Development of HIV-Resistant CAR T Cells by CRISPR/Cas-Mediated CAR Integration into the CCR5 Locus

Rothemejer, Frederik Holm; Lauritsen, Nanna Pi; Juhl, Anna Karina; Schleimann, Mariane H.; König, Saskia; Søgaard, Ole Schmeltz; Bak, Rasmus O.; Tolstrup, Martin

doi:10.3390/v15010202

Cited by 6 publications

(2 citation statements)

References 46 publications

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“…Other promising approaches will likely use bNAbs in combination with immune modulators to enhance antiviral immunity to selectively intercept and eliminate cells supporting viral replication upon ART cessation. Other compelling combination approaches may be feasible but would require further study and may be complicated by safety concerns: ie, CCR5 WT/WT alloHSCT with a CCR5 inhibitor (eg, Maraviroc or Leronlimab) [ 141 ] or CCR5 Δ32/Δ32 CD4 + chimeric antigen receptor (CAR) T cells directed against multiple bNAb targets [ 161 ].…”

Section: Progress Towards a Curementioning

confidence: 99%

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Harper,

Betts,

Lichterfeld

et al. 2024

PAI

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Once a death sentence, HIV is now considered a manageable chronic disease due to the development of antiretroviral therapy (ART) regimens with minimal toxicity and a high barrier for genetic resistance. While highly effective in arresting AIDS progression and rendering the virus untransmissible in people living with HIV (PLWH) with undetectable viremia (U=U) [1, 2]), ART alone is incapable of eradicating the “reservoir” of resting, latently infected CD4+ T cells from which virus recrudesces upon treatment cessation. As of 2022 estimates, there are 39 million PLWH, of whom 86% are aware of their status and 76% are receiving ART [3]. As of 2017, ART-treated PLWH exhibit near normalized life expectancies without adjustment for socioeconomic differences [4]. Furthermore, there is a global deceleration in the rate of new infections [3] driven by expanded access to pre-exposure prophylaxis (PrEP), HIV testing in vulnerable populations, and by ART treatment [5]. Therefore, despite outstanding issues pertaining to cost and access in developing countries, there is strong enthusiasm that aggressive testing, treatment, and effective viral suppression may be able to halt the ongoing HIV epidemic (ie, UNAIDS’ 95-95-95 targets) [6–8]; especially as evidenced by recent encouraging observations in Sydney [9]. Despite these promising efforts to limit further viral transmission, for PLWH, a “cure” remains elusive; whether it be to completely eradicate the viral reservoir (ie, cure) or to induce long-term viral remission in the absence of ART (ie, control; Figure 1). In a previous salon hosted by Pathogens and Immunity in 2016 [10], some researchers were optimistic that a cure was a feasible, scalable goal, albeit with no clear consensus on the best route. So, how are these cure strategies panning out? In this commentary, 8 years later, we will provide a brief overview on recent advances and failures towards identifying determinants of viral persistence and developing a scalable cure for HIV. Based on these observations, and as in the earlier salon, we have asked several prominent HIV cure researchers for their perspectives.

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Section: Progress Towards a Curementioning

confidence: 99%

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Harper,

Betts,

Lichterfeld

et al. 2024

PAI

View full text Add to dashboard Cite

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“…Prevention of CAR-T cell infection is also key to maintaining CAR-T cell persistence and anti-HIV activity in vivo. One approach to avoiding infection of CAR-T cells is by knocking out the CCR5 gene via ex vivo genetic editing using zinc-finger nucleases (ZFNs), transcription activator-like nucleases (TALENs) or CRISPR-Cas9 technology [ 34 , 51 ]. The CCR5 gene encodes for the main coreceptor for HIV entry and infection, so knockout of this gene in CAR-T cells may help generate permanent resistance to HIV infection.…”

Section: Difficulties and New Strategies To Achieve Hiv Cure With Car...mentioning

confidence: 99%

Opportunities for CAR-T Cell Immunotherapy in HIV Cure

Campos-Gonzalez

Martínez-Picado

Velasco-Hernández

et al. 2023

Viruses

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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.

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Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission

Su,

Mueller,

Goldstein

2024

Current Opinion in HIV and AIDS

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Purpose of review Successful sustained remission of HIV infection has been achieved after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation for treatment of leukemia in a small cohort of people living with HIV (PLWH). This breakthrough demonstrated that the goal of curing HIV was achievable. However, the high morbidity and mortality associated with bone marrow transplantation limits the routine application of this approach and provides a strong rationale for pursuing alternative strategies for sustained long-term antiretroviral therapy (ART)-free HIV remission. Notably, long-term immune-mediated control of HIV replication observed in elite controllers and posttreatment controllers suggests that potent HIV-specific immune responses could provide sustained ART-free remission in PLWH. The capacity of chimeric antigen receptor (CAR)-T cells engineered to target malignant cells to induce remission and cure in cancer patients made this an attractive approach to provide PLWH with a potent HIV-specific immune response. Here, we review the recent advances in the design and application of anti-HIV CAR-T-cell therapy to provide a functional HIV cure. Recent findings HIV reservoirs are established days after infection and persist through clonal expansion of infected cells. The continuous interaction between latently infected cells and the immune system shapes the landscape of HIV latency and likely contributes to ART-free viral control in elite controllers. CAR-T cells can exhibit superior antiviral activity as compared with native HIV-specific T cells, particularly because they can be engineered to have multiple HIV specificities, resistance to HIV infection, dual costimulatory signaling, immune checkpoint inhibitors, stem cell derivation, CMV TCR coexpression, and tissue homing ligands. These modifications can significantly improve the capacities of anti-HIV CAR-T cells to prevent viral escape, resist HIV infection, and enhance cytotoxicity, persistence, and tissue penetration. Collectively, these novel modifications of anti-HIV CAR-T cell design have increased their capacity to control HIV infection. Summary Anti-HIV CAR-T cells can be engineered to provide potent and sustained in-vitro and in-vivo antiviral function. The combination of anti-HIV CAR-T cells with other immunotherapeutics may contribute to long-term HIV remission in PLWH.

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Development of HIV-Resistant CAR T Cells by CRISPR/Cas-Mediated CAR Integration into the CCR5 Locus

Cited by 6 publications

References 46 publications

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Opportunities for CAR-T Cell Immunotherapy in HIV Cure

Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission

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