Mechanisms for Controlling HIV-1 Infection: A Gene Therapy Approach

Ognenovska, Katherine; Klemm, Vera; Ledger, Scott; Turville, Stuart; Symonds, Geoff; Kelleher, Anthony D.; Ahlenstiel, Chantelle

doi:10.5772/intechopen.79669

Cited by 3 publications

(3 citation statements)

References 109 publications

(152 reference statements)

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“…2 ). This results in deletions or additions at the selected gene target site [ 22 , 129 ]. Two main repair pathways are involved: (i) non-homologous end-joining (NHEJ) where the break ends are directly ligated without a homologous template and (ii) homology-directed repair pathway (HDR) in which homologous sequences are introduced to guide the repair [ 130 ].…”

Section: Hiv Cure Strategiesmentioning

confidence: 99%

HIV cure strategies: which ones are appropriate for Africa?

Abana

Lamptey

Bonney

et al. 2022

Cell. Mol. Life Sci.

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Although combination antiretroviral therapy (ART) has reduced mortality and improved lifespan for people living with HIV, it does not provide a cure. Patients must be on ART for the rest of their lives and contend with side effects, unsustainable costs, and the development of drug resistance. A cure for HIV is, therefore, warranted to avoid the limitations of the current therapy and restore full health. However, this cure is difficult to find due to the persistence of latently infected HIV cellular reservoirs during suppressive ART. Approaches to HIV cure being investigated include boosting the host immune system, genetic approaches to disable co-receptors and the viral genome, purging cells harboring latent HIV with latency-reversing latency agents (LRAs) (shock and kill), intensifying ART as a cure, preventing replication of latent proviruses (block and lock) and boosting T cell turnover to reduce HIV-1 reservoirs (rinse and replace). Since most people living with HIV are in Africa, methods being developed for a cure must be amenable to clinical trials and deployment on the continent. This review discusses the current approaches to HIV cure and comments on their appropriateness for Africa.

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Section: Hiv Cure Strategiesmentioning

confidence: 99%

HIV cure strategies: which ones are appropriate for Africa?

Abana

Lamptey

Bonney

et al. 2022

Cell. Mol. Life Sci.

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show abstract

“…Although combinatorial antiretroviral therapy (cART) is capable of potently suppressing HIV-replication as well as delaying the onset of AIDS, the phenomenon of viral mutagenesis enables viral escape from these drugs Jai et al Journal of Genetic Engineering and Biotechnology (2022) 20:172 [2]. Due to this drawback, new biological therapeutics are currently under research.…”

Section: Introductionmentioning

confidence: 99%

Multiplexed shRNA-miRs as a candidate for anti HIV-1 therapy: strategies, challenges, and future potential

Jai

Shirleen

Hanbali

et al. 2022

Journal of Genetic Engineering and Biotechnology

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The spread of HIV is on the rise and has become a global issue, especially for underdeveloped and developing countries. This is due to the fact that HIV majorly occurs asymptomatically and is implausible for early diagnosis. Recent advances in research and science have enabled the investigation of a new potential treatment involving gene-based therapy, known as RNA interference (RNAi) that will direct gene silencing and further compensate for natural variants and viral mutants. Several types of small regulatory RNA are discussed in this present study, including microRNA (miRNA), small interfering RNA (siRNA), and short hairpin RNA (shRNA).This paper examines the mechanism of RNAi as a viable HIV therapy, using a minimum of four shRNAs to target both dispensable host components (CCR5) and viral genes (Gag, Env, Tat, Pol I, Pol II and Vif). Moreover, a multiplexed mechanism of shRNAs and miRNA is known to be effective in preventing viral escape due to mutation as the miRNA develops a general polycistronic platform for the expression of a large amount of shRNA-miRs. Several administration methods as well as the advantages of this RNAi treatment are also discussed in this study. The administration methods include (1) ex vivo delivery with the help of viral vectors, nanoparticles, and electroporation, (2) nonspecific in vivo delivery using non-viral carriers including liposomes, dendrimers and aptamers, as well as (3) targeted delivery that uses antibodies, modified nanoparticles, nucleic acid aptamers, and tissue-specific serotypes of AAV. Moreover, the advantages of this treatment are related to the effectiveness in silencing the HIV gene, which is more compatible compared to other gene therapy treatments, such as ZFN, TALEN, and CRISPR/Cas9.

