Editing out HIV: application of gene editing technology to achieve functional cure.
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ABSTRACT:
SUBMITTER: Xun J
PROVIDER: S-EPMC8684261 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The major advances achieved in devising successful combined antiretroviral therapy (cART) have enabled the sustained control of HIV replication. However, this is associated with costly lifelong treatment, partial immune restoration, chronic inflammation and persistent viral reservoirs. In this context, new therapeutic strategies deserve investigation as adjuncts to cART so as to potentiate immune responses that are capable of completely containing HIV pathogenicity, particularly if cART is discontinued. This may seem a dauntingly high hurdle given the results to date. This review outlines the key research efforts that have recently resurrected immunotherapeutic options, and some of the approaches tested to date. These areas include promising cytokines or vaccine strategies, using different viral or non-viral vectors based on polyvalent "mosaic" antigens and highly conserved HIV envelope peptides, broadly neutralizing antibodies or new properties of antibodies to improve the control of immune system homeostasis. These novel immunotherapeutic strategies appear promising per se, or in combination with TLR-agonists in order to bypass the complexity of the interplay between immune activation, massive CD4+ T-cell loss and viral persistence.
| S-EPMC5122442 | biostudies-literature
Project description:Purpose of reviewIn the absence of antiretroviral therapy (ART), more than 50% of perinatally HIV-infected children die by 2 years of age. Early ART from infancy is therefore a global recommendation and significantly improves immune health, child survival, and disease outcome. However, even early treatment does not prevent or eradicate the latent reservoir necessitating life-long ART. Adherence to life-long ART is challenging for children and longstanding ART during chronic HIV infection led to higher risks of non-AIDS co-morbidities and virologic failure in infected children. Thus, HIV-infected children are an important population for consideration for immune-based interventions to achieve ART-free remission and functional cure. This review summarizes how the uniqueness of the early life immune system can be harnessed for the development of ART-free remission and functional cure, which means complete virus control in absence of ART. In addition, recent advances in therapeutics in the HIV cure field and their potential for the treatment of pediatric HIV infections are discussed.Recent findingsPreclinical studies and clinical trials demonstrated that immune-based interventions target HIV replication, limit size of virus reservoir, maintain virus suppression, and delay time to virus rebound. However, these studies have been performed so far only in carefully selected HIV-infected adults, highlighting the need to evaluate the efficacy of immune-based therapeutics in HIV-infected children and to design interventions tailored to the early life maturing immune system. Immune-based therapeutics alone or in combination with ART should be actively explored as potential strategies to achieve viral remission and functional cure in HIV-infected pediatric populations.
| S-EPMC7296986 | biostudies-literature
Project description:9 years since the report of a cure for HIV after C-C chemokine receptor type 5 Δ32 stem cell transplantation, no other case of HIV cure has been reported, despite much research. However, substantial progress has been made in understanding the biology of the latent HIV reservoir, and in measuring the amount of virus that persists after antiretroviral therapy (ART) with increasingly sophisticated approaches. This knowledge is being translated into a long pipeline of clinical trials seeking to reduce viral persistence in participants on suppressive treatment and ultimately to allow safe cessation of ART. In this Review, we discuss the main barriers preventing the development of an HIV cure, methods used to measure HIV persistence in individuals on ART, clinical strategies that aim to cure HIV, and future directions for studies in the field of HIV cure research.
| S-EPMC6559798 | biostudies-literature
Project description:Despite significant advances in HIV drug treatment regimens, which grant near-normal life expectancies to infected individuals who have good virological control, HIV infection itself remains incurable. In recent years, novel gene- and cell-based therapies have gained increasing attention due to their potential to provide a functional or even sterilizing cure for HIV infection with a one-shot treatment. A functional cure would keep the infection in check and prevent progression to AIDS, while a sterilizing cure would eradicate all HIV viruses from the patient. Genome editing is the most precise form of gene therapy, able to achieve permanent genetic disruption, modification, or insertion at a predesignated genetic locus. The most well-studied candidate for anti-HIV genome editing is CCR5, an essential coreceptor for the majority of HIV strains, and the lack of which confers HIV resistance in naturally occurring homozygous individuals. Genetic disruption of CCR5 to treat HIV has undergone clinical testing, with seven completed or ongoing trials in T cells and hematopoietic stem and progenitor cells, and has shown promising safety and potential efficacy profiles. Here we summarize clinical findings of CCR5 editing for HIV therapy, as well as other genome editing-based approaches under pre-clinical development. The anticipated development of more sophisticated genome editing technologies should continue to benefit HIV cure efforts.
