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HAL Id: inserm-00663876

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Submitted on 27 Jan 2012

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Purging the HIV-1 reservoir through the disruption of

the PD-1 pathway

Sandrine Dafonseca, Nicolas Chomont, Mohamed El Far, Mohamed-Rachid

Boulassel, Jean-Pierre Routy, Rafick Sékaly

To cite this version:

Sandrine Dafonseca, Nicolas Chomont, Mohamed El Far, Mohamed-Rachid Boulassel, Jean-Pierre

Routy, et al.. Purging the HIV-1 reservoir through the disruption of the PD-1 pathway. International

AIDS Society’s Workshop ”Towards a Cure”: HIV Reservoirs and Strategies to Control Them, Jul

2010, Vienne, Austria. pp.O15, �10.1186/1758-2652-13-S3-O15�. �inserm-00663876�

(2)

O R A L P R E S E N T A T I O N

Open Access

Purging the HIV-1 reservoir through the

disruption of the PD-1 pathway

S DaFonseca

1*

, N Chomont

1

, M El Far

2,3,4

, R Boulassel

5

, J Routy

5,6

, R Sékaly

1,2,3,4,6

From International AIDS Society’s Workshop “Towards a Cure”: HIV Reservoirs and Strategies to Control Them

Vienna, Austria. 16-17 July 2010

Background

The main obstacle to HIV-1 eradication is a small pool of TCM(central memory) and TTM (transitional mem-ory) latently infected CD4+ T cells that persist in patients receiving HAART. The mechanisms implicated in the establishment and persistence of the HIV reser-voir are still unknown. The PD-1 receptor is expressed by CD4+ T cells from HIV-infected patients, and effi-ciently inhibits T cell proliferation. Here, we investigate a possible role for this receptor in the establishment and maintenance of a cellular reservoir for HIV.

Methods

PBMCs were obtained by leukapheresis from HAART-naïve, chronically HIV-1-infected subjects and were sub-jected to total CD4+ T cells negative selection. Viral production was induced through TCR triggering (CD3/ CD28) with or without co-triggering of the PD-1 path-way with an Ig-PD-L1 chimera. Cell culture superna-tants were serially harvested; viral release was quantified by QRT-PCR or p24 ELISA. The frequency of CD4+ T cells harbouring HIV DNA was determined by Q-PCR.

Results

Cell sorting and Q-PCR experiments showed that PD-1high cells from viremic donors preferentially harbour HIV-1 integrated DNA when compared with their PD-1low coun-terparts, indicating that these cells constitute a preferential reservoir for the virus. Triggering of the PD-1 pathway inhibits 50% of HIV-1 production in primary CD4+ T cells at day 1 and up to 95% at day 3. Importantly, this inhibition was restricted to PD-1highcells, demonstrating the specificity of this mechanism. Moreover, we observed

that the disruption of the PD-1/PD-L1 interaction enhances the spontaneous release of HIV-1 virions by CD4+ T cells.

Conclusions

Our results suggest that: (1) the PD-1 receptor can be used as a specific marker to target the HIV-1 reservoir; (2) viral production is inhibited after triggering of the PD-1 receptor; and (3) viral production was enhanced after blocking of this inhibitory pathway. Altogether, our results demonstrate a crucial role for PD-1 in the establishment.

Author details

1Vaccine and Gene Therapy Institute, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, USA.2Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM) Saint-Luc, 264 René Lévesque Est, Montréal, Québec H2X1P1, Canada.3Laboratoire d’Immunologie, Département de Microbiologie et d’Immunologie, Université de Montréal, Québec, Canada.4INSERM U743, CR-CHUM, Université de Montréal, 264 René Lévesque Est, Montréal, Québec H2X1P1, Canada. 5Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre (MUHC), McGill University, 687 Pine Avenue West, Montréal, Québec H3A 1A1, Canada.6Department of Microbiology and Immunology, 3775 University Street, McGill University, Montréal, Québec H3A2B4, Canada.

Published: 4 November 2010

doi:10.1186/1758-2652-13-S3-O15

Cite this article as: DaFonseca et al.: Purging the HIV-1 reservoir through the disruption of the PD-1 pathway.Journal of the International AIDS Society 2010 13(Suppl 3):O15.

* Correspondence: sdafonseca@vgti-fl.org 1

Vaccine and Gene Therapy Institute, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, USA

Full list of author information is available at the end of the article

DaFonsecaet al. Journal of the International AIDS Society 2010, 13(Suppl 3):O15 http://www.jiasociety.org/content/13/S3/O15

© 2010 DaFonseca et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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