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• W2894088295 abstract "Conventional HIV gene therapy approaches are based on engineering HIV target cells that are non-permissive to viral replication. However, expansion of gene-modified HIV target cells has been limited in patients. Alternative genetic strategies focus on generating gene-modified producer cells that secrete antiviral proteins (AVPs). The secreted AVPs interfere with HIV entry, and, therefore, they extend the protection against infection to unmodified HIV target cells. Since any cell type can potentially secrete AVPs, hematopoietic and non-hematopoietic cell lineages can function as producer cells. Secretion of AVPs from non-hematopoietic cells opens the possibility of using a genetic approach for HIV prevention. Another strategy aims at modifying cytotoxic T cells to selectively target and eliminate infected cells. This review provides an overview of the different genetic approaches for HIV treatment and prevention. Conventional HIV gene therapy approaches are based on engineering HIV target cells that are non-permissive to viral replication. However, expansion of gene-modified HIV target cells has been limited in patients. Alternative genetic strategies focus on generating gene-modified producer cells that secrete antiviral proteins (AVPs). The secreted AVPs interfere with HIV entry, and, therefore, they extend the protection against infection to unmodified HIV target cells. Since any cell type can potentially secrete AVPs, hematopoietic and non-hematopoietic cell lineages can function as producer cells. Secretion of AVPs from non-hematopoietic cells opens the possibility of using a genetic approach for HIV prevention. Another strategy aims at modifying cytotoxic T cells to selectively target and eliminate infected cells. This review provides an overview of the different genetic approaches for HIV treatment and prevention. The human immunodeficiency virus type-1 (HIV) is the causative agent of AIDS. Worldwide, over 36.7 million individuals are living with HIV and over 2 million new infections occur annually.1UNAIDS. (2016). Global AIDS update. Joint United Nations Programme on HIV/AIDS. http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf.Google Scholar Drug-based antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) help to manage and prevent HIV infection, respectively. Limitations of ART and PrEP include the need for lifelong adherence, the emergence of drug-resistant virus strains, drug-associated short- and long-term toxicities, the direct costs of the drugs, and the indirect costs such as regular doctor visits. Despite major advances in biomedical research, a cure or reliable vaccine remains elusive. The viral reservoir, a pool of long-lived infected CD4+ T cells and macrophages established during the acute phase of infection, represents a major obstacle to a cure. The reservoir is much larger than initially anticipated, and it is unclear whether complete elimination of the infected cells is possible. The development of an HIV vaccine is hindered by the genetic diversity of HIV and the ability of the virus to evade immune responses. While naturally occurring antibodies with broad and potent HIV neutralization activity have been identified, they only appear in a minority of patients, take years to develop, and contain a high degree of somatic mutations. Therefore, it remains questionable whether such antibodies can be elicited by conventional vaccination strategies. Conventional gene therapy strategies focus on generating an immune system that is resistant to HIV in order to suppress viral replication in the absence of ART. The case of the Berlin patient is generally seen as a proof of principle that replacing a patient’s immune system with genetically resistant cells can result in a functional cure. Timothy Ray Brown was infected with HIV and diagnosed with acute myeloid leukemia. For the treatment of his leukemia, he received five rounds of chemotherapy, two rounds of total-body radiation, two rounds of immunosuppressive therapy, and two allogeneic bone marrow transplants from a donor with a naturally occurring mutation in the CCR5 gene (CCR5Δ32).2Hütter G. Nowak D. Mossner M. Ganepola S. Müssig A. Allers K. Schneider T. Hofmann J. Kücherer C. Blau O. et al.Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.N. Engl. J. Med. 2009; 360: 692-698Crossref PubMed Scopus (1036) Google Scholar After the treatment, his entire immune system was replaced with CCR5-negative donor cells (100% chimerism), and he was cured of HIV and leukemia.3Allers K. Hütter G. Hofmann J. Loddenkemper C. Rieger K. Thiel E. Schneider T. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation.Blood. 2011; 117: 2791-2799Crossref PubMed Scopus (456) Google Scholar However, due to the risks associated with the treatment and the difficulty in finding matched donors with the CCR5Δ32 mutation, this procedure is not amenable for the treatment of a larger population. Using genetic approaches to secrete antiviral proteins (AVPs) that interfere with HIV entry represents an alternative strategy to control HIV replication. Proof of principle that the administration of recombinant AVPs can suppress viral replication has been provided in a clinical trial and in a pre-clinical macaque model. In the clinical trial, twice daily infusions of soluble CD4 (sCD4) resulted in sustained suppression of viremia.4Schacker T. Collier A.C. Coombs R. Unadkat J.D. Fox I. Alam J. Wang J.P. Eggert E. Corey L. Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection.J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 1995; 9: 145-152PubMed Google Scholar In the pre-clinical model, infected animals were infused with a combination of two antibodies. Upon a single administration, viremia was suppressed for 3–5 weeks in chronically infected animals, and subsequent administrations prevented virus rebound.5Shingai M. Nishimura Y. Klein F. Mouquet H. Donau O.K. Plishka R. Buckler-White A. Seaman M. Piatak Jr., M. Lifson J.D. et al.Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia.Nature. 2013; 503: 277-280Crossref PubMed Scopus (291) Google Scholar Since almost any cell type can be modified to secrete AVPs, hematopoietic and non-hematopoietic cells can serve as producer cells for the secreted AVPs. Strategies using gene-modified T cells or hematopoietic stem and/or progenitor cells (HSPCs) require ex vivo gene modification, and they should mainly be used for therapeutic purposes. Liver and muscle are highly vascularized and can be directly modified in vivo. Since in vivo gene modification is non-invasive and less complex than ex vivo gene therapy, liver- or muscle-directed genetic modification could be used for therapy and prevention. Another approach to control HIV replication focuses on engineering CD8+ T cells that can recognize and kill infected cells. While initial clinical trials were disappointing, the recent successes of modifying CD8+ T cells to kill cancer cells have rekindled the interest in using retargeted CD8+ T cells to eliminate HIV-positive cells. This review provides an overview of the different genetic approaches. Conventional HIV gene therapy approaches focus on rendering HIV target cells non-permissive to viral replication. To this end, CD4+ T cells or CD34+ HSPCs are extracted from a patient, genetically modified ex vivo to express one or multiple antiviral genes, and infused into the same patient (Figure 1A). HSPCs are usually not infected by HIV, but they give rise to lymphoid progenitors that migrate from the bone marrow to the thymus, where T cell differentiation and thymic education occur. The de novo development of T cells predominantly takes place before adolescence. In adults, the size of the thymus is decreased and the contribution of HSPCs to T cell homeostasis declines. Instead, T cell numbers are largely maintained through the division of T cells outside of the central lymphoid organs, such as