on second-generation CAR-T cells carrying the CD4-binding site as extracellular domain, since this part of the CD4 molecule has a high affinity for the gp120 HIV-1 proteins. The rationale is to target cells that express this viral protein on their surface. Although some optimistic results have been obtained, this approach has the disadvantage that the CD4 molecule on the surface of the CD8+ T cells makes them susceptible to HIV-1 infection. For that reason, the new generation of CARs includes broadly neutralizing antibodies (bNAbs) as an additional domain to target HIV-1. Since this is field is currenty under intense development, the goal of this Special Issue of Viruses is to explore new advances in CAR-T cell therapies as immunotherapies to cure HIV.

Primary research and review articles pertaining to CAR-T cell development as an immunotherapy to study and eliminate HIV latency are invited. Topics of interest include, but are not limited to, the following:

  • New tools for targeting cells latently infected with HIV using gene/cellular therapy;
  • New developments in CAR-T cells to improve technical issues;
  • T cell populations more suitable for developing CAR-T cells in the HIV context;
  • In vitro studies using CAR-T cells to eliminate the HIV virus;
  • Clinical trials to assay the use of CAR-T cells in HIV infection;
  • The use of CAR-T cells in other viral infections.

Dr. Maria Salgado
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.

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

  • CAR-T cells
  • HIV cure
  • immunotherapy
  • eradication

Published Papers (5 papers)

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Editorial

Jump to: Research, Review

2 pages, 156 KiB  
Editorial
CAR-T Cell Therapy for HIV Cure
by Maria Salgado
Viruses 2023, 15(9), 1793; https://doi.org/10.3390/v15091793 - 23 Aug 2023
Viewed by 1000
Abstract
The HIV-1 latent reservoir is considered the major barrier to achieve the eradication, although some evidences indicate that curing HIV-1 is a feasible goal [...] Full article
(This article belongs to the Special Issue CAR-T Cell Therapy for HIV Cure 2023)

Research

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26 pages, 1606 KiB  
Article
Cytotoxic T Lymphocytes Control Growth of B16 Tumor Cells in Collagen–Fibrin Gels by Cytolytic and Non-Lytic Mechanisms
by Barun Majumder, Sadna Budhu and Vitaly V. Ganusov
Viruses 2023, 15(7), 1454; https://doi.org/10.3390/v15071454 - 27 Jun 2023
Cited by 3 | Viewed by 1189
Abstract
Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving the transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While the molecular mechanisms of how CTLs kill their [...] Read more.
Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving the transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While the molecular mechanisms of how CTLs kill their targets are relatively well understood, we still lack a solid quantitative understanding of the kinetics and efficiency by which CTLs kill their targets in vivo. Collagen–fibrin-gel-based assays provide a tissue-like environment for the migration of CTLs, making them an attractive system to study T cell cytotoxicity in in vivo-like conditions. Budhu.et al. systematically varied the number of peptide (SIINFEKL)-pulsed B16 melanoma cells and SIINFEKL-specific CTLs (OT-1) and measured the remaining targets at different times after target and CTL co-inoculation into collagen–fibrin gels. The authors proposed that their data were consistent with a simple model in which tumors grow exponentially and are killed by CTLs at a per capita rate proportional to the CTL density in the gel. By fitting several alternative mathematical models to these data, we found that this simple “exponential-growth-mass-action-killing” model did not precisely describe the data. However, determining the best-fit model proved difficult because the best-performing model was dependent on the specific dataset chosen for the analysis. When considering all data that include biologically realistic CTL concentrations (E≤107cell/mL), the model in which tumors grow exponentially and CTLs suppress tumor’s growth non-lytically and kill tumors according to the mass–action law (SiGMA model) fit the data with the best quality. A novel power analysis suggested that longer experiments (∼3–4 days) with four measurements of B16 tumor cell concentrations for a range of CTL concentrations would best allow discriminating between alternative models. Taken together, our results suggested that the interactions between tumors and CTLs in collagen–fibrin gels are more complex than a simple exponential-growth-mass–action killing model and provide support for the hypothesis that CTLs’ impact on tumors may go beyond direct cytotoxicity. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy for HIV Cure 2023)
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13 pages, 1378 KiB  
Article
Development of HIV-Resistant CAR T Cells by CRISPR/Cas-Mediated CAR Integration into the CCR5 Locus
by Frederik Holm Rothemejer, Nanna Pi Lauritsen, Anna Karina Juhl, Mariane Høgsbjerg Schleimann, Saskia König, Ole Schmeltz Søgaard, Rasmus O. Bak and Martin Tolstrup
Viruses 2023, 15(1), 202; https://doi.org/10.3390/v15010202 - 10 Jan 2023
Cited by 6 | Viewed by 4167
Abstract
Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been highly successful in treating B cell malignancies and holds great potential as a curative strategy for HIV infection. Recent advances in the use of anti-HIV broadly neutralizing antibodies (bNAbs) have provided vital [...] Read more.
Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been highly successful in treating B cell malignancies and holds great potential as a curative strategy for HIV infection. Recent advances in the use of anti-HIV broadly neutralizing antibodies (bNAbs) have provided vital information for optimal antigen targeting of CAR T cells. However, CD4+ CAR T cells are susceptible to HIV infection, limiting their therapeutic potential. In the current study, we engineered HIV-resistant CAR T cells using CRISPR/Cas9-mediated integration of a CAR cassette into the CCR5 locus. We used a single chain variable fragment (scFv) of the clinically potent bNAb 10-1074 as the antigen-targeting domain in our anti-HIV CAR T cells. Our anti-HIV CAR T cells showed specific lysis of HIV-infected cells in vitro. In a PBMC humanized mouse model of HIV infection, the anti-HIV CAR T cells expanded and transiently limited HIV infection. In conclusion, this study provides proof-of-concept for developing HIV-resistant CAR T cells using CRISPR/Cas9 targeted integration. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy for HIV Cure 2023)
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Review

