Close Link between CD4+and CD8+T Cell Proliferation Defects in Patients with Human Immunodeficiency Virus Disease and Relationship to Extended Periods of CD4+Lymphopenia

Abstract Background Gag-specific T lymphocytes play a key role in the control of human immunodeficiency virus (HIV) replication. Their restoration will be important for future reservoir targeting strategies. In this study, we aimed to identify immune correlates of Gag-specific CD8 T-cell proliferation in youths with perinatally acquired HIV-1 infection. Methods The ANRS-EP38-IMMIP study included youths of 15 to 24 years of age. Fifty-three were taking combination anti-retroviral therapy and aviremic at the time of the study and had undergone valid 5-6-carboxyfluorescein diacetate succimidyl ester-based flow cytometry T-cell proliferation assays. Plasma analytes were quantified by enzyme-linked immunosorbent assay or multiplex assays. Peripheral blood cells were phenotyped by flow cytometry. Logistic regression was used to study the association between Gag-specific T-cell proliferation and immune markers. Results Patients with Gag-specific CD8 T-cell proliferation had higher levels of plasma transforming growth factor (TGF)-β1, a lower proportion of naive cells among regulatory T cells (Tregs), and higher percentages of CD4 and CD8 T cells expressing the α4β7 integrin or CD161 molecule than those without a Gag-specific response. These associations were significant based on analyses including potential confounders. Conclusions Preserved Gag-specific CD8 T-cell proliferation was associated with higher TGF-β1 levels and increased percentages of T cells with a gut-homing phenotype at least 15 years after HIV infection during the perinatal period.

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Different rates of CD4+ and CD8+ T-cell proliferation in interleukin-2-treated human immunodeficiency virus-positive subjects

Cytometry ◽

10.1002/cyto.1132 ◽

2001 ◽

Vol 46 (4) ◽

pp. 233-237 ◽

Cited By ~ 11

Author(s):

Laura Caggiari ◽

Stefania Zanussi ◽

Cinzia Crepaldi ◽

Maria Teresa Bortolin ◽

Cristina Caffau ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Proliferation ◽

T Cell ◽

Interleukin 2 ◽

Cd8 T Cell ◽

T Cell Proliferation ◽

Immunodeficiency Virus

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Interleukin-2 reconstitutes defective human immunodeficiency virus (HIV), and cytomegalovirus (CMV) specific CD8+ T cell proliferation in HIV infection

Journal of Medical Virology ◽

10.1002/jmv.20675 ◽

2006 ◽

Vol 78 (9) ◽

pp. 1147-1157 ◽

Cited By ~ 13

Author(s):

Jie Yu ◽

Huiyuan Chen ◽

Helen Horton ◽

Anju Bansal ◽

Julie M. McElrath ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Proliferation ◽

T Cell ◽

Hiv Infection ◽

Interleukin 2 ◽

Cd8 T Cell ◽

T Cell Proliferation ◽

Immunodeficiency Virus

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Alterations of T-cell receptor variable region expression in human immunodeficiency virus disease

Cytometry ◽

10.1002/cyto.990220102 ◽

1995 ◽

Vol 22 (1) ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

J. Philip McCoy ◽

W. Roy Overton ◽

Linda Blumstein ◽

John D. Baxter ◽

Kathleen M. Gekowski ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Receptor ◽

Virus Disease ◽

Variable Region ◽

Cell Receptor ◽

Human Immunodeficiency Virus Disease ◽

Immunodeficiency Virus

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High Beta-Chemokine Expression Levels in Lymphoid Tissues of Simian/Human Immunodeficiency Virus 89.6-Vaccinated Rhesus Macaques Are Associated with Uncontrolled Replication of Simian Immunodeficiency Virus Challenge Inoculum

Journal of Virology ◽

10.1128/jvi.78.12.6399-6408.2004 ◽

2004 ◽

Vol 78 (12) ◽

pp. 6399-6408 ◽

Cited By ~ 10

Author(s):

Lisa LaFranco-Scheuch ◽

Kristina Abel ◽

Norbert Makori ◽

Kristina Rothaeusler ◽

Christopher J. Miller

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Viral Replication ◽

Simian Immunodeficiency Virus ◽

T Cell Proliferation ◽

Expression Levels ◽

Immunodeficiency Virus

ABSTRACT Viral suppression by noncytolytic CD8+ T cells, in addition to that by classic antiviral CD8+ cytotoxic T lymphocytes, has been described for human immunodeficiency virus and simian immunodeficiency virus (SIV) infections. However, the role of soluble effector molecules, especially beta-chemokines, in antiviral immunity is still controversial. In an attenuated vaccine model, approximately 60% of animals immunized with simian/human immunodeficiency virus (SHIV) 89.6 and then challenged intravaginally with SIVmac239 controlled viral replication (viral RNA level in plasma, <104 copies/ml) and were considered protected (K. Abel, L. Compton, T. Rourke, D. Montefiori, D. Lu, K. Rothaeusler, L. Fritts, K. Bost, and C. J. Miller, J. Virol. 77:3099-3118, 2003). To determine the in vivo importance of beta-chemokine secretion and CD8+-T-cell proliferation in the control of viral replication in this vaccine model, we examined the relationship between viral RNA levels in the axillary and genital lymph nodes of vaccinated, protected (n = 20) and vaccinated, unprotected (n = 11) monkeys by measuring beta-chemokine mRNA levels and protein expression, the frequency of CD8+ T cells expressing beta-chemokines, and the extent of CD8+-T-cell proliferation. Tissues from uninfected (n = 3) and unvaccinated, SIVmac239-infected (n = 9) monkeys served as controls. Axillary and genital lymph nodes from unvaccinated and vaccinated, unprotected monkeys had significantly higher beta-chemokine mRNA expression levels and increased numbers of beta-chemokine-positive cells than did vaccinated, protected animals. Furthermore, the lymph nodes of vaccinated, unprotected monkeys had significantly higher numbers of beta-chemokine+ CD8+ T cells than did vaccinated, protected monkeys. Lymph nodes from vaccinated, unprotected animals also had significantly more CD8+-T-cell proliferation and marked lymph node hyperplasia than the lymph nodes of vaccinated, protected monkeys. Thus, higher levels of virus replication were associated with increased beta-chemokine secretion and there is no evidence that beta-chemokines contributed to the SHIV89.6-mediated control of viral replication after intravaginal challenge with SIVmac239.