| S-EPMC5144849 | biostudies-other
Project description:This review will highlight some of the recent advances in genome engineering with applications for both clinical and basic science investigations of HIV-1.Over the last year, the field of HIV cure research has seen major breakthroughs with the success of the first phase I clinical trial involving gene editing of CCR5 in patient-derived CD4(+) T cells. This first human use of gene-editing technology was accomplished using zinc finger nucleases (ZFNs). Zinc finger nucleases and the advent of additional tools for genome engineering, including transcription activator-like effector nucleases (TALENS) and the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, have made gene editing remarkably simple and affordable. Here we will discuss the different gene-editing technologies, the use of gene editing in HIV research over the past year, and potential applications of gene editing for both in-vitro and in-vivo studies.Genome-engineering technologies have rapidly progressed over the past few years such that these systems can be easily applied in any laboratory for a variety of purposes. For HIV-1, upcoming clinical trials will determine if gene editing can provide the long-awaited functional cure. In addition, manipulation of host genomes, whether in vivo or in vitro, can facilitate development of better animal models and culture methods for studying HIV-1 transmission, pathogenesis, and virus-host interactions.
| S-EPMC4420178 | biostudies-other
Project description:Antiretroviral therapy has prolonged the lives of people living with human immunodeficiency virus type 1 (HIV-1), transforming the disease into one that can be controlled with lifelong therapy. The search for an HIV-1 vaccine has plagued researchers for more than three decades with little to no success from clinical trials. Due to these failures, scientists have turned to alternative methods to develop next generation therapeutics that could allow patients to live with HIV-1 without the need for daily medication. One method that has been proposed has involved the use of a number of powerful gene editing tools; Zinc Finger Nucleases (ZFN), Transcription Activator-like effector nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to edit the co-receptors (CCR5 or CXCR4) required for HIV-1 to infect susceptible target cells efficiently. Initial safety studies in patients have shown that editing the CCR5 locus is safe. More in depth in vitro studies have shown that editing the CCR5 locus was able to inhibit infection from CCR5-utilizing virus, but CXCR4-utilizing virus was still able to infect cells. Additional research efforts were then aimed at editing the CXCR4 locus, but this came with other safety concerns. However, in vitro studies have since confirmed that CXCR4 can be edited without killing cells and can confer resistance to CXCR4-utilizing HIV-1. Utilizing these powerful new gene editing technologies in concert could confer cellular resistance to HIV-1. While the CD4, CCR5, CXCR4 axis for cell-free infection has been the most studied, there are a plethora of reports suggesting that the cell-to-cell transmission of HIV-1 is significantly more efficient. These reports also indicated that while broadly neutralizing antibodies are well suited with respect to blocking cell-free infection, cell-to-cell transmission remains refractile to this approach. In addition to stopping cell-free infection, gene editing of the HIV-1 co-receptors could block cell-to-cell transmission. This review aims to summarize what has been shown with regard to editing the co-receptors needed for HIV-1 entry and how they could impact the future of HIV-1 therapeutic and prevention strategies.