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14 pages, 994 KiB  
Review
Challenges in HIV-1 Latent Reservoir and Target Cell Quantification in CAR-T Cell and Other Lentiviral Gene Modifying HIV Cure Strategies
by Amanda M. Buck, Tyler-Marie Deveau, Timothy J. Henrich and Amelia N. Deitchman
Viruses 2023, 15(5), 1126; https://doi.org/10.3390/v15051126 - 9 May 2023
Cited by 3 | Viewed by 2664
Abstract
Gene-modification therapies are at the forefront of HIV-1 cure strategies. Chimeric antigen receptor (CAR)-T cells pose a potential approach to target infected cells during antiretroviral therapy or following analytical treatment interruption (ATI). However, there are technical challenges in the quantification of HIV-1-infected and [...] Read more.
Gene-modification therapies are at the forefront of HIV-1 cure strategies. Chimeric antigen receptor (CAR)-T cells pose a potential approach to target infected cells during antiretroviral therapy or following analytical treatment interruption (ATI). However, there are technical challenges in the quantification of HIV-1-infected and CAR-T cells in the setting of lentiviral CAR gene delivery and also in the identification of cells expressing target antigens. First, there is a lack of validated techniques to identify and characterize cells expressing the hypervariable HIV gp120 in both ART-suppressed and viremic individuals. Second, close sequence homology between lentiviral-based CAR-T gene modification vectors and conserved regions of HIV-1 creates quantification challenges of HIV-1 and lentiviral vector levels. Consideration needs to be taken into standardizing HIV-1 DNA/RNA assays in the setting of CAR-T cell and other lentiviral vector-based therapies to avoid these confounding interactions. Lastly, with the introduction of HIV-1 resistance genes in CAR-T cells, there is a need for assays with single-cell resolution to determine the competence of the gene inserts to prevent CAR-T cells from becoming infected in vivo. As novel therapies continue to arise in the HIV-1 cure field, resolving these challenges in CAR-T-cell therapy will be crucial. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy for HIV Cure 2023)
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13 pages, 2294 KiB  
Review
Opportunities for CAR-T Cell Immunotherapy in HIV Cure
by Gerard Campos-Gonzalez, Javier Martinez-Picado, Talia Velasco-Hernandez and Maria Salgado
Viruses 2023, 15(3), 789; https://doi.org/10.3390/v15030789 - 19 Mar 2023
Cited by 5 | Viewed by 5102
Abstract
Chimeric antigen receptor (CAR) technology is having a huge impact in the blood malignancy field and is becoming a well-established therapy for many types of leukaemia. In recent decades, efforts have been made to demonstrate that CAR-T cells have potential as a therapy [...] Read more.
Chimeric antigen receptor (CAR) technology is having a huge impact in the blood malignancy field and is becoming a well-established therapy for many types of leukaemia. In recent decades, efforts have been made to demonstrate that CAR-T cells have potential as a therapy to achieve a sterilizing cure for human immunodeficiency virus (HIV) infection. However, translation of this technology to the HIV scenario has not been easy, as many challenges have appeared along the way that hinder the consolidation of CAR-T cells as a putative therapy. Here, we review the origin and development of CAR-T cells, describe the advantages of CAR-T cell therapy in comparison with other therapies, and describe the major obstacles currently faced regarding application of this technology in the HIV field, specifically, viral escape, CAR-T cell infectivity, and accessibility to hidden reservoirs. Nonetheless, promising results in successfully tackling some of these issues that have been obtained in clinical trials suggest a bright future for CAR-T cells as a consolidated therapy. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy for HIV Cure 2023)
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