Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation

Cardozo-Ojeda, E Fabian; Duke, Elizabeth R; Peterson, Christopher W.; Reeves, Daniel B.; Mayer, Bryan T.; Kiem, Hans–Peter; Schiffer, Joshua T

doi:10.7554/elife.57646

Cited by 11 publications

(7 citation statements)

References 89 publications

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“…Mathematical models are well suited to study the phenomenon of drug resistance and viral rebound (Ribeiro and Bonhoeffer, 2000; Rong et al, 2010; Zhang et al, 2014; Ke et al, 2018; Perelson and Ke, 2021; Cardozo-Ojeda et al, 2021b; Perelson et al, 2023). Thus, to better understand the crucial factors leading to the emergence of resistant virus associated with high viral load rebound, we built models that include feasible mechanisms that can increase the availability of potential virus producing cells: the natural proliferation of target cells such as epithelial cells expressing the ACE-2 receptor (Fang et al, 2020) and the loss of protection from infection by the innate immune response (Voigt et al, 2016) and fit these models to data from individuals who experienced viral rebound due to the emergence of resistant virus during BAM treatment.…”

Section: Introductionmentioning

confidence: 99%

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

Phan,

Zitzmann,

Chew

et al. 2023

Preprint

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The COVID-19 pandemic has led to over 760 million cases and 6.9 million deaths worldwide. To mitigate the loss of lives, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with susceptible variants. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response anti-viral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

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Section: Introductionmentioning

confidence: 99%

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

Phan,

Zitzmann,

Chew

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In this regard, increasing CD4 + and CD8 + CE-XTC frequencies in both blood and tissues, protecting the CD4 + NHP CE-XTC against infection, and/or enhancing their virus-specific function could tip the balance towards stable control of viremia in the absence of suppressive ART. We have investigated numerous approaches to protect CD4 + T cells against infection, including expression of peptide-based fusion inhibitors ( 54 ) and gene-editing of the HIV coreceptor CCR5 ( 47 , 54 , 55 ). We have also developed strategies to enhance virus-specific immunity via short- or long-term expression of chimeric antigen receptors ( 48 , 56 , 57 ) and broadly neutralizing antibodies ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Efficient ex vivo expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates

et al. 2023

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HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. This is due in part to these cells’ recognition of immunodominant but variable regions of the virus, which facilitates viral escape via mutations that do not incur viral fitness costs. HIV-specific T cells targeting conserved viral elements are associated with viral control but are relatively infrequent in people living with HIV (PLWH). The goal of this study was to increase the number of these cells via an ex vivo cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell (HXTC) process. Using a nonhuman primate (NHP) model of HIV infection, we sought to determine i) the feasibility of manufacturing ex vivo-expanded virus-specific T cells targeting viral conserved elements (CE, CE-XTCs), ii) the in vivo safety of these products, and iii) the impact of simian/human immunodeficiency virus (SHIV) challenge on their expansion, activity, and function. NHP CE-XTCs expanded up to 10-fold following co-culture with the combination of primary dendritic cells (DCs), PHA blasts pulsed with CE peptides, irradiated GM-K562 feeder cells, and autologous T cells from CE-vaccinated NHP. The resulting CE-XTC products contained high frequencies of CE-specific, polyfunctional T cells. However, consistent with prior studies with human HXTC and these cells’ predominant CD8+ effector phenotype, we did not observe significant differences in CE-XTC persistence or SHIV acquisition in two CE-XTC-infused NHP compared to two control NHP. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses.

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“…The complete elimination of CCR5 expression in the lineages by gene editing the CD34 + CD90 + HSCs will be a safer and long-lasting approach as this provides no choice for gp-120 HIV variants to infect hematopoietic cells. CCR5 Δ32 heterozygous genotype showed delayed but not completely prevented HIV-1 infection underlines the need for biallelic CCR5 editing ( 47 ).The mathematical modeling predicted that the autologous HSPC graft with an editing efficiency of 76% or greater is required to control the viral rebound ( 48 ). Thus, high frequency bi-allelic CCR5 knockout in HSCs is crucial for clinical success.…”

Section: Discussionmentioning

confidence: 99%

The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

et al. 2022

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Transplantation of allogenic hematopoietic stem and progenitor cells (HSPCs) with C-C chemokine receptor type 5 (CCR5) Δ32 genotype generates HIV-1 resistant immune cells. CCR5 gene edited autologous HSPCs can be a potential alternative to hematopoietic stem cell transplantation (HSCT) from HLA-matched CCR5 null donor. However, the clinical application of gene edited autologous HSPCs is critically limited by the quality of the graft, as HIV also infects the HSPCs. In this study, by using mobilized HSPCs from healthy donors, we show that the CD34+CD90+ hematopoietic stem cells (HSCs) express 7-fold lower CD4/CCR5 HIV receptors, higher levels of SAMHD1 anti-viral restriction factor, and possess lower susceptibility to HIV infection than the CD34+CD90- hematopoietic progenitor cells. Further, the treatment with small molecule cocktail of Resveratrol, UM729 and SR1(RUS) improved the in vivo engraftment potential of CD34+CD90+ HSCs. To demonstrate that CD34+CD90+ HSC population as an ideal graft for HIV gene therapy, we sort purified CD34+CD90+ HSCs, treated with RUS and then gene edited the CCR5 with single sgRNA. On transplantation, 100,000 CD34+CD90+ HSCs were sufficient for long-term repopulation of the entire bone marrow of NBSGW mice. Importantly, the gene editing efficiency of ~90% in the infused product was maintained in vivo, facilitating the generation of CCR5 null immune cells, resistant to HIV infection. Altogether, CCR5 gene editing of CD34+CD90+ HSCs provide an ideal gene manipulation strategy for autologous HSCT based gene therapy for HIV infection.

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Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation

Cited by 11 publications

References 89 publications

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

Efficient ex vivo expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates

The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

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