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“…Gene transfer approaches to block human immunodeficiency virus type 1 (HIV-1) infection or inhibit viral replication in cells have tested an array of agents, such as HIV-1-specific antibody mimetics, ribozymes, small interfering RNA (siRNA), short hairpin RNA (shRNA), gp41-based peptides C46 and C34, zinc finger nucleases to CCR5, CRISPR-Cas9 targeting HIV-1 and cellular genes, and various dominant negative mutant forms of HIV-1 Rev and Tat (1–5). Early HIV-1 gene transfer clinical trials used retrovirus-based vectors to deliver a mutant HIV-1 rev called M10, a dominant negative inhibitor of wild-type rev (6, 7).…”

Section: Introductionmentioning

confidence: 99%

Strong In Vivo Inhibition of HIV-1 Replication by Nullbasic, a Tat Mutant

Jin

Sun

et al. 2019

mBio

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Nullbasic is a mutant form of the HIV-1 transcriptional activator protein (Tat) that strongly inhibits HIV-1 transcription and replication in lymphocytes in vitro. To investigate Nullbasic inhibition in vivo, we employed an NSG mouse model where animals were engrafted with primary human CD4+ cells expressing a Nullbasic-ZsGreen1 (NB-ZSG) fusion protein or ZSG. NB-ZSG and ZSG were delivered by using a retroviral vector where CD4+ cells were transduced either prior to (preinfection) or following (postinfection) HIV-1 infection. The transduced cells were analyzed in vitro up to 10 days postinfection (dpi) and in vivo up to 39 dpi. Compared to ZSG, NB-ZSG strongly inhibited HIV-1 replication both in vitro and in vivo using preinfection treatment. In vitro, HIV-1 mRNA levels in cells were reduced by up to 60-fold. In vivo, HIV-1 RNA was undetectable in plasma samples during the course of the experiment, and HIV-1 mRNA levels in resident CD4+ cells in organ tissue were reduced up to 2,800-fold. Postinfection treatment of HIV-1-infected cells with NB-ZSG attenuated HIV-1 infection for up to 14 days. In vitro, a 25-fold reduction of viral mRNA in cells was observed but diminished to a <2-fold reduction by 10 dpi. In vivo, HIV-1 RNA was undetectable in plasma of NB-ZSG mice at 14 dpi but afterwards was not significantly different between NB-ZSG mice and control mice. However, we observed higher levels of CD4+ cells in NB-ZSG mice than in control mice, suggesting that NB-ZSG imparted a survival advantage to HIV-1-infected animals. IMPORTANCE HIV-1 infection is effectively controlled by antiviral therapy that inhibits virus replication and reduces viral loads below detectable levels in patients. However, therapy interruption leads to viral rebound due to latently infected cells, which serve as a source of continued viral infection. Interest in strategies leading to a functional cure for HIV-1 infection by long-term or permanent viral suppression is growing. Here, we show that a mutant form of the HIV-1 Tat protein, referred to as Nullbasic, inhibits HIV-1 transcription in infected CD4+ cells in vivo. Analysis shows that stable expression of Nullbasic in CD4+ cells could lead to durable anti-HIV-1 activity. Nullbasic, as a gene therapy candidate, could be a part of a functional-cure strategy to suppress HIV-1 transcription and replication.

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Mechanisms for Controlling HIV-1 Infection: A Gene Therapy Approach

Cited by 3 publications

References 109 publications

HIV cure strategies: which ones are appropriate for Africa?

HIV cure strategies: which ones are appropriate for Africa?

Multiplexed shRNA-miRs as a candidate for anti HIV-1 therapy: strategies, challenges, and future potential

Strong In Vivo Inhibition of HIV-1 Replication by Nullbasic, a Tat Mutant

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