Longitudinal Assessment of Changes in HIV-Specific Effector Activity in HIV-Infected Patients Starting Highly Active Antiretroviral Therapy in Primary Infection

Alter, Galit; Hatzakis, George; Tsoukas, Christos; Pelley, Karen; Rouleau, Danielle; LeBlanc, Roger; Baril, Jean-Guy; Dion, Harold; Lefebvre, E.; Thomas, Réjean; Côté, Pierre; Lapointe, Normand; Routy, Jean‐Pierre; Sékaly, R P; Conway, Brian; Bernard, Nicole F.

doi:10.4049/jimmunol.171.1.477

Cited by 45 publications

(33 citation statements)

References 47 publications

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“…A similar situation may also occur during HIV infection. When viremia is controlled with effective antiretroviral therapy, or when antigen stimulation declines because of epitope mutation, the number of circulating HIV-specific CD8 T cells can substantially decline in chronically infected individuals (37)(38)(39)(40). One prediction of our study is that if antigen exposure is terminated during the early stages of infection (the acute phase), T cells may experience the necessary rest from antigen stimulation to differentiate into long-lived antigen-independent memory T cells.…”

Section: Discussionmentioning

confidence: 96%

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Antigen-independent memory CD8 T cells do not develop during chronic viral infection

Wherry

Barber

Kaech

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

454

462

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Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.

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Section: Discussionmentioning

confidence: 96%

“…have shown that if antiretroviral therapy is initiated during the early phase of infection, HIV-specific CD8 T cells are more efficiently maintained (38,39). Also, it has been reported that during latent gammaherpesvirus infection of mice virus-specific CD8 T cells appear to be maintained in an IL-15-independent manner (41).…”

Section: Discussionmentioning

confidence: 99%

Antigen-independent memory CD8 T cells do not develop during chronic viral infection

Wherry

Barber

Kaech

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

454

462

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“…ϩ T cell response to HIV components is highly variable and generally found in long-term nonprogressor patients (19) or in individuals treated soon after infection (41). The HIV-specific CD4…”

Section: Discussionmentioning

confidence: 99%

Scanning the HIV Genome for CD4+ T Cell Epitopes Restricted to HLA-DP4, the Most Prevalent HLA Class II Molecule

Cohen

Pouvelle‐Moratille

Wang

et al. 2006

The Journal of Immunology

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HLA-DP4 alleles are carried by 75% of individuals and are the most frequent HLA II alleles worldwide. Because we have recently characterized the peptide-binding specificity of HLA-DP4 molecules, we developed a peptide-binding prediction method to identify HLA-DP4-restricted peptides in multiple Ags. CD4+ T cell response plays a key role in the immune control of HIV infection, but few HIV-specific T cell epitopes with multi-individual specificity have been identified. They are mostly restricted to HLA-DR molecules, which are very polymorphic molecules. We therefore looked for HLA-DP4-restricted CD4+ T cell epitopes in the whole genome of HIV. Twenty-one peptides were selected from the HXB2 HIV genome based on the prediction of binding to HLA-DP4 molecules. They were submitted to HLA-DP4-binding assays. Seventeen peptides bound to the HLA-DP401 molecule, whereas 15 peptides bound to HLA-DP402. Six peptides bound very tightly to HLA-DP401 and were investigated for their capacity to induce specific CD4+ T cell lines in vitro using dendritic cells and CD4+ T cells collected from eight seronegative HLA-DP4+ donors. Four peptides from env and reverse transcriptase proteins induced in vitro-specific T cell lines restricted to HLA-DP4 molecules. Peptide-induced T cells recognized variants other than the HXB2 sequence and were stimulated by native Ags processed by immature dendritic cells. The reverse transcriptase peptide is present in 65% of the isolated HIV variants. To our knowledge, we describe the first HIV epitopes restricted to HLA-DP4 molecules.

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“…During chronic infection, changes within the T-cell compartment include a significant skewing of the hierarchy of the immune response (1,38), improper maturation of effector Tcell populations (10), and changes in both the phenotypic and the functional quality of the HIV-specific CTL (7). Subjected to the protracted exposure to high doses of antigen, HIVspecific T cells have evolved elaborate homeostatic mechanisms that allow them to resist elimination while, simultaneously, they attempt to dampen immunopathogenesis (36).…”

mentioning

confidence: 99%

Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8 ⁺ T Cells in Human Immunodeficiency Virus Type 1 Infection

Alter

Rihn

Streeck

et al. 2008

J Virol

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Virus-specific CD8+ T cells play a central role in the control of viral infections, including human immunodeficiency virus type 1 (HIV-1) infection. However, despite the presence of strong and broad HIV-specific CD8+ T-cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions and fail to clear the infection. Mounting evidence suggests that the upregulation of several inhibitory regulatory receptors on the surface of CD8+ T cells during HIV-1 infection may contribute directly to the impairment of T-cell function. Here, we investigated the role of killer immunoglobulin receptors (KIR), which are expressed on NK cells and on CD8+ T cells, in regulating CD8+ T-cell function in HIV-1 infection. KIR expression was progressively upregulated on CD8+ T cells during HIV-1 infection and correlated with the level of viral replication. Expression of KIR was associated with a profound inhibition of cytokine secretion, degranulation, proliferation, and activation by CD8+ T cells following stimulation with T-cell receptor (TCR)-dependent stimuli. In contrast, KIR+ CD8+ T cells responded potently to TCR-independent stimulation, demonstrating that these cells are functionally competent. KIR-associated suppression of CD8+ T-cell function was independent of ligand engagement, suggesting that these regulatory receptors may constitutively repress TCR activation. This ligand-independent repression of TCR activation of KIR+ CD8+ T cells may represent a significant barrier to therapeutic interventions aimed at improving the quality of the HIV-specific CD8+ T-cell response in infected individuals.

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Longitudinal Assessment of Changes in HIV-Specific Effector Activity in HIV-Infected Patients Starting Highly Active Antiretroviral Therapy in Primary Infection

Cited by 45 publications

References 47 publications

Antigen-independent memory CD8 T cells do not develop during chronic viral infection

Antigen-independent memory CD8 T cells do not develop during chronic viral infection

Scanning the HIV Genome for CD4+ T Cell Epitopes Restricted to HLA-DP4, the Most Prevalent HLA Class II Molecule

Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8 ⁺ T Cells in Human Immunodeficiency Virus Type 1 Infection

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Longitudinal Assessment of Changes in HIV-Specific Effector Activity in HIV-Infected Patients Starting Highly Active Antiretroviral Therapy in Primary Infection

Cited by 45 publications

References 47 publications

Antigen-independent memory CD8 T cells do not develop during chronic viral infection

Antigen-independent memory CD8 T cells do not develop during chronic viral infection

Scanning the HIV Genome for CD4+ T Cell Epitopes Restricted to HLA-DP4, the Most Prevalent HLA Class II Molecule

Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8 + T Cells in Human Immunodeficiency Virus Type 1 Infection

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Product

Resources

About

Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8 ⁺ T Cells in Human Immunodeficiency Virus Type 1 Infection