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Viruses
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Gene Therapy for Retroviral Infections
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Gene Therapy for Retroviral Infections

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 November 2013) | Viewed by 122613

Special Issue Editors

Prof. Dr. Irvin Chen

E-Mail Website
Guest Editor
David Geffen School of Medicine, UCLA, 615 Charles E. Young Dr. South, BSRB, Rm 161, Los Angeles, CA 90095, USA
Prof. Dr. Dong Sung An

E-Mail Website
Guest Editor
UCLA School of Nursing, 615 Charles E. Young Drive South, Los Angeles, CA 90095, USA

Special Issue Information

Dear Colleagues,

The main focus of this special issue is to review and present recent gene therapy research relevant to retroviral infections. Current highly active antiviral retroviral therapy (HAART) effectively suppresses HIV viral load to undetectable levels. However, HAART does not cure HIV infection. HIV persists in various cellular reservoirs under HAART and if therapy is ceased, viral loads rapidly rebound. Therefore, stable control of HIV infection without continuous treatment remains a long-term goal of HIV therapy. Because of the recent HIV cure achieved in one patient with D32/D32 homozygous CCR5 deficient bone marrow transplants, there has been emerging interest in developing novel HIV cure strategies. Gene therapy to genetically protect stem cells and/or their progenies from HIV infection may provide life-long protection by a single or a few treatments. We expect that this special issue will facilitate awareness of gene therapy research for the development of novel therapeutic strategies for HIV infection.

Prof. Dr. Irvin Chen
Prof. Dr. Dong Sung An
Guest Editors

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Published Papers (10 papers)

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Research

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286 KiB  
Article
CCR5 as a Natural and Modulated Target for Inhibition of HIV
by Bryan P. Burke, Maureen P. Boyd, Helen Impey, Louis R. Breton, Jeffrey S. Bartlett, Geoff P. Symonds and Gero Hütter
Viruses 2014, 6(1), 54-68; https://doi.org/10.3390/v6010054 - 30 Dec 2013
Cited by 28 | Viewed by 10880
Abstract
Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem [...] Read more.
Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem cells in a patient with HIV (“Berlin patient”) achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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481 KiB  
Article
Development of Hematopoietic Stem Cell Based Gene Therapy for HIV-1 Infection: Considerations for Proof of Concept Studies and Translation to Standard Medical Practice
by David L. DiGiusto, Rodica Stan, Amrita Krishnan, Haitang Li, John J. Rossi and John A. Zaia
Viruses 2013, 5(11), 2898-2919; https://doi.org/10.3390/v5112898 - 22 Nov 2013
Cited by 42 | Viewed by 13155
Abstract
Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected [...] Read more.
Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected RNA-based HIV-1 inhibitors in the CD4+ cells derived from GM-HSPC will protect them from HIV-1 infection and results in a sufficient immune repertoire to control HIV-1 viremia resulting in a functional cure for HIV-1/AIDS. Additionally, it is possible that the subset of protected T cells will also be able to facilitate the immune-based elimination of latently infected cells if they can be activated to express viral antigens. Thus, a single dose of disease resistant GM-HSPC could provide an effective treatment for HIV-1+ patients who require (or desire) an alternative to lifelong antiretroviral chemotherapy. We describe herein the results from several pilot clinical studies in HIV-1 patients and our strategies to develop second generation vectors and clinical strategies for HIV-1+ patients with malignancy who require ablative chemotherapy as part of treatment and others without malignancy. The important issues related to stem cell source, patient selection, conditioning regimen and post-infusion correlative studies become increasingly complex and are discussed herein. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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Review

