Disruption or Excision of Provirus as an Approach to HIV Cure

Jerome, Keith R.

doi:10.1089/apc.2016.0232

Cited by 8 publications

(3 citation statements)

References 30 publications

(29 reference statements)

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“…Besides cleavage efficiency, target site conservation, and reservoir size, a number of other factors will also contribute to the clinical success of this type of gene therapy for HIV cure [ 28 , 34 – 36 ]. For example, we have also not explicitly incorporated gene delivery in the current model but instead assumed that it is captured within the cleavage efficiency parameter ϵ .…”

Section: Discussionmentioning

confidence: 99%

Viral diversity is an obligate consideration in CRISPR/Cas9 designs for targeting the HIV reservoir

et al. 2018

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BackgroundRNA-guided CRISPR/Cas9 systems can be designed to mutate or excise the integrated HIV genome from latently infected cells and have therefore been proposed as a curative approach for HIV. However, most studies to date have focused on molecular clones with ideal target site recognition and do not account for target site variability observed within and between patients. For clinical success and broad applicability, guide RNA (gRNA) selection must account for circulating strain diversity and incorporate the within-host diversity of HIV.ResultsWe identified a set of gRNAs targeting HIV LTR, gag, and pol using publicly available sequences for these genes and ranked gRNAs according to global conservation across HIV-1 group M and within subtypes A–C. By considering paired and triplet combinations of gRNAs, we found triplet sets of target sites such that at least one of the gRNAs in the set was present in over 98% of all globally available sequences. We then selected 59 gRNAs from our list of highly conserved LTR target sites and evaluated in vitro activity using a loss-of-function LTR-GFP fusion reporter. We achieved efficient GFP knockdown with multiple gRNAs and found clustering of highly active gRNA target sites near the middle of the LTR. Using published deep-sequence data from HIV-infected patients, we found that globally conserved sites also had greater within-host target conservation. Lastly, we developed a mathematical model based on varying distributions of within-host HIV sequence diversity and enzyme efficacy. We used the model to estimate the number of doses required to deplete the latent reservoir and achieve functional cure thresholds. Our modeling results highlight the importance of within-host target site conservation. While increased doses may overcome low target cleavage efficiency, inadequate targeting of rare strains is predicted to lead to rebound upon cART cessation even with many doses.ConclusionsTarget site selection must account for global and within host viral genetic diversity. Globally conserved target sites are good starting points for design, but multiplexing is essential for depleting quasispecies and preventing viral load rebound upon therapy cessation.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0544-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Viral diversity is an obligate consideration in CRISPR/Cas9 designs for targeting the HIV reservoir

et al. 2018

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“…Current cure strategies focus on either purging the HIV-1 provirus reservoir, permanently inactivating latent proviruses, or targeting the provirus with gene editing approaches [12,[142][143][144][145][146][147]. Examples of some these proposed approaches include shock-and-kill to activate the latent pool so it can be immunologically targeted, block-and-lock approaches that rely on compounds or engineered transcriptional repressors that inactivate or repress HIV proviral transcription such as didehydro-Cortistatin, dCas9-KRAB or dCasDMNTs and targeting and inactivating proviruses using CRISPR-cas9 or zinc finger nucleases [148][149][150][151][152][153][154][155][156][157][158].…”

Section: Defective Viruses Immune Dysfunction and Cure Strategiesmentioning

confidence: 99%

Defective HIV-1 genomes and their potential impact on HIV pathogenesis

Henderson

2022

Retrovirology

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Defective HIV-1 proviruses represent a population of viral genomes that are selected for by immune pressures, and clonally expanded to dominate the persistent HIV-1 proviral genome landscape. There are examples of RNA and protein expression from these compromised genomes which are generated by a variety of mechanisms. Despite the evidence that these proviruses are transcribed and translated, their role in HIV pathogenesis has not been fully explored. The potential for these genomes to participate in immune stimulation is particularly relevant considering the accumulation of cells harboring these defective proviruses over the course of antiretroviral therapy in people living with HIV. The expression of defective proviruses in different cells and tissues could drive innate sensing mechanisms and inflammation. They may also alter antiviral T cell responses and myeloid cell functions that directly contribute to HIV-1 associated chronic comorbidities. Understanding the impact of these defective proviruses needs to be considered as we advance cure strategies that focus on targeting the diverse population of HIV-1 proviral genomes. Graphical abstract

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“…Estima-se que tal reservatório de células latentes infectadas pode permanecer neste estado por décadas, constituindo a maior barreira para a cura efetiva da infecção pelo HIV. Assim, avaliar novas estratégias promissoras que busquem solucionar este problema, é imprescindível (JEROME, 2016).…”

Section: Introductionunclassified