Advances in Developing CAR T-Cell Therapy for HIV Cure

Qi, Jin; Ding, Changming; Jiang, Xian; Gao, Yong

doi:10.3389/fimmu.2020.00361

Cited by 49 publications

(40 citation statements)

References 133 publications

(161 reference statements)

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“…Despite the recent success in treating hematological malignancies, CAR-T-based therapies are limited by obstacles such as antigen loss, poor T cell persistence, and immune-related toxicities (Sun et al, 2018 ; Shah and Fry, 2019 ). While HIV-targeting CARs showed limited success in the early clinical trials, primarily due to viral escape variants and susceptibility of CAR-T cells to HIV infection, new CAR-based therapies developed to overcome these hurdles have shown promising results in preclinical studies (reviewed in Kuhlmann et al, 2018 ; Wagner, 2018 ; Yang et al, 2018 ; Kim et al, 2019 ; Qi et al, 2020 ). Their clinical efficacy is being actively investigated ( Table 1 ).…”

Section: Adoptive T-cell Therapy For Hivmentioning

confidence: 99%

Virus-Specific T Cell Therapies for HIV: Lessons Learned From Hematopoietic Stem Cell Transplantation

Lee

Keller

Hanley

et al. 2020

Front. Cell. Infect. Microbiol.

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Human immunodeficiency virus (HIV) has caused millions of deaths and continues to threaten the health of millions of people worldwide. Despite anti-retroviral therapy (ART) substantially alleviating severity and limiting transmission, HIV has not been eradicated and its persistence can lead to other health concerns such as cancer. The only two cases of HIV cure to date are HIV + cancer patients receiving an allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a donor with the CCR5 32 mutation. While this approach has not led to such success in other patients and is not applicable to HIV + individuals without cancer, the encouraging results may point toward a breakthrough in developing a cure strategy for HIV. Adoptive transfer of virus-specific T cells (VSTs) post HSCT has been effectively used to treat and prevent reactivation of latent viral infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), making VSTs an attractive therapeutic to control HIV rebound. Here we will discuss the potential of using adoptive T cell therapies in combination with other treatments such as HSCT and latency reversing agents (LRAs) to achieve a functional cure for HIV.

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Section: Adoptive T-cell Therapy For Hivmentioning

confidence: 99%

Virus-Specific T Cell Therapies for HIV: Lessons Learned From Hematopoietic Stem Cell Transplantation

Lee

Keller

Hanley

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Of note, the first generation of anti-HIV CAR was generated more than 20 years ago, but due to low efficacy and susceptibility of engineered T cells to HIV infection, this approach aborted in the HIV context. 43 However, these efforts laid a foundation for the development of FDA-approved CD19 CARs to treat hematologic malignancies. 44 Given that, T cells responses encounter the same challenges in controlling HIV infection and cancer growth (such as antigen escape and persistence), successful achievements in cancer setting laid the basis for revisiting the concept of using CAR-expressing T cells as part of a strategy to cure HIV.…”

Section: Restoring Ctl Responses Against Hivmentioning

confidence: 99%

“…Among strategies to restore CTL responses in HIV context, redirecting immune cells toward HIV Ags using CARs has recently received much attention (Figure 1). Of note, the first generation of anti‐HIV CAR was generated more than 20 years ago, but due to low efficacy and susceptibility of engineered T cells to HIV infection, this approach aborted in the HIV context 43 . However, these efforts laid a foundation for the development of FDA‐approved CD19 CARs to treat hematologic malignancies 44 .…”

Section: Restoring Ctl Responses Against Hivmentioning

confidence: 99%

“…To effectively eliminate HIV reservoirs, future development of HIV therapy should emphasize on combining therapies. Gene therapy methods such as homozygous 32‐bp deletion in the CCR5 gene and CRISPR‐based gene editing can help in this regard by stopping new infection and removing the latent reservoir directly by excising the provirus 43 . However, it is necessary to pay more attention to the safety and risks of gene editing methods.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

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CAR T cells: Living HIV drugs

