Knowledge From London and Berlin: Finding Threads to a Functional HIV Cure

Ding, Jingyi; Liu, Yanxi; Lai, Yu

doi:10.3389/fimmu.2021.688747

Cited by 19 publications

(23 citation statements)

References 153 publications

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“…However, it is fitting for this era of personalized medicine and focus on what the individual or outliers within study samples can teach us [ 107 – 111 ]. In fact, looking at the HIV cure research field, the major milestones have been successful cure or HIV ART free remission in one person at a time, starting with Timothy Ray Brown (the “Berlin Patient”) in 2008 [ 21 , 112 , 113 ]. The range of pathologies in Last Gift participants likely influences the HIV reservoir, particularly in diseased tissues.…”

Section: Cns Reservoirs In the Last Giftmentioning

confidence: 99%

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

Riggs

Chaillon

Jiang³

et al. 2022

Curr HIV/AIDS Rep

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Purpose of Review Deep tissue HIV reservoirs, especially within the central nervous system (CNS), are understudied due to the challenges of sampling brain, spinal cord, and other tissues. Understanding the cellular characteristics and viral dynamics in CNS reservoirs is critical so that HIV cure trials can address them and monitor the direct and indirect effects of interventions. The Last Gift program was developed to address these needs by enrolling altruistic people with HIV (PWH) at the end of life who agree to rapid research autopsy. Recent Findings Recent findings from the Last Gift emphasize significant heterogeneity across CNS reservoirs, CNS compartmentalization including differential sensitivity to broadly neutralizing antibodies, and bidirectional migration of HIV across the blood–brain barrier. Our findings add support for the potential of CNS reservoirs to be a source of rebounding viruses and reseeding of systemic sites if they are not targeted by cure strategies. Summary This review highlights important scientific, practical, and ethical lessons learned from the Last Gift program in the context of recent advances in understanding the CNS reservoirs and key knowledge gaps in current research.

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Section: Cns Reservoirs In the Last Giftmentioning

confidence: 99%

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

Riggs

Chaillon

Jiang³

et al. 2022

Curr HIV/AIDS Rep

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“…CRISPR/Cas cleavage of CCR5 in hematopoietic cells was shown to cause loss of receptor expression on differentiated progeny cells [22]. Targeting CCR5 in hematopoietic stem cells as an approach to generate a CCR5 null immune system was supported by clinical reports of permanent suppression of HIV replication in two different patients who underwent allogeneic bone marrow transplantation using bone marrow from donors homozygous for the CCR5 D32 mutation [23][24][25][26]. To date, the most common sources of Cas endonucleases, Cas9, derive from the common human pathogens Staphylococcus aureus (SaCas9) and Streptococcus pyogenes (SpCas9), yet pre-existing immunity to these bacteria as well as the rather large molecular size of SpCas9 may limit the long-term utility of these editors in therapeutic approaches [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

CAS12e (CASX2) CLEAVAGE OF CCR5: IMPACT OF GUIDE RNA LENGTH AND PAM SEQUENCE ON CLEAVAGE ACTIVITY

Armstrong

Hudson

Hodge

et al. 2023

Preprint

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CRISPR/Cas is under development as a therapeutic tool for the cleavage, excision, and/or modification of genes in eukaryotic cells. While much effort has focused on CRISPR/Cas from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9), alternative CRISPR systems have been identified using metagenomic datasets from non-pathogenic microbes, including previously unknown class 2 systems, adding to a diverse toolbox of gene editors. The Cas12e (CasX1, CasX2) endonucleases from non-pathogenic Deltaproteobacteria (DpeCas12e) and Planctomycetes (PlmCas12e) are more compact than SpCas9, have a more selective protospacer adjacent motif (PAM) requirement, and deliver a staggered cleavage cut with 5-7 base overhangs. We investigated varying guide RNA (spacer) lengths and alternative PAM sequences to determine optimal conditions for PlmCas12e cleavage of the cellular gene CCR5 (CC-Chemokine receptor-5). CCR5 encodes one of two chemokine coreceptors required by HIV-1 to infect target cells, and a mutation of CCR5 (delta-32) is responsible for HIV-1 resistance and reported cures following bone marrow transplantation. Consequently, CCR5 has been an important target for gene editing utilizing CRISPR, TALENs, and ZFNs. We determined that CCR5 cleavage activity varied with the target site, guide RNA length, and the terminal nucleotide in the PAM sequence. Our analyses demonstrated a PlmCas12e PAM preference for purines (A, G) over pyrimidines (T, C) in the fourth position of the CasX2 PAM (TTCN). These analyses have contributed to a better understanding of CasX2 cleavage requirements and will position us more favorably to develop a therapeutic that creates the delta-32 mutation in the CCR5 gene in hematopoietic stem cells.

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“…Recibido: 8 de diciembre 2022 Aceptado: 31 de enero 2023 DOI: https://doi.org/10.47307/GMC.2023.131. 1.18 ORCID: https://orcid.org/0000-0002-7243-2238 1* ORCID: https://orcid.org/0000-0001-8275-4399 2 ORCID: https://orcid.org/0000-0002-3823-4561 3 ORCID: https://orcid.org/0000-0002-5121-3335 4 ORCID: https://orcid.org/0000-0003-3745-3700 5 ORCID: https://orcid.org/0000-0003-2442-2024 6 ORCID: https://orcid.org/0000-0003-0057-2079 7 ORCID: https://orcid.org/0000-0003-4443-4938 8 ORCID: https://orcid.org/0000-0003-1104-428X 9 ORCID: https://orcid.org/0000-0002-6276-7544 10 ORCID: https://orcid.org/0000-0001-8335-4370 11 ORCID: https://orcid.org/0000-0002-6842-3064 12…”

Section: Introductionmentioning

confidence: 99%

CRISPR and gene editing in HIV therapy: A scoping review

Tuta-Quintero¹

2023

Gac Méd Caracas

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Human immunodeficiency virus (HIV) is nowadays one of the major health problems worldwide. Several strategies have been explored for the eradication of latent HIV-1 reservoirs, current antiretroviral therapy stops the progression of HIV disease, however, as new therapies are being developed, CRISPR (clustered regularly interspaced short palindromic repeats) systems have recently been used as a genome editing technique. CRISPR is becoming progressively one of the possible cures, although it remains experimental, for HIV in medical research. This systematic review summarizes literature evidence of CRISPR gene editing in HIV/AIDS therapy. This study also identifies the research gaps in the current literature, helping to guide future research.

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Knowledge From London and Berlin: Finding Threads to a Functional HIV Cure

Cited by 19 publications

References 153 publications

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

CAS12e (CASX2) CLEAVAGE OF CCR5: IMPACT OF GUIDE RNA LENGTH AND PAM SEQUENCE ON CLEAVAGE ACTIVITY

CRISPR and gene editing in HIV therapy: A scoping review

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