Volume 13 Supplement 3

Workshop Report and Abstracts “Towards a Cure”: HIV Reservoirs and Strategies to Control Them

Open Access

Purging the HIV-1 reservoir through the disruption of the PD-1 pathway

Journal of the International AIDS Society201013(Suppl 3):O15

https://doi.org/10.1186/1758-2652-13-S3-O15

Published: 04 November 2010

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.

Authors’ Affiliations

(1)
Vaccine and Gene Therapy Institute
(2)
Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM) Saint-Luc
(3)
Laboratoire d’Immunologie, Département de Microbiologie et d’Immunologie, Université de Montréal
(4)
INSERM U743, CR-CHUM, niversité de Montréal
(5)
Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre (MUHC), McGill University
(6)
Department of Microbiology and Immunology, McGill University

Copyright

© DaFonseca et al; licensee BioMed Central Ltd. 2010

This article is published under license to 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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