Identification of therapeutic agents for HIV infection

a technology for hiv infection and which is applied in the field of identification of therapeutic agents, can solve the problems that the role of dcir has not yet been fully understood

Inactive Publication Date: 2010-03-11
UNIV LAVAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]It has been shown herein that cells expressing DCIR at the their surface become more readily infected by HIV or transfer HIV particles to CD4+ cells in a more efficient manner.

Problems solved by technology

But the role of DCIR has not yet been fully understood.

Method used

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  • Identification of therapeutic agents for HIV infection
  • Identification of therapeutic agents for HIV infection
  • Identification of therapeutic agents for HIV infection

Examples

Experimental program
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Effect test

example 1

DCIR is Expressed on IM-MDDC

[0176]A previous study has demonstrated that DCIR is expressed by all circulating CD14+ monocytes, in DC derived from CD34+ cord blood progenitors as well as on the surface of DC generated in vitro upon culturing blood monocytes with GM-CSF and IL-4 (i.e. immature monocyte-derived DC or IM-MDDC) 7. This last observation is of high importance because IM-MDDC are routinely used as an experimental cell system to study characteristics of mucosal myeloid DC and to define the complexity of interactions between DC and HIV-1 8. To confirm that DCIR expression is maintained in IM-MDDC, cell surface expression of DCIR was determined by immunofluorescence staining and flow cytometric analysis.

[0177]Purified monocytes were cultured with GM-CSF and IL-4 for 7 days to derive IM-MDDC. DCIR expression was determined by flow cytometry analysis after staining with a commercial PE-conjugated anti-DCIR monoclonal Ab. Expression of DCIR is shown in FIG. 1 as a dotted line whe...

example 2

Role of DCIR in HIV-1 Uptake by IM-MDDC and Infection-siRNA Studies

[0179]In order to evaluate the potential role of DCIR in HIV infection, we used a first strategy, namely RNA interference (i.e. small interfering RNA or siRNA) to reduce DCIR expression in IM-MDDC. For the virus transfer assay, IM-MDDC were intentionally exposed to low doses of virions to better reflect the events occurring during mucosal transmission in vivo. Moreover, all virus stocks used in transmission assays were produced upon acute infection of primary human cells (i.e. PBMCs) to more closely parallel the natural microenvironment.

[0180]We thus employed RNA interference to reduce DCIR expression in IM-MDDC and analyzed the possible effect on HIV-1 transfer. IM-MDDC were either left untreated (control), transfected with a control siRNA, or transfected with a DCIR-specific siRNA. After 40 hrs, flow cytometry analysis of DCIR was performed using a combination of PE-labelled anti-DCIR and isotype-matched control Ab...

example 3

DCIR is Involved in Trans- and Cis-Infection Pathways

[0184]Previously published data demonstrated that HIV-1 is transferred from DC to CD4+ T cells through both trans- and cis-infection pathways 9. Experiments were therefore carried out to define whether DCIR can contribute to HIV-1 dissemination via trans- and / or cis-infection processes. To solve this issue, virus transfer studies were performed using IM-MDDC that were initially transfected with the DCIR-specific siRNA and also treated with EFV, a non-nucleoside reverse transcriptase inhibitor. This antiretroviral compound hampers the late transfer (i.e. de novo virus production by IM-MDDC or cis-infection pathway) without affecting the early transfer mode (i.e. trans-infection pathway).

[0185]In FIG. 4A, IM-MDDC (1×106 cells) were treated with Oligofectamine and then either left untreated (control) or exposed to a non-specific siRNA and a DCIR-specific siRNA. Next, cells were either left untreated or treated with EFV. IM-MDDC (2×10...

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Abstract

A cell surface molecule designated DCIR (for dendritic cells ImmunoReceptor), a member of a recently described family of DC-expressing C-type lectin receptors, has been shown to participate to the capture of human immunodeficiency virus (HIV) and promote infection in trans and in cis of autologous CD4(+) T cells from human immature monocyte-derived DC. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Therapeutic agents for HIV infection are therefore provided herein. These therapeutic agents are useful for impairing the interaction between DCIR and HIV and as such may be useful for treatment or prevention of HIV infection. Also provided are assays for identifying additional therapeutics agents for treatment or prevention HIV infection.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the identification of therapeutic agents to prevent and / or control HIV infection. More particularly, the present invention relates to compounds and their use for impairing the interaction between a C-type lectin designated dendritic cell immunoreceptor (DCIR) and human immunodeficiency virus (HIV). These compounds may be particularly useful in the treatment or prevention of HIV infection.BACKGROUND OF THE INVENTION[0002]Dendritic cells (DCs) play a pivotal role in the establishment and dissemination of human immunodeficiency virus type 1 (HIV-1) infection as well as in the development of a virus-specific immune response. The involvement of this cell type in the overall pathogenesis of the disease was described soon after the discovery of this retrovirus, but its exact contribution remains elusive.[0003]The mechanism by which HIV-1 is transmitted from the mucosa to CD4+ T cells is not entirely understood. Three possibilitie...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K7/06C07K7/08A61P31/18A61K31/7052C12Q1/70
CPCA61K31/7052A61K2039/505C07K14/7056C07K16/2851C12Q1/18C07K2317/34G01N33/5047G01N33/56972G01N33/56988G01N2500/02G01N33/5023A61P31/18
Inventor LAMBERT, ALEXANDRAGILBERT, CAROLINETREMBLAY, MICHEL J.
Owner UNIV LAVAL
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