1758-2652-13-S3-O15 1758-2652 Oral presentation <p>Purging the HIV-1 reservoir through the disruption of the PD-1 pathway</p> DaFonseca S sdafonseca@vgti-fl.org Chomont N El Far M Boulassel R Routy J Sékaly R

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

Laboratoire 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

Laboratoire d’Immunologie, Département de Microbiologie et d’Immunologie, Université de Montréal, Québec, Canada

INSERM U743, CR-CHUM, Université de Montréal, 264 René Lévesque Est, Montréal, Québec H2X1P1, Canada

Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre (MUHC), McGill University, 687 Pine Avenue West, Montréal, Québec H3A 1A1, Canada

Department of Microbiology and Immunology, 3775 University Street, McGill University, Montréal, Québec H3A2B4, Canada

Journal of the International AIDS Society <p>Workshop Report and Abstracts “Towards a Cure”: HIV Reservoirs and Strategies to Control Them</p> Shirin Heidari, Marie-Capucine Pénicaud, Céline Cheng, International AIDS Society Meeting abstracts - A single PDF containing all abstracts in this supplement is available here. http://www.biomedcentral.com/content/pdf/1758-2652-13-S3-info.pdf <p>International AIDS Society’s Workshop “Towards a Cure”: HIV Reservoirs and Strategies to Control Them</p> Vienna, Austria 16-17 July 2010 1758-2652 2010 13 Suppl 3 O15 http://www.jiasociety.org/content/13/S3/O15 10.1186/1758-2652-13-S3-O15
04 11 2010 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.

Background

The main obstacle to HIV-1 eradication is a small pool of TCM (central memory) and TTM (transitional memory) latently infected CD4+ T cells that persist in patients receiving HAART. The mechanisms implicated in the establishment and persistence of the HIV reservoir are still unknown. The PD-1 receptor is expressed by CD4+ T cells from HIV-infected patients, and efficiently 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 subjected 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 pathway with an Ig-PD-L1 chimera. Cell culture supernatants 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 counterparts, 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-1high cells, 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.