Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection.

TitleSurface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection.
Publication TypeJournal Article
Year of Publication2011
AuthorsYamamoto T, Price DA, Casazza JP, Ferrari G, Nason M, Chattopadhyay PK, Roederer M, Gostick E, Katsikis PD, Douek DC, Haubrich R, Petrovas C, Koup RA
JournalBlood
Volume117
Issue18
Pagination4805-15
Date Published2011 May 5
ISSN1528-0020
KeywordsAnti-HIV Agents, Antigens, CD, Antigens, CD274, Apoptosis Regulatory Proteins, CD8-Positive T-Lymphocytes, Cytomegalovirus, Female, GPI-Linked Proteins, HIV Infections, HIV-1, Humans, Immunologic Memory, Male, Programmed Cell Death 1 Receptor, Receptors, Immunologic, T-Lymphocyte Subsets, Viremia
Abstract

A highly complex network of coinhibitory and costimulatory receptors regulates the outcome of virus-specific CD8(+) T-cell responses. Here, we report on the expression patterns of multiple inhibitory receptors on HIV-specific, cytomegalovirus-specific, and bulk CD8(+) T-cell memory populations. In contrast to cytomegalovirus-specific CD8(+) T cells, the majority of HIV-specific CD8(+) T cells exhibited an immature phenotype and expressed Programmed Death-1, CD160 and 2B4 but not lymphocyte activation gene-3. Notably, before antiretroviral therapy, simultaneous expression of these negative regulators correlated strongly with both HIV load and impaired cytokine production. Suppression of HIV replication by antiretroviral therapy was associated with reduced surface expression of inhibitory molecules on HIV-specific CD8(+) T cells. Furthermore, in vitro manipulation of Programmed Death-1 and 2B4 inhibitory pathways increased the proliferative capacity of HIV-specific CD8(+) T cells. Thus, multiple coinhibitory receptors can affect the development of HIV-specific CD8(+) T-cell responses and, by extension, represent potential targets for new immune-based interventions in HIV-infected persons.

DOI10.1182/blood-2010-11-317297
Alternate JournalBlood
PubMed ID21398582
PubMed Central IDPMC3100691
Grant ListAI36214 / AI / NIAID NIH HHS / United States
AI69432 / AI / NIAID NIH HHS / United States
G0501963 / / Medical Research Council / United Kingdom
K24 AI064086 / AI / NIAID NIH HHS / United States
K24 AI064086-06 / AI / NIAID NIH HHS / United States
K24 AI64086 / AI / NIAID NIH HHS / United States
P30 AI036214 / AI / NIAID NIH HHS / United States
U01 AI069432 / AI / NIAID NIH HHS / United States
Z99 AI999999 / / Intramural NIH HHS / United States