Curing HIV: Seeking to Target and Clear Persistent Infection

Margolis, David M.; Archin, Nancie M.; Cohen, Myron S.; Eron, Joseph J.; Ferrari, Guido; García, J. Víctor; Goonetilleke, Nilu; Joseph, Sarah; Swanstrom, Ronald; Turner, Anne-Marie W.; Wahl, Angela

doi:10.1016/j.cell.2020.03.005

Cited by 145 publications

(136 citation statements)

References 151 publications

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“…Several strategies have been explored for eradication of latent HIV-1 reservoirs. For example, “shock and kill” strategies aim to reduce the reservoir with compounds that induce HIV-1 expression so that latent cells are cleared by anti-HIV immunity or HIV-1 mediated cell death [ 16 , 17 , 18 , 19 ]. Cytokines, protein kinase C agonists, histone deacetylases inhibitors, and SMAC mimetics are some examples of compounds that have been employed as latency-reversing agents, but, despite inducing modest HIV-1 transcription, they have had limited impact on decreasing the HIV-1 reservoir in in vivo models [ 17 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Olson

Basukala

Lee

et al. 2020

Viruses

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The major barrier to HIV-1 cure is the persistence of latent provirus, which is not eradicated by antiretroviral therapy. The “shock and kill” approach entails stimulating viral production with latency-reversing agents followed by the killing of cells actively producing the virus by immune clearance. However, this approach does not induce all intact proviruses, leaving a residual reservoir. CRISPR/Cas9 has been utilized to excise integrated Human Immunodeficiency Virus (HIV) DNA from infected cells in an RNA-guided, sequence-specific manner. Here, we seek to epigenetically silence the proviral DNA by introducing nuclease-deficient disabled Cas9 (dCas9) coupled with a transcriptional repressor domain derived from Kruppel-associated box (KRAB). We show that specific guide RNAs (gRNAs) and dCas9-KRAB repress HIV-1 transcription and reactivation of latent HIV-1 provirus. This repression is correlated with chromatin changes, including decreased H3 histone acetylation and increased histone H3 lysine 9 trimethylation, histone marks that are associated with transcriptional repression. dCas9-KRAB-mediated inhibition of HIV-1 transcription suggests that CRISPR can be engineered as a tool for block-and-lock strategies.

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Section: Introductionmentioning

confidence: 99%

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Olson

Basukala

Lee

et al. 2020

Viruses

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“…T cell immunotherapy is a useful and often curative strategy for treating hematologic cancers (44)(45)(46)(47)(48)(49)(50)(51)(52)(53). A similar approach could be used to target latent reservoirs of HIV (54,55). Such reservoirs are limited to immune cells and are thought to be reduced or even eliminated by GvH responses after allo-HSCT (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

Identifying a Minor Histocompatibility Antigen in Mauritian Cynomolgus Macaques Encoded by APOBEC3C

et al. 2020

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Allogeneic hematopoietic stem cell transplants can lead to dramatic reductions in human immunodeficiency virus (HIV) reservoirs. This effect is partially mediated by donor T cells recognizing lymphocyte-expressed minor histocompatibility antigens (mHAgs). The potential to mark malignant and latently infected cells for destruction makes mHAgs attractive targets for cellular immunotherapies. However, testing such HIV reservoir reduction strategies will likely require preclinical studies in non-human primates (NHPs). In this study, we used a combination of alloimmunization, whole exome sequencing, and bioinformatics to identify an mHAg in Mauritian cynomolgus macaques (MCMs). We mapped the minimal optimal epitope to a 10-mer peptide (SW10) in apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3C (APOBEC3C) and determined the major histocompatibility complex class I restriction element as Mafa-A1 * 063, which is expressed in almost 90% of MCMs. APOBEC3C SW10-specific CD8 + T cells recognized immortalized B cells but not fibroblasts from an mHAg-positive MCM. These results provide a framework for identifying mHAgs in a non-transplant setting and suggest that APOBEC3C SW10 could be used as a model antigen to test mHAg-targeted therapies in NHPs.

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“…HIV-1 induces AIDS and affects several millions of people worldwide. The pandemic persists despite the implementation of highly active antiretroviral therapies [18,19], which must be taken lifelong (for review: [20]). The major causes of HIV-1 resistance to antivirals are due to the high mutation rate of the virus [21] as well as the viral latency with the persistence of silent-HIV reservoirs in infected cells [22].…”

Section: Microfluidics For Studying Hiv Infectionmentioning

confidence: 99%

Advances in Continuous Microfluidics-Based Technologies for the Study of HIV Infection

Eid

Mougel

Socol

2020

Viruses

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HIV-1 is the causative agent of acquired immunodeficiency syndrome (AIDS). It affects millions of people worldwide and the pandemic persists despite the implementation of highly active antiretroviral therapy. A wide spectrum of techniques has been implemented in order to diagnose and monitor AIDS progression over the years. Besides the conventional approaches, microfluidics has provided useful methods for monitoring HIV-1 infection. In this review, we introduce continuous microfluidics as well as the fabrication and handling of microfluidic chips. We provide a review of the different applications of continuous microfluidics in AIDS diagnosis and progression and in the basic study of the HIV-1 life cycle.

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Curing HIV: Seeking to Target and Clear Persistent Infection

Cited by 145 publications

References 151 publications

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Identifying a Minor Histocompatibility Antigen in Mauritian Cynomolgus Macaques Encoded by APOBEC3C

Advances in Continuous Microfluidics-Based Technologies for the Study of HIV Infection

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