| S-EPMC6304358 | biostudies-literature
Project description:Genome editing is a relevant, versatile, and preferred tool for crop improvement, as well as for functional genomics. In this review, we summarize the advances in gene-editing techniques, such as zinc-finger nucleases (ZFNs), transcription activator-like (TAL) effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR) associated with the Cas9 and Cpf1 proteins. These tools support great opportunities for the future development of plant science and rapid remodeling of crops. Furthermore, we discuss the brief history of each tool and provide their comparison and different applications. Among the various genome-editing tools, CRISPR has become the most popular; hence, it is discussed in the greatest detail. CRISPR has helped clarify the genomic structure and its role in plants: For example, the transcriptional control of Cas9 and Cpf1, genetic locus monitoring, the mechanism and control of promoter activity, and the alteration and detection of epigenetic behavior between single-nucleotide polymorphisms (SNPs) investigated based on genetic traits and related genome-wide studies. The present review describes how CRISPR/Cas9 systems can play a valuable role in the characterization of the genomic rearrangement and plant gene functions, as well as the improvement of the important traits of field crops with the greatest precision. In addition, the speed editing strategy of gene-family members was introduced to accelerate the applications of gene-editing systems to crop improvement. For this, the CRISPR technology has a valuable advantage that particularly holds the scientist's mind, as it allows genome editing in multiple biological systems.
| S-EPMC7461041 | biostudies-literature
Project description:The current treatment strategy for HIV-1 involves prolonged and intensive combined antiretroviral therapy (cART), which successfully suppresses plasma viremia. It has transformed HIV-1 infection into a chronic disease. However, despite the success of cART, a latent form of HIV-1 infection persists as integrated provirus in resting memory CD4(+) T cells. Virus can reactivate from this reservoir upon cessation of treatment, and hence HIV requires lifelong therapy. The reservoir represents a major barrier to eradication. Understanding molecular mechanisms regulating HIV-1 transcription and latency are crucial to develop alternate treatment strategies, which impact upon the reservoir and provide a path toward a "functional cure" in which there is no detectable viremia in the absence of cART. Numerous reports have suggested ncRNAs are involved in regulating viral transcription and latency. This review will discuss the latest developments in ncRNAs, specifically short interfering (si)RNA and short hairpin (sh)RNA, targeting molecular mechanisms of HIV-1 transcription, which may represent potential future therapeutics. It will also briefly address animal models for testing potential therapeutics and current gene therapy clinical trials.
| S-EPMC4584958 | biostudies-literature
Project description:Recent clinical research suggests that an HIV-infected patient with lymphoma who was transplanted with bone marrow homozygous for a disrupted mutant CCR5 allele has no remaining HIV replication and is effectively cured of HIV. Here, we discuss the approaches of disrupting host and viral genes involved in HIV replication and pathogenesis with the aim of curing patients with HIV.Data from the 'Berlin patient' suggest that targeted gene disruption can lead to an HIV cure. This review discusses the recent advances in the field of gene disruption toward the development of an anti-HIV therapy. We will introduce the strategies to disrupt host and viral genes using precise disruptions, imprecise disruptions, or site-specific recombination. Furthermore, the production of engineered rare-cutting endonucleases (zinc finger nucleases, TAL effector nucleases, and homing endonucleases) and recombinases that can recognize specific DNA target sequences and facilitate gene disruption will be discussed.The discovery of a gene disruption approach that would cure or efficiently confine HIV infection could have broad implications for the treatment of millions of people infected with HIV. An efficient 'one-shot' curative therapy not only would give infected patients hope of a drug-free or treatment-free future, but also could reduce the huge financial burden faced by many countries because of widespread administration of highly active antiretroviral therapy.
| S-EPMC4226633 | biostudies-literature
Project description:BackgroundXinjiang wild apple is an important tree of the Tianshan Mountains, and in recent years, it has undergone destruction by many biotic and abiotic stress and human activities. It is necessary to use new technologies to research its genomic function and molecular improvement. The clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system has been successfully applied to genetic improvement in many crops, but its editing capability varies depending on the different combinations of the synthetic guide RNA (sgRNA) and Cas9 protein expression devices.ResultsIn this study, we used 2 systems of vectors with paired sgRNAs targeting to MsPDS. As expected, we successfully induced the albino phenotype of calli and buds in both systems.ConclusionsWe conclude that CRISPR/Cas9 is a powerful system for editing the wild apple genome and expands the range of plants available for gene editing.
| S-EPMC8287690 | biostudies-literature