Targeting persistent HIV infection: Where and how, if possible?

Wayengera, Misaki

doi:10.1016/j.hivar.2011.01.002

Cited by 6 publications

(11 citation statements)

References 66 publications

(172 reference statements)

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“…Over the past 10 years of our work with REases, LVs have emerged as potent and versatile vectors for ex vivo or in vivo gene transfer into dividing and non-dividing cells [ 15 , 41 ]. The latter -- ability to infect non-dividing cells - presents a unique opportunity when targeting of proviral HIV DNA in resting CD4 + memory cells is considered [ 5 , 6 , 42 ]. Moreover, in conjunction with zinc-finger nuclease technology and HIV, LVs allow for site-specific gene correction or addition in predefined chromosomal loci where proviral HIV resides [ 5 , 40 , 43 ].…”

Section: Methods Results and Discussionmentioning

confidence: 99%

“…There are now over 33 million people currently infected with HIV world-over, and 25 million lives have already been lost to AIDS. Despite the advent of a powerful regimen of highly active anti-retroviral therapy (HAART) to treat HIV/AIDS, HAART has its limitations [ 4 , 5 ]. Specifically, while HAART targets actively replicating HIV, latent-HIV infection, particularly proviral HIV DNA integrated with resting CD4+ve cells, ultimately acts as a source of rebound viremia once treatment is stopped.…”

Section: Introductionmentioning

confidence: 99%

“…Overall, in the absence of a vaccine that is 100% effective, novel strategies to tackle the unique challenge of latent HIV infection among patients on HAART are urgently sought [ 7 ]. Although different mechanisms for the maintenance of reservoirs of latent HIV-infection have been advanced, the spectrum of emerging trial anti-HIV latency 'pro-drugs' is largely limited to those agents functioning via the awakening of resting host (CD4+ memory) cells; a strategy primarily meant to exorcise the latent provirus [ 5 , 6 ]. Specifically, most of the trial anti-HIV latency pro-drugs (operating by non-specific stimulation of T cell receptors, TCR) function either globally via nuclear factor of activated T cells (NFAT) and protein C-kinase (PCK), or specifically via reductive oxidative substrates (ROS) and cytokines such as tumor necrotic factor-alpha (TNF-α) and interleukin-7 [ 8 - 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Proviral HIV-genome-wide and pol-gene specific Zinc Finger Nucleases: Usability for targeted HIV gene therapy

Wayengera

2011

Theor Biol Med Model

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BackgroundInfection with HIV, which culminates in the establishment of a latent proviral reservoir, presents formidable challenges for ultimate cure. Building on the hypothesis that ex-vivo or even in-vivo abolition or disruption of HIV-gene/genome-action by target mutagenesis or excision can irreversibly abrogate HIV's innate fitness to replicate and survive, we previously identified the isoschizomeric bacteria restriction enzymes (REases) AcsI and ApoI as potent cleavers of the HIV-pol gene (11 and 9 times in HIV-1 and 2, respectively). However, both enzymes, along with others found to cleave across the entire HIV-1 genome, slice (SX) at palindromic sequences that are prevalent within the human genome and thereby pose the risk of host genome toxicity. A long-term goal in the field of R-M enzymatic therapeutics has thus been to generate synthetic restriction endonucleases with longer recognition sites limited in specificity to HIV. We aimed (i) to assemble and construct zinc finger arrays and nucleases (ZFN) with either proviral-HIV-pol gene or proviral-HIV-1 whole-genome specificity respectively, and (ii) to advance a model for pre-clinically testing lentiviral vectors (LV) that deliver and transduce either ZFN genotype.Methods and ResultsFirst, we computationally generated the consensus sequences of (a) 114 dsDNA-binding zinc finger (Zif) arrays (ZFAs or ZifHIV-pol) and (b) two zinc-finger nucleases (ZFNs) which, unlike the AcsI and ApoI homeodomains, possess specificity to >18 base-pair sequences uniquely present within the HIV-pol gene (ZifHIV-polFN). Another 15 ZFNs targeting >18 bp sequences within the complete HIV-1 proviral genome were constructed (ZifHIV-1FN). Second, a model for constructing lentiviral vectors (LVs) that deliver and transduce a diploid copy of either ZifHIV-polFN or ZifHIV-1FN chimeric genes (termed LV- 2xZifHIV-polFN and LV- 2xZifHIV-1FN, respectively) is proposed. Third, two preclinical models for controlled testing of the safety and efficacy of either of these LVs are described using active HIV-infected TZM-bl reporter cells (HeLa-derived JC53-BL cells) and latent HIV-infected cell lines.ConclusionLV-2xZifHIV-polFN and LV- 2xZifHIV-1FN may offer the ex-vivo or even in-vivo experimental opportunity to halt HIV replication functionally by directly abrogating HIV-pol-gene-action or disrupting/excising over 80% of the proviral HIV DNA from latently infected cells.