CD4+ stem memory T cells (TSCMs). However, thymic output increases again in the first year after an HSPC transplant, resulting in the production of T cells with a new T cell receptor (TCR) repertoire. Therefore, gene-modified HSPCs and CD4+ T cells have the potential to give rise to new gene-modified HIV target cells. Following infusion, mixed populations of gene-modified and unmodified cells coexist in the patient. Ideally, the gene-modified HIV target cells would have a survival advantage over unmodified cells and replace the unmodified HIV target cell population over time, resulting in an immune system that is resistant to HIV (Figure 1B). The antiviral gene products tested to date can generally be classified into RNA-based and protein-based therapeutics. They interfere with various stages of the HIV replication cycle by targeting viral factors or by targeting cellular factors that are essential for viral replication but dispensable for the host (Figure 1C). The steps of HIV entry are receptor binding, co-receptor binding, and membrane fusion. CD4 serves as the receptor, while CXCR4 or CCR5 usually function as a co-receptor. Receptor binding and co-receptor binding are mediated by the HIV envelope (Env) protein gp120, which is difficult to target because of its high variability and the inaccessibility of conserved sites within gp120. Targeting the receptor, CD4, also proves difficult due to the central role CD4 plays in the immune system. Similarly, CXCR4 is essential during embryonic development and plays an important role in the tissue recruitment of immune cells in adults.6Chatterjee S. Behnam Azad B. Nimmagadda S. The intricate role of CXCR4 in cancer.Adv. Cancer Res. 2014; 124: 31-82Crossref PubMed Scopus (189) Google Scholar However, individuals born with a naturally occurring mutation in the CCR5 gene (CCR5Δ32) are apparently healthy.7Samson M. Libert F. Doranz B.J. Rucker J. Liesnard C. Farber C.M. Saragosti S. Lapoumeroulie C. Cognaux J. Forceille C. et al.Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.Nature. 1996; 382: 722-725Crossref PubMed Scopus (2273) Google Scholar Consequently, multiple approaches have been developed to reduce CCR5 on the surface of HIV target cells. Cytokines and antibody derivatives with endoplasmic reticulum retention signal (intrakines and intrabodies, respectively) were designed to retain CCR5 inside gene-modified cells.8Yang A.G. Bai X. Huang X.F. Yao C. Chen S. Phenotypic knockout of HIV type 1 chemokine coreceptor CCR-5 by intrakines as potential therapeutic approach for HIV-1 infection.Proc. Natl. Acad. Sci. USA. 1997; 94: 11567-11572Crossref PubMed Scopus (92) Google Scholar, 9Yang A.G. Zhang X. Torti F. Chen S.Y. Anti-HIV type 1 activity of wild-type and functional defective RANTES intrakine in primary human lymphocytes.Hum. Gene Ther. 1998; 9: 2005-2018Crossref PubMed Google Scholar, 10Schroers R. Davis C.M. Wagner H.J. Chen S.Y. Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection.Gene Ther. 2002; 9: 889-897Crossref PubMed Scopus (34) Google Scholar, 11Swan C.H. Bühler B. Steinberger P. Tschan M.P. Barbas 3rd, C.F. Torbett B.E. T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery.Gene Ther. 2006; 13: 1480-1492Crossref PubMed Scopus (70) Google Scholar Ribozymes and small hairpin RNAs (shRNAs) have been utilized to target CCR5 mRNA,12Nazari R. Ma X.Z. Joshi S. Inhibition of human immunodeficiency virus-1 entry using vectors expressing a multimeric hammerhead ribozyme targeting the CCR5 mRNA.J. Gen. Virol. 2008; 89: 2252-2261Crossref PubMed Scopus (18) Google Scholar, 13Bai J. Gorantla S. Banda N. Cagnon L. Rossi J. Akkina R. Characterization of anti-CCR5 ribozyme-transduced CD34+ hematopoietic progenitor cells in vitro and in a SCID-hu mouse model in vivo.Mol. Ther. 2000; 1: 244-254Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 14Shimizu S. Kamata M. Kittipongdaja P. Chen K.N. Kim S. Pang S. Boyer J. Qin F.X. An D.S. Chen I.S. Characterization of a potent non-cytotoxic shRNA directed to the HIV-1 co-receptor CCR5.Genet. Vaccines Ther. 2009; 7: 8Crossref PubMed Scopus (33) Google Scholar, 15Anderson J.S. Walker J. Nolta J.A. Bauer G. Specific transduction of HIV-susceptible cells for CCR5 knockdown and resistance to HIV infection: a novel method for targeted gene therapy and intracellular immunization.J. Acquir. Immune Defic. Syndr. 