Genetic Strategies for HIV Treatment and Prevention

Falkenhagen, Alexander; Joshi, Sadhna

doi:10.1016/j.omtn.2018.09.018

Cited by 16 publications

(16 citation statements)

References 203 publications

(237 reference statements)

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“…A promising prevention plan, which has been used in a clinical trial, utilizes the cell that is capable of secreting antiviral proteins (AVPs). AVPs have the capability to defend HIV target cells that have not been previously altered [15]. These findings are hopeful because both hematopoietic and non-hematopoietic cells can release AVPs allowing for all cell types to be reached [15].…”

Section: Aids Therapy and Treatmentsmentioning

confidence: 98%

“…AVPs have the capability to defend HIV target cells that have not been previously altered [15]. These findings are hopeful because both hematopoietic and non-hematopoietic cells can release AVPs allowing for all cell types to be reached [15]. A potential treatment for HIV also involves the use of hematopoietic cells, specifically RNA-based hematopoietic cells [16].…”

Section: Aids Therapy and Treatmentsmentioning

confidence: 99%

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Kinases: Understanding Their Role in HIV Infection

Martini

Rahman

Ojegba

et al. 2019

WJA

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Antiviral drugs currently on the market primarily target proteins encoded by specific viruses. The drawback of these drugs is that they lack antiviral mechanisms that account for resistance or viral mutation. Thus, there is a pressing need for researchers to explore and investigate new therapeutic agents with other antiviral strategies. Viruses such as the human immunodeficiency virus (HIV) alter canonical signaling pathways to create a favorable biochemical environment for infectivity. We used Qiagen Ingenuity Pathway Analysis (IPA) software to review the function of several cellular kinases and the resulting perturbed signaling pathways during HIV infection such as NF-κB signaling. These host cellular kinases such as ADK, PKR, MAP3K11 are involved during HIV infection at various stages of the life cycle. Additionally IPA analysis indicated that these modified host cellular kinases are known to have interactions with each other especially AKT1, a serine/threonine kinase involved in multiple pathways. We present a list of cellular host kinases and other proteins that interact with these kinases. This approach to understanding the relationship between HIV infection and kinase activity may introduce new drug targets to arrest HIV infectivity.

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Section: Aids Therapy and Treatmentsmentioning

confidence: 98%

Section: Aids Therapy and Treatmentsmentioning

confidence: 99%

Kinases: Understanding Their Role in HIV Infection

Martini

Rahman

Ojegba

et al. 2019

WJA

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“…Gene therapy holds considerable promise for functional cure of HIV infection, and in this context, genetically engineered HIV-resistant cells represent a powerful strategy which has been proven by the cure of the "Berlin patient" and the "London patient"; these two patients were transplanted with allogeneic hematopoietic stem cells (HSCs) harboring a naturally occurring CCR5Δ32 mutation (3,4). However, such a procedure is not easy to duplicate and thus is not practical for the treatment of a larger population; instead, disruption of CCR5 by gene editing has been extensively explored (5)(6)(7). While CCR5 editing confers resistance to CCR5-tropic (R5) viruses, this strategy would be ineffective for CXCR4-tropic (X4) and dual-tropic (R5X4) viruses.…”

mentioning

confidence: 99%

“…A phase I clinical trial showed that infusion of maC46-modified autologous T cells into HIV-infected patients with advanced disease and HAART failure was well tolerated, with a significant increase of CD4 counts (25). Moreover, maC46 has been explored for combination gene therapy with a short hairpin RNA (shRNA) or a high-affinity P2-CCL5 intrakine to CCR5 (6,(26)(27)(28)(29)(30). Compared to T20, the CHR-derived peptide C34 has more potent anti-HIV activity, and thus, it has been widely used as a template to develop new HIV-1 fusion inhibitors (31).…”

mentioning

confidence: 99%

A Membrane-Anchored Short-Peptide Fusion Inhibitor Fully Protects Target Cells from Infections of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Tang

