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Title: Decreased number of CD4{sup +} and CD8{sup +} T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques

Abstract

Acute HIV/SIV (human/simian immunodeficiency virus) infection results in severe CD4{sup +} T cell depletion in lymphoid compartments. During the chronic phase of infection, CD4{sup +} T cell numbers rebound in blood but remain low in the gut-associated lymphoid tissue (GALT), even when viral replication is suppressed by antiretroviral therapy (ART). Thus, strategies to repopulate lymphoid compartments may ameliorate the clinical outcome of HIV/SIV infection. Interleukin (IL)-7 is a key cytokine for the maintenance of homeostatic proliferation of T cells. In HIV/SIV infection, IL-7 expression is increased, likely to compensate for T cell loss, suggesting that supraphysiological administration of IL-7 could provide additional benefit. However, the ability of T cells to respond to IL-7 is dependent on the level of expression of the IL-7 receptor (IL-7R) in T cells in various body compartments. In here, we investigated the proportion of IL-7R{sup +} T cells in blood, spleen, gut, and genitourinary tract of healthy and SIV-infected macaques with various degrees of CD4{sup +} T cell depletion. We found that the percentage of T cells expressing IL-7R was significantly lower in both CD4{sup +} and CD8{sup +} T cell subsets in SIV-infected macaques than in healthy animals and this decrease directly correlated withmore » the CD4{sup +} T cell number. Importantly, the proportion of CD4{sup +} and CD8{sup +} T cells expressing IL-7R in blood paralleled that found in tissues. IL-7R{sup +} T cells within the SIV-specific CD8{sup +} T cells varied and were lowest in most tissues of viremic macaques, likely reflecting continuous antigen stimulation of effector cells.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [1];  [1];  [2];  [1];  [4]
  1. Animal Models and Retroviral Vaccines Section, National Cancer Institute, NCI, 41/D804, Bethesda, MD 20892-5065 (United States)
  2. (Poland)
  3. Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 20892 (United States)
  4. Animal Models and Retroviral Vaccines Section, National Cancer Institute, NCI, 41/D804, Bethesda, MD 20892-5065 (United States). E-mail: franchig@mail.nih.gov
Publication Date:
OSTI Identifier:
20850583
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 356; Journal Issue: 1-2; Other Information: DOI: 10.1016/j.virol.2006.07.031; PII: S0042-6822(06)00508-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; ANIMALS; ANTIGENS; BLOOD; CELL PROLIFERATION; RECEPTORS; SPLEEN; STIMULATION; THERAPY

Citation Formats

Moniuszko, Marcin, Medical University of Bialystok, Bialystok, Edghill-Smith, Yvette, Venzon, David, Stevceva, Liljana, Nacsa, Janos, Tryniszewska, Elzbieta, Medical University of Bialystok, Bialystok, Tsai, Wen-Po, and Franchini, Genoveffa. Decreased number of CD4{sup +} and CD8{sup +} T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques. United States: N. p., 2006. Web. doi:10.1016/j.virol.2006.07.031.
Moniuszko, Marcin, Medical University of Bialystok, Bialystok, Edghill-Smith, Yvette, Venzon, David, Stevceva, Liljana, Nacsa, Janos, Tryniszewska, Elzbieta, Medical University of Bialystok, Bialystok, Tsai, Wen-Po, & Franchini, Genoveffa. Decreased number of CD4{sup +} and CD8{sup +} T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques. United States. doi:10.1016/j.virol.2006.07.031.
Moniuszko, Marcin, Medical University of Bialystok, Bialystok, Edghill-Smith, Yvette, Venzon, David, Stevceva, Liljana, Nacsa, Janos, Tryniszewska, Elzbieta, Medical University of Bialystok, Bialystok, Tsai, Wen-Po, and Franchini, Genoveffa. Wed . "Decreased number of CD4{sup +} and CD8{sup +} T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques". United States. doi:10.1016/j.virol.2006.07.031.