2009; 52: 152-161Crossref PubMed Scopus (30) Google Scholar while genome-editing enzymes, such as zinc-finger nucleases (ZFNs),16Holt N. Wang J. Kim K. Friedman G. Wang X. Taupin V. Crooks G.M. Kohn D.B. Gregory P.D. Holmes M.C. Cannon P.M. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo.Nat. Biotechnol. 2010; 28: 839-847Crossref PubMed Scopus (501) Google Scholar, 17Perez E.E. Wang J. Miller J.C. Jouvenot Y. Kim K.A. Liu O. Wang N. Lee G. Bartsevich V.V. Lee Y.L. et al.Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases.Nat. Biotechnol. 2008; 26: 808-816Crossref PubMed Scopus (718) Google Scholar transcription activator-like effector nucleases (TALENs),18Mock U. Machowicz R. Hauber I. Horn S. Abramowski P. Berdien B. Hauber J. Fehse B. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5.Nucleic Acids Res. 2015; 43: 5560-5571Crossref PubMed Scopus (61) Google Scholar, 19Benjamin R. Berges B.K. Solis-Leal A. Igbinedion O. Strong C.L. Schiller M.R. TALEN gene editing takes aim on HIV.Hum. Genet. 2016; 135: 1059-1070Crossref PubMed Scopus (4) Google Scholar and CRISPR-associated protein-9 nuclease (Cas9) have been employed to introduce mutations into the CCR5 gene.20Cho S.W. Kim S. Kim J.M. Kim J.S. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease.Nat. Biotechnol. 2013; 31: 230-232Crossref PubMed Scopus (1034) Google Scholar, 21Kang H. Minder P. Park M.A. Mesquitta W.T. Torbett B.E. Slukvin I.I. CCR5 Disruption in Induced Pluripotent Stem Cells Using CRISPR/Cas9 Provides Selective Resistance of Immune Cells to CCR5-tropic HIV-1 Virus.Mol. Ther. Nucleic Acids. 2015; 4: e268Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 22Xu L. Yang H. Gao Y. Chen Z. Xie L. Liu Y. Liu Y. Wang X. Li H. Lai W. et al.CRISPR/Cas9-Mediated CCR5 Ablation in Human Hematopoietic Stem/Progenitor Cells Confers HIV-1 Resistance In Vivo.Mol. Ther. 2017; 25: 1782-1789Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Following engagement of CD4 and the co-receptor, HIV Env gp41 facilitates the fusion of the viral and cellular membranes. In the absence of target cell binding, gp41 is not accessible because it is shielded by gp120.23Wei X. Decker J.M. Wang S. Hui H. Kappes J.C. Wu X. Salazar-Gonzalez J.F. Salazar M.G. Kilby J.M. Saag M.S. et al.Antibody neutralization and escape by HIV-1.Nature. 2003; 422: 307-312Crossref PubMed Scopus (1752) Google Scholar, 24Stewart-Jones G.B. Soto C. Lemmin T. Chuang G.Y. Druz A. Kong R. Thomas P.V. Wagh K. Zhou T. Behrens A.J. et al.Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.Cell. 2016; 165: 813-826Abstract Full Text Full Text PDF PubMed Google Scholar It contains highly conserved sequences, such as the heptad repeats.25Chan D.C. Fass D. Berger J.M. Kim P.S. Core structure of gp41 from the HIV envelope glycoprotein.Cell. 1997; 89: 263-273Abstract Full Text Full Text PDF PubMed Google Scholar, 26Holguín A. De Arellano E.R. Soriano V. Amino acid conservation in the gp41 transmembrane protein and natural polymorphisms associated with enfuvirtide resistance across HIV-1 variants.AIDS Res. Hum. Retroviruses. 2007; 23: 1067-1074Crossref PubMed Scopus (0) Google Scholar The membrane-associated fusion inhibitor C46 (maC46) comprises a transmembrane domain and a short peptide derived from the heptad repeat 2 of gp41. Expression of the gene encoding maC46 results in high concentrations of maC46 on the surface of gene-modified cells, where it binds to the heptad repeat 1 of gp41, thereby locking gp41 in a fusion inactive state.27Melikyan G.B. Egelhofer M. von Laer D. Membrane-anchored inhibitory peptides capture human immunodeficiency virus type 1 gp41 conformations that engage the target membrane prior to fusion.J. Virol. 