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Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Blood ◽

10.1182/blood-2010-03-273482 ◽

2010 ◽

Vol 116 (20) ◽

pp. 4168-4174 ◽

Cited By ~ 23

Author(s):

Xiaolei Wang ◽

Huanbin Xu ◽

Bapi Pahar ◽

Xavier Alvarez ◽

Linda C. Green ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Rhesus Macaques ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Lymphoid Tissues ◽

Immunodeficiency Virus

Abstract Infants infected with HIV have a more severe course of disease and persistently higher viral loads than HIV-infected adults. However, the underlying pathogenesis of this exacerbation remains obscure. Here we compared the rate of CD4+ and CD8+ T-cell proliferation in intestinal and systemic lymphoid tissues of neonatal and adult rhesus macaques, and of normal and age-matched simian immunodeficiency virus (SIV)–infected neonates. The results demonstrate infant primates have much greater rates of CD4+ T-cell proliferation than adult macaques, and that these proliferating, recently “activated” CD4+ T cells are infected in intestinal and other lymphoid tissues of neonates, resulting in selective depletion of proliferating CD4+ T cells in acute infection. This depletion is accompanied by a marked increase in CD8+ T-cell activation and production, particularly in the intestinal tract. The data indicate intestinal CD4+ T cells of infant primates have a markedly accelerated rate of proliferation and maturation resulting in more rapid and sustained production of optimal target cells (activated memory CD4+ T cells), which may explain the sustained “peak” viremia characteristic of pediatric HIV infection. Eventual failure of CD4+ T-cell turnover in intestinal tissues may indicate a poorer prognosis for HIV-infected infants.

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T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART)

Blood ◽

10.1182/blood.v95.1.249 ◽

2000 ◽

Vol 95 (1) ◽

pp. 249-255 ◽

Cited By ~ 314

Author(s):

Mette D. Hazenberg ◽

James W. T. Cohen Stuart ◽

Sigrid A. Otto ◽

Jan C. C. Borleffs ◽

Charles A. B. Boucher ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Proliferation ◽

T Cell ◽

Highly Active Antiretroviral Therapy ◽

Cd8 T Cell ◽

Ki 67 ◽

Highly Active ◽

Immunodeficiency Virus ◽

Dividing Cells ◽

Hiv 1

Abstract In human immunodeficiency virus (HIV)-1 infection, highly increased T-cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4+ and CD8+ lymphocyte subpopulations before and during highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67+CD4+ and CD8+ lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4+ T cells in the blood was found when the number of these cells were below 100 per μL.. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4+ T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4+CD27+ memory pool. In the CD8+ T-cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27+ CD 45RO+ and CD27−CD45RO+ memory CD8+ T-cell pool, corresponding with the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8+T-cell subsets. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)

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Effects of cyclosporin on T-cell subsets in human immunodeficiency virus disease

Clinical Immunology and Immunopathology ◽

10.1016/0090-1229(88)90071-2 ◽

1988 ◽

Vol 47 (2) ◽

pp. 181-198 ◽

Cited By ~ 73

Author(s):

Jean-Marie Andrieu ◽

Philippe Even ◽

Alain Venet ◽

Jean-Marc Tourani ◽

Marc Stern ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Virus Disease ◽

T Cell Subsets ◽

Human Immunodeficiency Virus Disease ◽

Immunodeficiency Virus

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T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART)

Blood ◽

10.1182/blood.v95.1.249.001k40_249_255 ◽

2000 ◽

Vol 95 (1) ◽

pp. 249-255 ◽

Cited By ~ 2

Author(s):

Mette D. Hazenberg ◽

James W. T. Cohen Stuart ◽

Sigrid A. Otto ◽

Jan C. C. Borleffs ◽

Charles A. B. Boucher ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Proliferation ◽

T Cell ◽

Highly Active Antiretroviral Therapy ◽

Cd8 T Cell ◽

Ki 67 ◽

Highly Active ◽

Immunodeficiency Virus ◽

Dividing Cells ◽

Hiv 1

In human immunodeficiency virus (HIV)-1 infection, highly increased T-cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4+ and CD8+ lymphocyte subpopulations before and during highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67+CD4+ and CD8+ lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4+ T cells in the blood was found when the number of these cells were below 100 per μL.. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4+ T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4+CD27+ memory pool. In the CD8+ T-cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27+ CD 45RO+ and CD27−CD45RO+ memory CD8+ T-cell pool, corresponding with the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8+T-cell subsets. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)

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