@article{osti_20850583,
title = {Decreased number of CD4{sup +} and CD8{sup +} T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques},
author = {Moniuszko, Marcin and Medical University of Bialystok, Bialystok and Edghill-Smith, Yvette and Venzon, David and Stevceva, Liljana and Nacsa, Janos and Tryniszewska, Elzbieta and Medical University of Bialystok, Bialystok and Tsai, Wen-Po and Franchini, Genoveffa},
abstractNote = {Acute HIV/SIV (human/simian immunodeficiency virus) infection results in severe CD4{sup +} T cell depletion in lymphoid compartments. During the chronic phase of infection, CD4{sup +} T cell numbers rebound in blood but remain low in the gut-associated lymphoid tissue (GALT), even when viral replication is suppressed by antiretroviral therapy (ART). Thus, strategies to repopulate lymphoid compartments may ameliorate the clinical outcome of HIV/SIV infection. Interleukin (IL)-7 is a key cytokine for the maintenance of homeostatic proliferation of T cells. In HIV/SIV infection, IL-7 expression is increased, likely to compensate for T cell loss, suggesting that supraphysiological administration of IL-7 could provide additional benefit. However, the ability of T cells to respond to IL-7 is dependent on the level of expression of the IL-7 receptor (IL-7R) in T cells in various body compartments. In here, we investigated the proportion of IL-7R{sup +} T cells in blood, spleen, gut, and genitourinary tract of healthy and SIV-infected macaques with various degrees of CD4{sup +} T cell depletion. We found that the percentage of T cells expressing IL-7R was significantly lower in both CD4{sup +} and CD8{sup +} T cell subsets in SIV-infected macaques than in healthy animals and this decrease directly correlated with the CD4{sup +} T cell number. Importantly, the proportion of CD4{sup +} and CD8{sup +} T cells expressing IL-7R in blood paralleled that found in tissues. IL-7R{sup +} T cells within the SIV-specific CD8{sup +} T cells varied and were lowest in most tissues of viremic macaques, likely reflecting continuous antigen stimulation of effector cells.},
doi = {10.1016/j.virol.2006.07.031},
journal = {Virology},
number = 1-2,
volume = 356,
place = {United States},
year = {Wed Dec 20 00:00:00 EST 2006},
month = {Wed Dec 20 00:00:00 EST 2006}
}
  • High-level T cell expression of PD-1 during SIV infection is correlated with impaired proliferation and function. We evaluated the phenotype and distribution of T cells and Tregs during antiretroviral therapy plus PD-1 modulation (using a B7-DC-Ig fusion protein) and post-ART. Chronically SIV-infected rhesus macaques received: 11 weeks of ART (Group A); 11 weeks of ART plus B7-DC-Ig (Group B); 11 weeks of ART plus B7-DC-Ig, then 12 weeks of B7-DC-Ig alone (Group C). Continuous B7-DC-Ig treatment (Group C) decreased rebound viremia post-ART compared to pre-ART levels, associated with decreased PD-1{sup hi} expressing T cells and Tregs in PBMCs, and PD-1{supmore » hi} Tregs in lymph nodes. It transiently decreased expression of Ki67 and α{sub 4}β{sub 7} in PBMC CD4{sup +} and CD8{sup +} Tregs for up to 8 weeks post-ART and maintained Ag-specific T-cell responses at low levels. Continued immune modulation targeting PD-1{sup hi} cells during and post-ART helps maintain lower viremia, keeps a favorable T cell/Treg repertoire and modulates antigen-specific responses. - Highlights: • B7-DC-Ig modulates PD-1{sup hi} cells in SIV-infected rhesus macaques during and post-ART. • Continued PD-1 modulation post-ART maintains PD-1{sup hi} cells at low levels. • Continued PD-1 modulation post-ART maintains a favorable T cell and Treg repertoire.« less
