Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy

Pakker, Nadine; Kroon, Eugène; Roos, M. T. L.; Otto, S.; Hall, David B.; Wit, Fwnm; Hamann, Dörte; Ende, M.E. van der; Claessen, F. A. P.; Kauffmann, Robert H.; Koopmans, P.P.; Kroon, F.P.; Napel, C.H.H. ten; Sprenger, Herman; Weigel, H. M.; Montaner, Julio S. G.; Lange, Joep M. A.; Reiss, Peter; Schellekens, P. T. A.; Miedema, Frank

doi:10.1097/00002030-199902040-00008

Cited by 103 publications

(55 citation statements)

References 35 publications

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“…[43][44][45] These studies mostly demonstrated improved agspecific Ig production in the presence of HAART, while pre-HAART trials showed mixed ag-specific responses. [46][47][48][49][50][51] While the impact of HIV infection on the circulating CD27 + B220 − B cell population is obvious, the CD27 + B220 + B cell population is not unscathed. Our conclusion that this population may be GC-related contributes to defects in serological memory and vaccine response observed in both HIV + adults and children.…”

Section: Discussionmentioning

confidence: 99%

A Splenic Marginal Zone-Like Peripheral Blood CD27⁺B220⁻B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

Morrow

Valentı́n

Little

et al. 2008

AIDS Research and Human Retroviruses

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Peripheral blood CD27 + B cells are reduced in HIV-1-infected individuals. In healthy individuals, the human peripheral blood CD27 + B cell pool consists of two subsets defined by the expression, or lack thereof, of the CD45 isoform B220. We investigated the presence of circulating B220 + and B220 − memory B cells in HIV + individuals and found that the reduction in CD27 + memory B cells occurs primarily among CD27 + B220 − B cells. Studies conducted using healthy controls indicate that CD27 + B220 − B cells have a splenic marginal zone like the immunophenotype IgM hi IgD lo CD21 + CD23 − , express TLR9, and proliferate and secrete IgG and IgM in response to B cell-specific ODN. CD27 + B220 + B cells have the immunophenotype IgM lo IgD hi CD21 + CD23 + , express activation-induced cytidine deaminase, and proliferate in response to SAC but do not secrete immunoglobulin. The AICD expression, along with CD86 expression, by CD27 + B220 + suggests these cells are of germinal center origin. The preferential depletion of CD27 + B220 − B cells mirrors alterations in spleen morphology and resident B cell populations due to HIV infection reported by other investigators and may play an important role in the defective B cell immunity against Tindependent pathogens such as pneumococcus observed in HIV-1-infected individuals.

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Section: Discussionmentioning

confidence: 99%

A Splenic Marginal Zone-Like Peripheral Blood CD27⁺B220⁻B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

Morrow

Valentı́n

Little

et al. 2008

AIDS Research and Human Retroviruses

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“…Two patients (3431 and 3429) were treated with a combination of three RTIs (Nevirapine, AZT, and Didanosine), and one (3419) was treated with two RTIs (AZT and Didanosine; ref. 53). Blood was collected at the start of treatment, at weeks 1, 2, and 4, then every 4 weeks until week 60, and subsequently at 2-monthly intervals, with the same HIV RNA assay described above, except that ultracentrifuging was used to obtain a lower detection limit of 20 copies per ml.…”

