scholarly journals Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1

2007 ◽  
Vol 204 (4) ◽  
pp. 705-714 ◽  
Author(s):  
Zhifeng Sun ◽  
Paul W. Denton ◽  
Jacob D. Estes ◽  
Florence A. Othieno ◽  
Bangdong L. Wei ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Hiv Transmission ◽  
Human Lymphocytes ◽  
Systemic Infection ◽  
Developed Countries ◽  
Humanized Mice ◽  
Hematopoietic Stem ◽  
Hiv 1

Intrarectal infection between men who have sex with men represents a predominant form of human immunodeficiency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate that human lymphocytes generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract of humanized mice with human CD4+ T cells rendering them susceptible to intrarectal HIV transmission. HIV infection after a single intrarectal inoculation results in systemic infection with depletion of CD4+ T cells in gut-associated lymphoid tissue and other pathologic sequela that closely mimics those observed in HIV infected humans. This novel model provides the basis for the development and evaluation of novel approaches aimed at immune reconstitution of human gut-associated lymphoid tissue and for the development, testing, and implementation of microbicides to prevent intrarectal HIV-1 transmission.

scholarly journals Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells

Cell Reports ◽  
2015 ◽  
Vol 12 (10) ◽  
pp. 1555-1563 ◽  
Author(s):  
Nicole L.K. Galloway ◽  
Gilad Doitsh ◽  
Kathryn M. Monroe ◽  
Zhiyuan Yang ◽  
Isa Muñoz-Arias ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Cell Transmission ◽  
Hiv 1

scholarly journals SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue

2018 ◽  
Vol 14 (8) ◽  
pp. e1007269 ◽  
Author(s):  
Dorota Kmiec ◽  
Bengisu Akbil ◽  
Swetha Ananth ◽  
Dominik Hotter ◽  
Konstantin M. J. Sparrer ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Proteasomal Degradation ◽  
Hiv 1

scholarly journals HIV-1–induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 699-704 ◽  
Author(s):  
Angélique Biancotto ◽  
Sarah J. Iglehart ◽  
Christophe Vanpouille ◽  
Cristian E. Condack ◽  
Andrea Lisco ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Lymphoid Tissues ◽  
Strong Positive Correlation ◽  
New Targets ◽  
Hla Dr ◽  
Human Lymphoid Tissue ◽  
Hiv 1

We demonstrate mechanisms by which HIV-1 appears to facilitate its own infection in ex vivo–infected human lymphoid tissue. In this system, HIV-1 readily infects various CD4+ T cells, but productive viral infection was supported predominantly by activated T cells expressing either CD25 or HLA-DR or both (CD25/HLA-DR) but not other activation markers: There was a strong positive correlation (r = 0.64, P = .001) between virus production and the number of CD25+/HLA-DR+ T cells. HIV-1 infection of lymphoid tissue was associated with activation of both HIV-1–infected and uninfected (bystanders) T cells. In these tissues, apoptosis was selectively increased in T cells expressing CD25/HLA-DR and p24gag but not in cells expressing either of these markers alone. In the course of HIV-1 infection, there was a significant increase in the number of activated (CD25+/HLA-DR+) T cells both infected and uninfected (bystander). By inducing T cells to express particular markers of activation that create new targets for infection, HIV-1 generates in ex vivo lymphoid tissues a vicious destructive circle of activation and infection. In vivo, such self-perpetuating cycle could contribute to HIV-1 disease.

scholarly journals Lentivector Knockdown of CCR5 in Hematopoietic Stem and Progenitor Cells Confers Functional and Persistent HIV-1 Resistance in Humanized Mice

2015 ◽  
Vol 89 (13) ◽  
pp. 6761-6772 ◽  
Author(s):  
Renier Myburgh ◽  
Sandra Ivic ◽  
Michael S. Pepper ◽  
Gustavo Gers-Huber ◽  
Duo Li ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Immune System ◽  
Humanized Mice ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Hiv 1 ◽  
Selection Of