  • A rare T-cell subpopulation, CD4{sup -z}8{sup -}{alpha}{beta} cells, may be differentiated through a pathway (or pathways) different from the pathway(s) of conventional CD4+ or CD8+ cells. In the present study, the frequencies of CD4{sup -}8{sup -} T cells in peripheral-blood {alpha}{beta} T cells in 409 atomic bomb survivors were determined to investigate late effects of radiation on the composition of human T-cell subpopulations. The frequency of CD4{sup -}8{sup -}{alpha}{beta} T-cell decreased significantly with the subject`s age and was higher in females than males. A significant increase in the frequency was found in the survivors exposed to more than 1.5Gy, suggestingmore » that the previous radiation exposure altered differentiation and development of T cells. 25 refs., 4 figs., 3 tabs.« less
  • A subset of human T cells has recently been described. These cells express the CD3 complex but they do not carry the classical T-cell receptor (TCR)-..gamma../-..beta.. heterodimer on their surface (WT31/sup -/ CD3/sup +/). Instead, they express a TCR-..gamma.. chain associated with another type of polypeptide termed TCR-delta. The authors report here that a T-cell clone with natural killer (NK)-like activity, WM-14, had a disulfide bridged TCR-..gamma.. homodimer associated with CD3 on its surface. The TCR-..gamma.. chains of WM-14 cells were present in three different glycosylation forms of 43, 40, and 38 kDa, but they appeared to contain the samemore » polypeptide backbone. Since cytotoxicity by WM-14 could be inhibited by anti-CD3 antibodies, they concluded that the TCR-..gamma..-CD3 complex was involved in the NK-like unrestricted killer activity. Although normal CD3-..gamma.., CD3-delta, and CD3-element of chains were present in this clone, the association with the TCR-..gamma.. homodimer may be the cause of a complete processing of the N-linked oligosaccharides attached to the CD3-delta chain.« less
  • While CD8+ T cell responses are clearly important in anti-viral immunity during HIV/SIV infection, the mechanisms by which CD8+ T cells induce this effect remain poorly understood, as emphasized by the failure of the Merck adenovirus-based, cytotoxic T lymphocyte (CTL)-inducing AIDS vaccine in a large phase IIb clinical trial. In this study, we measured the in vivo effect of CD8+ lymphocytes on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques by treating two groups of animals (i.e., CD8+ lymphocyte-depleted or controls) with antiretroviral therapy (PMPA and FTC). The lifespan of productively infected cells was calculatedmore » based on the slope of the decline of SIV plasma viremia using a well-accepted mathematical model. We found that, in both early (i.e., day 57 post-inoculation) and late (i.e., day 177 post-inoculation) chronic SIV infection, depletion of CD8+ lymphocytes did not result in an increased lifespan of productively infected cells in vivo. This result indicates that direct killing of cells producing virus is unlikely to be a major mechanism underlying the anti-viral effect of CD8+ T cells during SIV infection. These results have profound implications for the development of AIDS vaccines.« less
  • Since the liver drains antigens from the intestinal tract, and since the intestinal tract is a major site of viral replication, we examined the dynamics of liver macrophages (Kupffer cells) throughout SIV infection. Absolute numbers of Kupffer cells increased in the livers in acute infection, and in animals with AIDS. Significantly higher percentages of proliferating (BrdU+) Kupffer cells were detected in acute infection and in AIDS with similar trends in blood monocytes. Significantly higher percentages of apoptotic (AC3+) Kupffer cells were also found in acute and AIDS stages. However, productively infected cells were not detected in liver of 41/42 animalsmore » examined, despite abundant infected cells in gut and lymph nodes of all animals. Increased rates of Kupffer cell proliferation resulting in an increase in Kupffer cells without productive infection indicate SIV infection affects Kupffer cells, but the liver does not appear to be a major site of productive viral replication. - Highlights: • Kupffer cells increase in the liver of SIV-infected macaques. • Increased proliferation and apoptosis of Kupffer cells occurs in SIV infection. • Productively infected cells are rarely detected in the liver. • The liver is not a major site for SIV replication.« less