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565 KiB  
Review
Gene Therapy Targeting HIV Entry
by Chuka Didigu and Robert Doms
Viruses 2014, 6(3), 1395-1409; https://doi.org/10.3390/v6031395 - 21 Mar 2014
Cited by 11 | Viewed by 7993
Abstract
Despite the unquestionable success of antiretroviral therapy (ART) in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic [...] Read more.
Despite the unquestionable success of antiretroviral therapy (ART) in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic hematopoietic stem cell transplant (HSCT) using HIV-resistant cells, and more recently, the report of short-term but sustained, ART-free control of HIV replication following allogeneic HSCT, using HIV susceptible cells, have served to both reignite interest in HIV cure research, and suggest potential mechanisms for a cure. In this review, we highlight some of the obstacles facing HIV cure research today, and explore the roles of gene therapy targeting HIV entry, and allogeneic stem cell transplantation in the development of strategies to cure HIV infection. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
618 KiB  
Review
Passive Immunization against HIV/AIDS by Antibody Gene Transfer
by Lili Yang and Pin Wang
Viruses 2014, 6(2), 428-447; https://doi.org/10.3390/v6020428 - 27 Jan 2014
Cited by 13 | Viewed by 12930
Abstract
Despite tremendous efforts over the course of many years, the quest for an effective HIV vaccine by the classical method of active immunization remains largely elusive. However, two recent studies in mice and macaques have now demonstrated a new strategy designated as Vectored [...] Read more.
Despite tremendous efforts over the course of many years, the quest for an effective HIV vaccine by the classical method of active immunization remains largely elusive. However, two recent studies in mice and macaques have now demonstrated a new strategy designated as Vectored ImmunoProphylaxis (VIP), which involves passive immunization by viral vector-mediated delivery of genes encoding broadly neutralizing antibodies (bnAbs) for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing antibodies. This unorthodox approach raises new promise for combating the ongoing global HIV pandemic. In this article, we survey the status of antibody gene transfer, review the revolutionary progress on isolation of extremely bnAbs, detail VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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455 KiB  
Review
Gene Therapy Strategies to Exploit TRIM Derived Restriction Factors against HIV-1
by Emma Chan, Greg J. Towers and Waseem Qasim
Viruses 2014, 6(1), 243-263; https://doi.org/10.3390/v6010243 - 14 Jan 2014
Cited by 27 | Viewed by 8869
Abstract
Restriction factors are a collection of antiviral proteins that form an important aspect of the innate immune system. Their constitutive expression allows immediate response to viral infection, ahead of other innate or adaptive immune responses. We review the molecular mechanism of restriction for [...] Read more.
Restriction factors are a collection of antiviral proteins that form an important aspect of the innate immune system. Their constitutive expression allows immediate response to viral infection, ahead of other innate or adaptive immune responses. We review the molecular mechanism of restriction for four categories of restriction factors; TRIM5, tetherin, APOBEC3G and SAMHD1 and go on to consider how the TRIM5 and TRIMCyp proteins in particular, show promise for exploitation using gene therapy strategies. Such approaches could form an important alternative to current anti-HIV-1 drug regimens, especially if combined with strategies to eradicate HIV reservoirs. Autologous CD4+ T cells or their haematopoietic stem cell precursors engineered to express TRIMCyp restriction factors, and provided in a single therapeutic intervention could then be used to restore functional immunity with a pool of cells protected against HIV. We consider the challenges ahead and consider how early clinical phase testing may best be achieved. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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705 KiB  
Review
Stem-Cell-Based Gene Therapy for HIV Infection
by Anjie Zhen and Scott Kitchen
Viruses 2014, 6(1), 1-12; https://doi.org/10.3390/v6010001 - 24 Dec 2013
Cited by 25 | Viewed by 11144
Abstract
Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements [...] Read more.
Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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473 KiB  
Review
Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice
by Michael S. Bennett and Ramesh Akkina
Viruses 2013, 5(12), 3119-3141; https://doi.org/10.3390/v5123119 - 12 Dec 2013
Cited by 11 | Viewed by 11560
Abstract
In the absence of an effective vaccine and lack of a complete cure, gene therapy approaches to control HIV infection offer feasible alternatives. Due to the chronic nature of infection, a wide window of opportunity exists to gene modify the HIV susceptible cells [...] Read more.
