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PD-1 and its ligand PD-L1 are progressively up-regulated on CD4 and CD8 T-cells in HIV-2 infection irrespective of the presence of viremia

Tendeiro, Ritaa,*; Foxall, Russell B.a,*; Baptista, António P.a; Pinto, Franciscoa; Soares, Rui S.a; Cavaleiro, Ritaa; Valadas, Emíliab; Gomes, Perpétuac,d,e; Victorino, Rui M.M.a,f; Sousa, Ana E.a

doi: 10.1097/QAD.0b013e32835374db
Basic Science

Objective: Hyper-immune activation is a main determinant of HIV disease progression, potentially counter-acted by T-cell inhibitory pathways. Here we investigated, for the first time, inhibitory molecules in HIV-2 infection, a naturally occurring attenuated form of HIV disease, associated with reduced viremia and very slow rates of CD4 T-cell decline.

Design: Programmed death (PD)-1/PD-L1, an important pathway in limiting immunopathology, and its possible relationship with T-cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a recently identified inhibitory molecule, were studied in untreated HIV-2 and HIV-1 cohorts, matched for degree of CD4 T-cell depletion, and noninfected individuals.

Methods: Flow cytometric analysis of T-cell expression of PD-1, PD-L1 and TIM-3, combined with markers of cell differentiation, activation, cycling and survival. Statistical analysis was performed using ANOVA, Mann–Whitney/Wilcoxon tests, Spearman's correlations, multiple linear regressions and canonical correlation analysis.

Results: T-cell expression of PD-1 and PD-L1 was tightly associated and directly correlated with CD4 T-cell depletion and immune activation in HIV-2 infection. No such correlation was found for PD-L1 expression in HIV-1-positive patients. Central memory and intermediate memory cells, rather than terminally differentiated T-cells, expressed the highest levels of both PD-1 and PD-L1 molecules. Conversely, TIM-3 expression was independent of T-cell differentiation and dissociated from cell cycling, suggesting distinct induction mechanisms. Importantly, in contrast with HIV-1, no significant increases in TIM-3 expression were found in the HIV-2 cohort.

Conclusions: Our data suggest that PD-1/PD-L1 molecules, rather than markers of T-cell exhaustion, may act as modulators of T-cell immune activation, contributing to the slower course of HIV-2 infection. These data have implications for the design of antiretroviral therapy-complementary immune-based strategies.

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aUnidade de Imunologia Clínica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa

bClínica de Doenças Infecciosas, Hospital de Santa Maria

cLaboratório de Biologia Molecular, Serviço de Medicina Transfusional, Centro Hospitalar Lisboa Ocidental, Hospital Egas Moniz

dCentro de Malária e Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa

eCentro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Ciências da Saúde Sul, Caparica

fClínica Universitária de Medicina 2, Centro Hospitalar Lisboa Norte, Hospital Universitário de Santa Maria, Lisboa, Portugal.

*These authors contributed equally to this work.

Correspondence to Ana E. Sousa, MD, PhD, Unidade de Imunologia Clínica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal. Tel: +351 21 7999525; fax: +351 21 7999527; e-mail:

Received 30 January, 2012

Revised 27 February, 2012

Accepted 8 March, 2012

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© 2012 Lippincott Williams & Wilkins, Inc.