2006; 80: 3249-3258Crossref PubMed Scopus (45) Google Scholar In a similar approach, the fusion inhibitor C34 was fused to CXCR4 (C34-CXCR4).28Leslie G.J. Wang J. Richardson M.W. Haggarty B.S. Hua K.L. Duong J. Secreto A.J. Jordon A.P. Romano J. Kumar K.E. et al.Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.PLoS Pathog. 2016; 12: e1005983Crossref PubMed Scopus (0) Google Scholar Although C34-CXCR4 confers protection to gene-modified HIV target cells, it is not clear to what extent expression of CXCR4 affects the natural function of these cells. Once entry takes place, the viral capsid proteins are lost in the cytoplasm of host cells, a process that is defined as uncoating. The alpha isoform of tripartite motif-containing protein 5 (TRIM5α) is a natural retrovirus restriction factor, and it inhibits uncoating of retroviruses by interacting with the capsid proteins.29Grütter M.G. Luban J. TRIM5 structure, HIV-1 capsid recognition, and innate immune signaling.Curr. Opin. Virol. 2012; 2: 142-150Crossref PubMed Scopus (62) Google Scholar While human TRIM5α is ineffective against HIV, rhesus macaque TRIM5α efficiently protects cells from HIV infection.30Sayah D.M. Sokolskaja E. Berthoux L. Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1.Nature. 2004; 430: 569-573Crossref PubMed Scopus (493) Google Scholar, 31Stremlau M. Owens C.M. Perron M.J. Kiessling M. Autissier P. Sodroski J. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.Nature. 2004; 427: 848-853Crossref PubMed Scopus (1344) Google Scholar Expression of a chimeric human and rhesus macaque TRIM5α has been shown to protect HIV target cells from infection.32Anderson J. Akkina R. Human immunodeficiency virus type 1 restriction by human-rhesus chimeric tripartite motif 5alpha (TRIM 5alpha) in CD34(+) cell-derived macrophages in vitro and in T cells in vivo in severe combined immunodeficient (SCID-hu) mice transplanted with human fetal tissue.Hum. Gene Ther. 2008; 19: 217-228Crossref PubMed Scopus (0) Google Scholar, 33Anderson J.S. Javien J. Nolta J.A. Bauer G. Preintegration HIV-1 inhibition by a combination lentiviral vector containing a chimeric TRIM5 alpha protein, a CCR5 shRNA, and a TAR decoy.Mol. Ther. 2009; 17: 2103-2114Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Following uncoating and reverse transcription, the HIV genome integrates into transcriptionally active sites of host chromosomes. Recently, an RNA aptamer has been identified that targets the HIV integrase.34Pang K.M. Castanotto D. Li H. Scherer L. Rossi J.J. Incorporation of aptamers in the terminal loop of shRNAs yields an effective and novel combinatorial targeting strategy.Nucleic Acids Res. 2018; 46: e6Crossref PubMed Google Scholar Aptamers are short DNA or RNA oligonucleotides with a stable three-dimensional conformation that enables them to bind to molecular targets with high specificity and affinity. In an elegant approach, the integrase-targeting RNA aptamer, incorporated as the terminal loop of an shRNA, was expressed by gene-modified HIV target cells, and it inhibited HIV replication in cell cultures.34Pang K.M. Castanotto D. Li H. Scherer L. Rossi J.J. Incorporation of aptamers in the terminal loop of shRNAs yields an effective and novel combinatorial targeting strategy.Nucleic Acids Res. 2018; 46: e6Crossref PubMed Google Scholar Other approaches have focused on inhibiting HIV gene expression in infected cells. The two HIV regulatory proteins, transactivator of transcription (Tat) and regulator of expression of virion proteins (Rev), have been targeted because they are expressed early during replication and are essential for viral gene expression. Tat interacts with the transactivation response (TAR) element present at the 5-prime end of nascent HIV transcripts and greatly enhances transcription of the integrated HIV genome,35Kao S.Y. Calman A.F. Luciw P.A. Peterlin B.M. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product.Nature. 1987; 330: 489-493Crossref PubMed Google Scholar, 36Feng S. Holland E.C. HIV-1 tat trans-activation requires the loop sequence within tar.Nature. 1988; 334: 165-167Crossref PubMed Google Scholar while Rev binds to the Rev response element (RRE) of unspliced and singly spliced HIV mRNAs and promotes their export from the nucleus to the cytoplasm.37Felber B.K. Hadzopoulou-Cladaras M. Cladaras C. Copeland T. Pavlakis G.N. rev protein of human immunodeficiency virus type 1 affects the stability and transport of the viral mRNA.Proc. Natl. Acad. Sci. USA. 1989; 86: 1495-1499Crossref PubMed Google Scholar Ribozymes and shRNAs have been designed to target a site in the overlapping open reading frames of tat and rev RNA.38Michienzi A. Castanotto D. Lee N. Li S. Zaia J.A. Rossi J.J. RNA-mediated inhibition of HIV in a gene therapy setting.Ann. N Y Acad. Sci. 2003; 1002: 63-71Crossref PubMed Scopus (0) Google Scholar, 39DiGiusto D.L. Krishnan A. Li L. Li H. Li S. Rao A. Mi S. Yam P. Stinson S. Kalos M. et al.RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma.Sci. Transl. Med. 2010; 2: 36ra43Crossref PubMed Scopus (290) Google Scholar TAR and RRE decoy RNAs mimic their natural counterpart and act by occupying the RNA-binding sites of Tat and Rev.39DiGiusto D.L. Krishnan A. Li L. Li H. Li S. Rao A. Mi S. Yam P. Stinson S. Kalos M. et al.RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma.Sci. Transl. Med. 2010; 2: 36ra43Crossref PubMed Scopus (290) Google Scholar, 40Kohn D.B. Bauer G. Rice C.R. Rothschild J.C. Carbonaro D.A. Valdez P. Hao Ql. Zhou C. Bahner I. Kearns K. et al.A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children.Blood. 1999; 94: 368-371Crossref PubMed Google Scholar Additionally, trans-dominant negative Rev mutant proteins, e.g., RevM10, have been used to disrupt Rev function by binding and inactivating the wild-type protein.41Woffendin C. Ranga U. Yang Z. Xu L. Nabel G.J. Expression of a protective gene-prolongs survival of T cells in human immunodeficiency virus-infected patients.Proc. Natl. Acad. Sci. 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Mascola J.R. et al.Gene transfer in humans using a conditionally replicating lentiviral vector.Proc. Natl. Acad. Sci. USA. 2006; 103: 17372-17377Crossref PubMed Scopus (383) Google Scholar The enzyme double-stranded RNA (dsRNA)-dependent adenosine deaminase recognizes the dsRNA complexes and converts adenosines to inosines, which are recognized as guanines and thus cause mutations.45George C.X. Gan Z. Liu Y. Samuel C.E. Adenosine deaminases acting on RNA, RNA editing, and interferon action.J. Interferon Cytokine Res. 2011; 31: 99-117Crossref PubMed Scopus (0) Google Scholar Infection of cells expressing the env antisense RNAs (VRX496) results in the accumulation of mutations in HIV Env proteins and the production of severely attenuated progeny viruses.44Levine B.L. Humeau L.M. Boyer J. MacGregor R.R. Rebello T. Lu X. Binder G.K. Slepushkin V. Lemiale F. Mascola J.R. et al.Gene transfer in humans using a conditionally replicating lentiviral vector.Proc. Natl. Acad. Sci. USA. 2006; 103: 17372-17377Crossref PubMed Scopus (383) Google Scholar MazF is an endoribonuclease derived from Escherichia coli that cleaves adenine-cytosine-adenine (ACA) in single-stranded RNA. While MazF is not specific for HIV, HIV transcripts are rich in ACA sequences, and MazF expression has been shown to reduce HIV infection in target cells.46Okamoto M. Chono H. Kawano Y. Saito N. Tsuda H. Inoue K. Kato I. Mineno J. Baba M. Sustained inhibition of HIV-1 replication by conditional expression of the E. coli-derived endoribonuclease MazF in CD4+ T cells.Hum. Gene Ther. Methods. 2013; 24: 94-103Crossref PubMed Scopus (0) Google Scholar In a different approach, a recombinase has been developed that recognizes a conserved region in the long terminal repeats (LTRs) located on either side of the provirus DNA. The recombinase excises the provirus from the gene-modified HIV-infected cells, thereby curing them from infection.47Karpinski J. Hauber I. Chemnitz J. Schäfer C. Paszkowski-Rogacz M. Chakraborty D. Beschorner N. Hofmann-Sieber H. Lange U.C. Grundhoff A. et al.Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity.Nat. Biotechnol. 2016; 34: 401-409Crossref PubMed Scopus (0) Google Scholar Similarly, the CRISPR/Cas9 system has been used to excise HIV provirus DNA from infected cells.48Ebina H. Misawa N. Kanemura Y. Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus.Sci. Rep. 2013; 3: 2510Crossref PubMed Scopus (272) Google Scholar However, HIV was shown to rapidly develop resistance to excision by Cas9.49Wang Z. Pan Q. Gendron P. Zhu W. Guo F. Cen S. Wainberg M.A. Liang C. CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape.Cell Rep. 2016; 15: 481-489Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 50Wang G. Zhao N. Berkhout B. Das A.T. CRISPR-Cas9 Can Inhibit HIV-1 Replication but NHEJ Repair Facilitates Virus Escape.Mol. Ther. 2016; 24: 522-526Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar The high mutation rate of HIV is indeed a major challenge for HIV gene therapies, as the antiviral gene products must confer lifelong protection to HIV target cells. While CCR5 is a cellular target with a low chance to mutate, HIV can switch co-receptor usage from CCR5 to CXCR4,51Hoffmann C. The epidemiology of HIV coreceptor tropism.Eur. J. Med. Res. 2007; 12: 385-390PubMed Google Scholar and half of all circulating HIV isolates are capable of utilizing CXCR4 as a co-receptor. One possibility to prevent escape from inhibition is to combine different antiviral genes, similar to combination ART. For example, a vector encoding the tat/rev shRNA, a TAR decoy RNA, and a CCR5 ribozyme (rHIV7-shI-TAR-CCR5RZ) has been developed to inhibit HIV entry and gene expression,39DiGiusto D.L. Krishnan A. Li L. Li H. Li S. Rao A. Mi S. Yam P. Stinson S. Kalos M. et al.RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma.Sci. Transl. Med. 2010; 2: 36ra43Crossref PubMed Scopus (290) Google Scholar while a vector encoding maC46 and a CCR5 shRNA (Cal-1) has been designed to inhibit two different steps of entry.52Wolstein O. Boyd M. Millington M. Impey H. Boyer J. Howe A. Delebecque F. Cornetta K. Rothe M. Baum C. et al.Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.Mol. Ther. Methods Clin. Dev. 2014; 1: 11Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Based on promising results obtained in vitro, several antiviral genes advanced to testing in clinical trials (Table 1). All clinical trials completed to date have shown that the approaches are safe and that long-term engraftment of gene-modified cells can be achieved in patients. In some trials, modest clinical benefits were documented. For example, a trend toward a lower viral load was observed in patients receiving infusions of T cells modified to express the antisense RNA VRX496.53Tebas P. Stein D. Binder-Scholl G. Mukherjee R. Brady T. Rebello T. Humeau L. Kalos M. Papasavvas E. Montaner L.J. et al.Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.Blood. 2013; 121: 1524-1533Crossref PubMed Scopus (55) Google Scholar While antisense-mediated genetic pressure on HIV was demonstrated, no enrichment of gene-modified cells occurred.53Tebas P. Stein D. Binder-Scholl G. Mukherjee R. Brady T. Rebello T. Humeau L. Kalos M. Papasavvas E. Montaner L.J. et al.Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.Blood. 2013; 121: 1524-1533Crossref PubMed Scopus (55) Google Scholar Other trials have reported a modest survival advantage for g" @default.
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• W2894088295 creator A5052985547 @default.
• W2894088295 creator A5064611185 @default.
• W2894088295 date "2018-12-01" @default.
• W2894088295 modified "2023-10-01" @default.
• W2894088295 title "Genetic Strategies for HIV Treatment and Prevention" @default.
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