In the absence of an effective vaccine and lack of a complete cure, gene therapy approaches to control HIV infection offer feasible alternatives. Due to the chronic nature of infection, a wide window of opportunity exists to gene modify the HIV susceptible cells that continuously arise from the bone marrow source. To evaluate promising gene therapy approaches that employ various anti-HIV therapeutic molecules, an ideal animal model is necessary to generate important efficacy and preclinical data. In this regard, the humanized mouse models that harbor human hematopoietic cells susceptible to HIV infection provide a suitable in vivo system. This review summarizes the currently used humanized mouse models and different anti-HIV molecules utilized for conferring HIV resistance. Humanized mouse models are compared for their utility in this context and provide perspectives for new directions. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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531 KiB  
Review
Genetic Modification of Hematopoietic Stem Cells as a Therapy for HIV/AIDS
by Patrick Younan, John Kowalski and Hans-Peter Kiem
Viruses 2013, 5(12), 2946-2962; https://doi.org/10.3390/v5122946 - 28 Nov 2013
Cited by 11 | Viewed by 12180
Abstract
The combination of genetic modification and hematopoietic stem cell (HSC) transplantation may provide the necessary means to develop an alternative treatment option to conventional antiretroviral therapy. As HSCs give rise to all hematopoietic cell types susceptible to HIV infection, modification of HSCs is [...] Read more.
The combination of genetic modification and hematopoietic stem cell (HSC) transplantation may provide the necessary means to develop an alternative treatment option to conventional antiretroviral therapy. As HSCs give rise to all hematopoietic cell types susceptible to HIV infection, modification of HSCs is an ideal strategy for the development of infection-resistant immune cell populations. Although promising results have been obtained in multiple animal models, additional evidence is needed to convincingly demonstrate the feasibility of this approach as a treatment of HIV-1 infected patients. Here, we review the potential of HSC transplantation and the recently identified limitations of this approach. Using the Berlin Patient as a model for a functional cure, we contrast the confines of autologous versus allogeneic transplantation. Finally, we suggest that although autologous, gene-modified HSC-transplantation may significantly reduce plasma viremia, reaching the lower detection limits currently obtainable through daily HAART will remain a challenging endeavor that will require innovative combinatorial therapies. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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559 KiB  
Review
Newer Gene Editing Technologies toward HIV Gene Therapy
by N. Manjunath, Guohua Yi, Ying Dang and Premlata Shankar
Viruses 2013, 5(11), 2748-2766; https://doi.org/10.3390/v5112748 - 14 Nov 2013
Cited by 65 | Viewed by 24802
Abstract
Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a [...] Read more.
Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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477 KiB  
Review
Foamy Virus Vectors for HIV Gene Therapy
by Miles E. Olszko and Grant D. Trobridge
Viruses 2013, 5(10), 2585-2600; https://doi.org/10.3390/v5102585 - 22 Oct 2013
Cited by 16 | Viewed by 8180
Abstract
Highly active antiretroviral therapy (HAART) has vastly improved outcomes for patients infected with HIV, yet it is a lifelong regimen that is expensive and has significant side effects. Retroviral gene therapy is a promising alternative treatment for HIV/AIDS; however, inefficient gene delivery to [...] Read more.
Highly active antiretroviral therapy (HAART) has vastly improved outcomes for patients infected with HIV, yet it is a lifelong regimen that is expensive and has significant side effects. Retroviral gene therapy is a promising alternative treatment for HIV/AIDS; however, inefficient gene delivery to hematopoietic stem cells (HSCs) has so far limited the efficacy of this approach. Foamy virus (FV) vectors are derived from non-pathogenic viruses that are not endemic to the human population. FV vectors have been used to deliver HIV-inhibiting transgenes to human HSCs, and they have several advantages relative to other retroviral vectors. These include an attractive safety profile, broad tropism, a large transgene capacity, and the ability to persist in quiescent cells. In addition, the titers of FV vectors are not reduced by anti-HIV transgenes that affect the production of lentivirus (LV) vectors. Thus FV vectors are very promising for anti-HIV gene therapy. This review covers the advantages of FV vectors and describes their preclinical development for anti-HIV gene therapy. Full article
(This article belongs to the Special Issue Gene Therapy for Retroviral Infections)
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