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Section: Methods Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proviral HIV-genome-wide and pol-gene specific Zinc Finger Nucleases: Usability for targeted HIV gene therapy

Wayengera

2011

Theor Biol Med Model

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“…All these mechanisms lead to chronic immune activation, the key factor in HIV-1 immunopathogenesis. The disease progression ( Clerici et al, 1996 ; Rodriguez et al, 2006 ; Schader and Wainberg, 2011 ; Wayengera, 2011 ) is associated with the gradual T lymphocyte decline, first taking toll of helper CD4 + T cells and then the cytotoxic CD8 + T cells. The pronounced decline of CD4 + T cells occurs due to the destruction of both infected and uninfected cells mainly because of apoptosis of activated cells, diminished hematopoiesis and thymic maturation.…”

Section: Introductionmentioning

confidence: 99%

Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview

et al. 2016

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As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular factors which are also involved in the replication of HIV and hence their role as potential candidates will be discussed. HIV/AIDS being an exceptional epidemic, demands an exceptional approach and that forms very much focus for the current review.

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“…All these mechanisms lead to chronic immune activation, the key factor in HIV-1 immunopathogenesis. The disease progression [35][36][37][38][39] is associated with the gradual T lymphocyte decline, first taking toll of helper CD4 + T cells and then the cytotoxic CD8 + T cells. The pronounced decline of CD4 + T cells occurs due to the destruction of both infected and uninfected cells mainly because of apoptosis of activated cells, diminished hematopoiesis and thymic maturation.…”

Section: Introductionmentioning

confidence: 99%

Cell cycle checkpoints and pathogenesis of HIV-1 infection: a brief overview

Kurapati

Samikkannu

Atluri

et al. 2014

Journal of Basic and Clinical Physiology and Pharmacology

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To understand HIV pathogenesis or development is no simple undertaking and neither is the cell cycle which is highly complex that requires the coordination of multiple events and machinery. It is interesting that these two processes are interrelated, intersect and interact as HIV-1 infection results in cell cycle arrest at the G2 phase which is accompanied by massive CD4+ T cell death. For its own benefit, in an impressive manner and with the overabundance of tactics, HIV maneuvers DNA damage responses and cell cycle check points for viral replication at different stages from infection, to latency and to pathogenesis. Although the cell cycle is the most critical aspect involved in both viral and cellular replication, in this review, our main focus is on recent developments, including our own observations in the field of cell cycle proteins, checkpoints and strategies utilized by the viruses to manipulate these pathways to promote their own replication and survival. We will also discuss the emerging concept of targeting the replication initiation machinery for HIV therapy.

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Targeting persistent HIV infection: Where and how, if possible?

Cited by 6 publications

References 66 publications

Proviral HIV-genome-wide and pol-gene specific Zinc Finger Nucleases: Usability for targeted HIV gene therapy

Proviral HIV-genome-wide and pol-gene specific Zinc Finger Nucleases: Usability for targeted HIV gene therapy

Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview

Cell cycle checkpoints and pathogenesis of HIV-1 infection: a brief overview

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