Jin

Chen

et al. 2019

J Virol

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Emerging studies demonstrate that the antiviral activity of viral fusion inhibitor peptides can be dramatically improved when being chemically or genetically anchored to the cell membrane, where viral entry occurs. We previously reported that the short-peptide fusion inhibitor 2P23 and its lipid derivative possess highly potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). To develop a sterilizing or functional-cure strategy, here we genetically linked 2P23 and two control peptides (HIV-1 fusion inhibitor C34 and hepatitis B virus [HBV] entry inhibitor 4B10) with a glycosylphosphatidylinositol (GPI) attachment signal. As expected, GPI-anchored inhibitors were efficiently expressed on the plasma membrane of transduced TZM-bl cells and primarily directed to the lipid raft site without interfering with the expression of CD4, CCR5, and CXCR4. GPI-anchored 2P23 (GPI-2P23) completely protected TZM-bl cells from infections of divergent HIV-1, HIV-2, and SIV isolates as well as a panel of enfuvirtide (T20)-resistant mutants. GPI-2P23 also rendered the cells resistant to viral envelope-mediated cell-cell fusion and cell-associated virion-mediated cell-cell transmission. Moreover, GPI-2P23-modified human CD4+ T cells (CEMss-CCR5) fully blocked both R5- and X4-tropic HIV-1 isolates and displayed a robust survival advantage over unmodified cells during HIV-1 infection. In contrast, it was found that GPI-anchored C34 was much less effective in inhibiting HIV-2, SIV, and T20-resistant HIV-1 mutants. Therefore, our studies have demonstrated that genetically anchoring a short-peptide fusion inhibitor to the target cell membrane is a viable strategy for gene therapy of both HIV-1 and HIV-2 infections. IMPORTANCE Antiretroviral therapy with multiple drugs in combination can efficiently suppress HIV replication and dramatically reduce the morbidity and mortality associated with AIDS-related illness; however, antiretroviral therapy cannot eradiate the HIV reservoirs, and lifelong treatment is required, which often results in cumulative toxicities, drug resistance, and a multitude of complications, thus necessitating the development of sterilizing-cure or functional-cure strategies. Here, we report that genetically anchoring the short-peptide fusion inhibitor 2P23 to the cell membrane can fully prevent infections from divergent HIV-1, HIV-2, and SIV isolates as well as a panel of enfuvirtide-resistant mutants. Membrane-bound 2P23 also effectively blocks HIV-1 Env-mediated cell-cell fusion and cell-associated virion-mediated cell-cell transmission, renders CD4+ T cells nonpermissive to infection, and confers a robust survival advantage over unmodified cells. Thus, our studies verify a powerful strategy to generate resistant cells for gene therapy of both the HIV-1 and HIV-2 infections.

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“…Anticorps monoclonaux : quand les cellules de l'immunité s'en mêlent musculaires avec des vecteurs viraux, lentivirus et virus adéno-associé, codant un anticorps neutralisant le VIH-1[5]. Une approche ex vivo consisterait, quant à elle, à isoler des cellules souches hématopoïétiques et à les transduire avec un vecteur lentiviral codant le bNAb avant de les réimplanter in vivo[6].…”

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Ingénierie de lymphocytes B humains produisant des anticorps neutralisant le virus VIH-1 par édition génique CRISPR-Cas9

Beretta

Mouquet

2019

Med Sci (Paris)

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Les anticorps (ou immunoglobulines, Ig) produits par les lymphocytes B sont essentiels aux réponses immunitaires induites par les infections et les vaccins. Les anticorps sont des glycoprotéines hétérodimériques résultant de l’association de deux chaînes lourdes (IgH), et de deux chaînes légères (IgL) d’immunoglobuline. Les chaînes IgH et IgL possèdent des régions « hypervariables », également appelées en anglais complementarity determining regions (CDR), situées dans leurs domaines variables, VH et VL, qui, en se combinant, forment le site de liaison à l’antigène ou paratope.

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Genetic Strategies for HIV Treatment and Prevention

Cited by 16 publications

References 203 publications

Kinases: Understanding Their Role in HIV Infection

Kinases: Understanding Their Role in HIV Infection

A Membrane-Anchored Short-Peptide Fusion Inhibitor Fully Protects Target Cells from Infections of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Ingénierie de lymphocytes B humains produisant des anticorps neutralisant le virus VIH-1 par édition génique CRISPR-Cas9

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