ABSTRACTGene-engineered CD34+hematopoietic stem and progenitor cells (HSPCs) can be used to generate an HIV-1-resistant immune system. However, a certain threshold of transduced HSPCs might be required for transplantation into mice for creating an HIV-resistant immune system. In this study, we combined CCR5 knockdown by a highly efficient microRNA (miRNA) lentivector with pretransplantation selection of transduced HSPCs to obtain a rather pure population of gene engineered CD34+cells. Low-level transduction of HSPCs and subsequent sorting by flow cytometry yielded >70% transduced cells. Mice transplanted with these cells showed functional and persistent resistance to a CCR5-tropic HIV strain: viral load was significantly decreased over months, and human CD4+T cells were preserved. In one mouse, viral mutations, resulting presumably in a CXCR4-tropic strain, overcame HIV resistance. Our results suggest that HSPC-based CCR5 knockdown may lead to efficient control of HIVin vivo. We overcame a major limitation of previous HIV gene therapy in humanized mice in which only a proportion of the cells in chimeric micein vivoare anti-HIV engineered. Our strategy underlines the promising future of gene engineering HIV-resistant CD34+cells that produce a constant supply of HIV-resistant progeny.IMPORTANCEMajor issues in experimental long-termin vivoHIV gene therapy have been (i) low efficacy of cell transduction at the time of transplantation and (ii) transduction resulting in multiple copies of heterologous DNA in target cells. In this study, we demonstrated the efficacy of a transplantation approach with a selection step for transduced cells that allows transplantation of an enriched population of HSPCs expressing a single (low) copy of a CCR5 miRNA. Efficient maintenance of CD4+T cells and a low viral titer resulted only when at least 70% of the HIV target cells were genetically modified. These findings imply that clinical protocols of HIV gene therapy require a selective enrichment of genetically targeted cells because positive selection of modified cells is likely to be insufficient below this threshold. This selection approach may be beneficial not only for HIV patients but also for other patients requiring transplantation of genetically modified cells.

scholarly journals Optimizing CD4+ T-Cells Transduction Protocol for Gene Therapy of HIV-1 Infected Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4429-4429
Author(s):  
Amani Ouedrani ◽  
Lounes Djerroudi ◽  
Isabelle Hmitou ◽  
Marina Cavazzana ◽  
Fabien Touzot
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Effector Memory ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Hiv 1

Abstract Gene therapy represents an alternative and promising strategy that could provide a path to a curative therapy for HIV-1 infection. One approach involves the introduction of protective gene into a cell, thereby conferring protection against HIV. We plan to conduct an open label phase I/II gene therapy trial for HIV-1 infected patients presenting with lymphoma. The patients will received autologous hematopoietic stem cells transplantation with gene modified CD34+ cells and CD4+ T-cells. CD34+ and CD4+ will be ex vivo transduced by the LVsh5/C46 lentiviral vector (Cal-1, Calimmune, Inc. Tucson, USA). LVsh5/C46 is a SIN lentiviral vector that inhibits two crucial steps of CD4+ T cell infection by the HIV virus: (i) attachment of the virus to its target by downregulation of CCR5 via a short hairpin RNA, (ii) fusion of the virus to the target cell through expression of the C46 inhibitor. We developed a transduction process for CD4+ T-cells using the TransAct™ reagent (Miltenyi Biotec, Bergisch Gladbach , Germany) for CD4+ T-cells activation. Compared to previously published T-cells transduction protocols, the use of Miltenyi TransAct™ permits an equivalent efficacy of transduction - evaluated by measurement of vector copy number through quantitative PCR - without major phenotypic modification. Indeed, CD4+ T-cells ex vivo transduced after activation with the TransAct™ reagent display very few changes in their surface marker with conservation of naive (CCR7+CD62L+CD45RA+), central memory (CCR7+CD62L+CD45RA-) and effector memory (CCR7-CD62L-CD45RA-) subsets in superimposable proportions as initially. Moreover, expression of CD25 remains below 15-25% of cells suggesting a more "gentle " activation of the transduced CD4+ T-cells. Our transduction process had no significant impact in TCRβ repertoire diversity as evaluated by high-throughput sequencing and analyzis of diversity through the Gini-Simpson index or the Shannon index. Finally, transduced CD4 + T-cells retained the ability to to be primed towards the TH1, TH2 and TH17 pathways suggesting that the transduction protocol used did not alter the functional properties of the target cells. Disclosures No relevant conflicts of interest to declare.

F-103 Cell-to-cell transmission of HIV-1 is required to trigger pyroptotic death of CD4 T cells in lymphoid tissue

2014 ◽  
Vol 67 ◽  
pp. 63
Author(s):  
Warner Greene ◽  
Nicole Galloway ◽  
Gilad Doitsh ◽  
Xin Geng ◽  
Zhiyuan Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Cell Transmission ◽  
Hiv 1
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