Restriction of HIV-1-based lentiviral vectors in adult primary marrow-derived and peripheral mobilized human CD34+ hematopoietic stem and progenitor cells occurs prior to viral DNA integration

Griffin, Daniel O.; Goff, Stephen P.

doi:10.1186/s12977-016-0246-0

Cited by 9 publications

(9 citation statements)

References 50 publications

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“…2). Secondly, CD34+ HSPCs have a strong restriction to lentiviruses such as HIV-1 (36,37), making it possible that the transcriptional responses to exogenous RNA in these cells could be stronger than that in other cells. While this may be the case, there appears to be a considerable extent of co-regulation of the genes involved across cell types.…”

Section: Discussionmentioning

confidence: 99%

Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

Nordor¹,

Siwo²

2020

Preprint

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All RNA viruses deliver their genomes into target host cells through processes distinct from normal trafficking of cellular RNA transcripts. The delivery of viral RNA into most cells hence triggers innate antiviral defenses that recognize viral RNA as foreign. In turn, viruses have evolved mechanisms to subvert these defenses, allowing them to thrive in target cells. Therefore, drugs activating defense to foreign or exogenous RNA could serve as broad-spectrum antiviral drugs. Here we show that transcriptional signatures associated with cellular responses to the delivery of a non-viral exogenous RNA sequence into human cells predicts small molecules with broad-spectrum antiviral activity. In particular, transcriptional responses to the delivery of cas9 mRNA into human hematopoietic stem and progenitor cells (HSPCs) highly matches those triggered by small molecules with broad-spectrum antiviral activity such as emetine, homoharringtonine, pyrvinium pamoate and anisomycin, indicating that these drugs are potentially active against other RNA viruses. Furthermore, these drugs have been approved for other indications and could thereby be repurposed to novel viruses. We propose that the antiviral activity of these drugs to SARS-CoV-2 should therefore be determined as they have been shown as active against other coronaviruses including SARS-CoV and MERS-CoV. These drugs could also be explored as potential adjuvants to COVID-19 vaccines in development due to their potential effect on the innate antiviral defenses that could bolster adaptive immunity when delivered alongside vaccine antigens.

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Section: Discussionmentioning

confidence: 99%

Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

Nordor¹,

Siwo²

2020

Preprint

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“…It is known from studying the time course of the replicative cycle of HIV that there is an initial period of time from exposure of a cell to HIV and before there is integration of provirus and production of new detectable HIV virions [ 18 , 19 ]. While initial serological testing left us with a 3 week window from exposure to detection, p24 antigen testing reduced this window and fortunately, the window between exposure and our ability to make the diagnosis is narrowed further through testing for HIV viral RNA and now is possible as soon as and prior to the onset of symptoms of acute disease [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

The diagnosis of symptomatic acute antiretroviral syndrome during the window period with antigen/antibody testing and HIV viral load

Griffin

2018

IDCases

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Despite much focus on moving toward a cure to end the epidemic human immunodeficiency virus (HIV) epidemic there are still thousands of new infections occurring every year in the United States. Although there is ongoing transmission of HIV in the United States and a growing population of people living with HIV, the acute presentation of HIV infection can be challenging to diagnose and is often not considered when patients present to healthcare providers. Although in certain states there are HIV testing laws that require that all persons between the ages of 13 and 64 be offered HIV testing in an opt-out approach, many patient presenting with an acute illness, that would warrant diagnostic testing for HIV, leave without having an HIV test performed for either diagnostic or screening purposes.We describe the case of a woman who presented to medical attention with symptoms later confirmed to be due to acute HIV infection. She was initially discharged from the hospital and only underwent HIV testing with confirmation of her diagnosis after readmission. We describe the algorithm where fourth generation testing combined with HIV viral load testing allowed for the diagnosis of acute HIV prior to the development of a specific immunoglobulin response. Consideration of this diagnosis, improved HIV screening, and understanding of the use of antigen/antibody screening tests, combined with Multispot and HIV viral RNA detection, when appropriate, can allow for early diagnosis of HIV before progression of disease and before undiagnosed patient spread the infection to new contacts.

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“…A number of different approaches have been investigated to understand the basis of the observed limitations to transduction of these cells and improve efficiency. Investigators have exposed CD34+ HSPCs to various chemicals such as Cyclosporin A, Cyclosporin H, Rapamycin, stem cell factor, thrombopoietin, Flt3 ligand, interleukins, proteasome inhibitors and other agents before transduction with various levels of success [4][5][6][7][8][9][10][11][12][13][14].…”

mentioning

confidence: 99%

“…The cells most susceptible to transfection may represent a population subset with distinct abilities to traffic incoming nucleic acids or virion cores within the cytoplasm, into the nucleus, or to suitable locations within the nucleus for proviral integration. These steps are known to be inefficient in HSPCs [4,5]. Close examination of the course of viral intermediates might allow a determination of any specific step in the life cycle that is enhanced in the transfected cells.…”

mentioning

confidence: 99%

“…Our prior work has demonstrated that the most significant block in human CD34+ cells is prior to nuclear entry and similar techniques involving quantitative PCR could be used to better understand the mechanism of this enhancement and the specific impact on various stages in the viral cycle [4,5]. The observation of increased virus susceptibility is critical to both research and clinical applications, because CD34+ cells are widely-utilized targets in both settings.…”

mentioning

confidence: 99%

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Successfully transfected primary peripherally mobilized human CD34+ hematopoietic stem and progenitor cells (HSPCs) demonstrate increased susceptibility to retroviral infection

Sebrow

Goff

Griffin

2020

Virol J

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Transfection, the process of introducing purified nucleic acids into cells, and viral transduction, viral-mediated nucleic acid transfer, are two commonly utilized techniques for gene delivery in the research setting. Transfection allows purified nucleic acid to be introduced into target cells through chemical-based techniques, nonchemical methods or particle-based methods, while viral transduction employs genomes or vectors based on adenoviruses, retroviruses (e.g. lentiviruses), adeno-associated viruses, or hybrid viruses. Transfected DNAs are often tested for potential effects on subsequent transduction, but it is not clear whether transfection itself rather than the particular nucleic acid being introduced might impact subsequent viral transfection. We observed a significant association between successfully transfected mobilized peripheral blood CD34+ human stem and progenitor cells (HSPCs) and permissiveness to subsequent lentiviral transduction, which was not evident in other cells such as 293 T cells and Jurkat cells. This association, apparently specific to CD34+ human stem and progenitor cells (HSPCs), is critical to both research and clinical applications as these cells are a frequent target of transfection and viral transduction owing to the durable nature of these cells in living systems. This finding may also present a significant opportunity to enhance the success of viral transduction for clinical applications.

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Restriction of HIV-1-based lentiviral vectors in adult primary marrow-derived and peripheral mobilized human CD34+ hematopoietic stem and progenitor cells occurs prior to viral DNA integration

Cited by 9 publications

References 50 publications

Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

The diagnosis of symptomatic acute antiretroviral syndrome during the window period with antigen/antibody testing and HIV viral load

Successfully transfected primary peripherally mobilized human CD34+ hematopoietic stem and progenitor cells (HSPCs) demonstrate increased susceptibility to retroviral infection

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