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Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression.

ABSTRACT: The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection (PHI) was performed. The aim was to seek for associations with functional properties of the CD8+ T-cell subsets, viral control and subsequent disease progression. Also, results were compared with samples from Chronics and Elite Controllers. It was found that normal maturation of total and HIV-specific CD8+ T-cells into memory subsets is skewed in PHI, but not at the dramatic level observed in Chronics. Within the HIV-specific compartment, this alteration was evidenced by an accumulation of effector memory CD8+ T (TEM) cells over fully differentiated terminal effector CD8+ T (TTE) cells. Furthermore, higher proportions of total and HIV-specific CD8+ TEM cells and higher HIV-specific TEM/(TEM+TTE) ratio correlated with markers of faster progression. Analysis of PD-1 expression on total and HIV-specific CD8+ T-cells from PHI subjects revealed not only an association with disease progression but also with skewed memory CD8+ T-cell differentiation. Most notably, significant direct correlations were obtained between the functional capacity of CD8+ T-cells to inhibit viral replication in vitro with higher proportions of fully-differentiated HIV-specific CD8+ TTE cells, both at baseline and at 12 months post-infection. Thus, a relationship between preservation of CD8+ T-cell differentiation pathway and cell functionality was established. This report presents evidence concerning the link among CD8+ T-cell function, phenotype and virus control, hence supporting the instauration of early interventions to prevent irreversible immune damage.

SUBMITTER: Ghiglione Y

PROVIDER: S-EPMC4122399 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression.

Ghiglione Yanina Y Falivene Juliana J Ruiz María Julia MJ Laufer Natalia N Socías María Eugenia ME Cahn Pedro P Giavedoni Luis L Sued Omar O Gherardi María Magdalena MM Salomón Horacio H Turk Gabriela G

PloS one 20140805 8

The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection ...[more]

PMID: 25093660

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Project description:BACKGROUND:In human immunodeficiency virus (HIV) infection, 10-15% of individuals exhibit a rapid decline in CD4+ T cells and become rapid progressors (RPs). Overall, understanding the factors affecting rapid disease progression in early HIV infection (EHI) can aid in treatment initiation. Recent studies show that eIF3s, classic scaffold proteins during the translation initiation process, can directly promote or inhibit the translation of mRNA, therefore participating in the regulation of cell function. However, to our knowledge, it has not been addressed whether eIF3s are involved in the diverse prognosis of HIV infection. METHODS:Expression of eIF3s in primary cells from early or chronic HIV-infected patients was detected by real-time PCR. To investigate the potential mechanisms of eIF3d in the regulation of CD8+ T cell function, complete transcriptomes of eIF3d-inhibited Jurkat T cells were sequenced by RNA sequencing (RNA-Seq). Additionally, to examine the effect of eIF3d on CD8+ T cell function, eIF3d expression was inhibited alone or in combination with SOCS-7 knockdown by siRNA in isolated CD8+ T cells. CD8+ T cell proliferation, IFN-r secretion and apoptosis were detected by flow cytometry. Moreover, the effect of eIF3d on HIV replication was evaluated in Jurkat cells, peripheral blood mononuclear cells (PBMCs) and CD4+ T cells with eIF3d knockdown using a pNL4-3 pseudotyped virus. RESULTS:At approximately 100 days of infection, only eIF3d was markedly decreased in RPs compared with chronic progressors (CPs). Expression of eIF3d correlated significantly with disease progression in EHI. Based on in vitro analyses, reduced eIF3d expression led to decreased proliferation and IFN-γ secretion and increased apoptosis in CD8+ T cells. Inhibited expression of eIF3d caused enhanced expression of SOCS-7, and inhibiting SOCS-7 expression by siRNA rescued the attenuated CD8+ T cell function caused by eIF3d. Finally, when eIF3d was inhibited in Jurkat cells, PBMCs and CD4+ T cells, pNL4-3-VSV-G virus replication was enhanced. CONCLUSIONS:The current data highlight the importance of eIF3d in HIV infection by inhibiting CD8+ T cell function and promoting viral replication. Our study provides potential targets for improved immune intervention.

Dataset Information

Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression.

Publications

Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression.

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