Namdari

Rezaei

Teymoori‐Rad

et al. 2020

Reviews in Medical Virology

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Human immunodeficiency virus type 1 (HIV-1), the virus that causes AIDS (acquired immunodeficiency syndrome), is a major global public health issue. Although the advent of combined antiretroviral therapy (ART) has made significant progress in inhibiting HIV replication in patients, HIV-infected cells remain the principal cellular reservoir of HIV, this allows HIV to rebound immediately upon stopping ART, which is considered the major obstacle to curing HIV infection. Chimeric antigen receptor (CAR) cell therapy has provided new opportunities for HIV treatment. Engineering T cells or hematopoietic stem cells (HSCs) to generate CAR T cells is a rapidly growing approach to develop an efficient immune cell to fight HIV. Herein, we review preclinical and clinical data available for the development of CAR T cells. Further, the advantages and disadvantages of clinical application of anti-HIV CAR T cells will be discussed.

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“…While curative measures for HIV-1 are under development, gene editing stands alone in having the ability to remove virus independently from host antiviral adaptive immunity. Although concurrent viral elimination strategies that include broadly neutralizing antibodies (bnAbs) (2), immune modulation (3), and chimeric antigen receptor (CAR)-T cells (4,5) show promise in mice, selection for bnAb resistant strains (6), viral rebound (3,7), and adverse side effects (8) have been reported in monkeys and humans. Treatments notably depend on host FcR-mediated cellular killing or antigen presentation in MHC-I and, as such, rely on host immunity for viral clearance.…”

Section: Introductionmentioning

confidence: 99%

Exonic Disruption Facilitates Antiviral CRISPR-Cas9 Activity for Multistrain HIV-1 Elimination

Herskovitz¹,

Hasan

Patel³

et al. 2021

Preprint

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A barrier to HIV-1 cure rests in the persistence of proviral DNA in infected CD4+ leukocytes. The high mutation rate of HIV-1 gives rise to numerous circulating strains with increased capacity for immune evasion and antiretroviral drug resistance. To facilitate viral elimination while accounting for this diversity, we propose genetic inactivation of proviral DNA with CRISPR-spCas9. We designed a library of “mosaic gRNAs” against a HIV-1 consensus sequence constructed from 4004 clinical strains, targeting the viral transcriptional regulator tat. Testing in 7 HIV-1 transmitted founder strains led, on average, to viral reductions of 82% with tandem TatD and TatE (TatDE) treatment. No off-target cleavages were recorded. Lentiviral transduction of TatDE attenuated latency reversal by 94% in HIV-infected, transcriptionally silent ACH2 T cells. In all, TatDE guide RNAs successfully disrupted 5 separate HIV-1 exons (tat1-2/rev1-2/gp41) providing a pathway for CRISPR-directed HIV-1 cure therapies.Significance StatementOver 38 million individuals worldwide are infected with HIV-1, which necessitates lifelong dependence on antiretroviral therapy (ART) to prevent viral replication that leads to AIDS. Efforts to rid hosts of HIV-1 are limited by the virus’ abilities to integrate proviral DNA in nuclei, mutate their genomes, and lay dormant for decades during ART treatment. We developed mosaic guide RNAs, TatD and TatE, for CRISPR-Cas9 that recognize the majority of known HIV-1 strains and inactivate 94% of proviral DNA in latently infected cells. Tandem TatDE-CRISPR inactivation of 5 viral exons (tat1-2, rev1-2, and gp41), which blocked HIV-1 replication for 28 days in CD4+ T cells without unwanted editing to the host genome, may serve as a viable strategy for HIV cure.

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Advances in Developing CAR T-Cell Therapy for HIV Cure

Cited by 49 publications

References 133 publications

Virus-Specific T Cell Therapies for HIV: Lessons Learned From Hematopoietic Stem Cell Transplantation

Virus-Specific T Cell Therapies for HIV: Lessons Learned From Hematopoietic Stem Cell Transplantation

CAR T cells: Living HIV drugs

Exonic Disruption Facilitates Antiviral CRISPR-Cas9 Activity for Multistrain HIV-1 Elimination

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