Section: Appendixmentioning

confidence: 99%

Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

Ferguson

DeWolf

Ghani

et al. 1999

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

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Antigen-induced stimulation of the immune system can generate heterogeneity in CD4؉ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4؉ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.T he advent of highly active antiretroviral therapy (HAART) has provided a wealth of information on the interaction between HIV and the human immune system and is continuing to stimulate the debate on the basic mechanisms of viral pathogenesis (1-3). Posttherapy patterns of viral load decline, and changes in CD4ϩ T cell population structure inform our knowledge of heterogeneity in within-host viral replication and immune system reconstitution. A central paradox remains, however. How does HIV cause immune system failure while infecting only a small overall proportion of CD4ϩ T cells? We address this question by placing the within-host dynamics of HIV replication within the context of an immune system that is heterogeneously structured in terms of the distribution of cell turnover rates by diverse and repeated antigenic stimulation. We use a model of antigen-driven T cell proliferation (4-8) to show that HIV infection can reduce the ability of a single antigen-specific activated CD4ϩ T cell subpopulation to help antigen clearance. The proliferation rate distribution of the entire CD4ϩ T cell population then emerges naturally from a consideration of the effect of constant immune system stimulation by multiple antigens. Inclusion of such population heterogeneity within a model of HIV replication in the lymph nodes is then shown to provide a conceptual framework capable of explaining the following key observations: a rapid multiphase decline in HIV RNA levels after treatment (9-15); a rapid initial rise in CD4ϩ T cells after treatment, followed by a phase of slower recovery (16-18); a low prevalence of HIV-infected CD4ϩ T cells in the peripheral blood and lymph nodes, as measured by HIV DNA levels (19-24); an increase in viral load after antigenic stimulation induced by vaccination (25-30); and faster CD4ϩ T cell replication after therapy than before treatment (31).One key point arising from this framework is that the CD4ϩ T cell population itself-not other cell classes-can provide the main reservoir (32-35) of long-lived infected cells, which have been shown by earlier models (36, 37) to be necessary to describe the observed multiphase posttreatment decline in HIV RNA levels. The hypothesis that long-lived CD4ϩ T cells are the dominant infected cell reservoir has ...

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Section: Introductionmentioning

confidence: 99%

“…It has been demonstrated that highly active antiretroviral therapy (HAART) results in reduced HIV-1 replication, increased CD4 cell counts in most treated patients, and progressive but incomplete recovery of CD4 ϩ T-cell functions. [1][2][3][4] Thus, treatment of chronic HIV infection does not result in most cases in a full recovery of HIV-specific helper and cytotoxic T lymphocyte (CTL) responses (reviewed in Sakaguchi et al 5 ).Recently, a CD4 ϩ T-cell subset with regulatory properties has been characterized in humans several years after their discovery in mice. [6][7][8][9][10] These cells, named "regulatory T" (Treg) cells express the ␣ chain of the interleukin 2 (IL-2) receptor (CD25) and can inhibit the proliferation of CD4 ϩ and CD8 ϩ T lymphocytes both in vitro and in vivo.…”

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confidence: 99%

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Weiss

Donkova-Petrini

Caccavelli

et al. 2004

Blood

351

312

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The present study demonstrates that CD4 ؉ CD25 ؉ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4 ؉ CD25 ؉ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 ( IntroductionHIV infection is mainly associated with a progressive decrease in the number of CD4 ϩ T lymphocytes and defective CD4-specific and CD8-specific T-cell responses against HIV and other pathogens. It has been demonstrated that highly active antiretroviral therapy (HAART) results in reduced HIV-1 replication, increased CD4 cell counts in most treated patients, and progressive but incomplete recovery of CD4 ϩ T-cell functions. [1][2][3][4] Thus, treatment of chronic HIV infection does not result in most cases in a full recovery of HIV-specific helper and cytotoxic T lymphocyte (CTL) responses (reviewed in Sakaguchi et al 5 ).Recently, a CD4 ϩ T-cell subset with regulatory properties has been characterized in humans several years after their discovery in mice. [6][7][8][9][10] These cells, named "regulatory T" (Treg) cells express the ␣ chain of the interleukin 2 (IL-2) receptor (CD25) and can inhibit the proliferation of CD4 ϩ and CD8 ϩ T lymphocytes both in vitro and in vivo. 9,11 It has been demonstrated that transfer of such cells can protect neonatally thymectomized mice from autoimmune diseases, whereas their depletion results in the development of systemic autoimmune diseases. [12][13][14] Moreover, alloantigen-induced CD4 ϩ CD25 ϩ regulatory T cells were reported to prevent rejection initiated by CD4 ϩ cells in both organ and bone marrow transplantation. 15,16 Although CD25 is usually considered as an activation marker, it has been shown that CD4 ϩ CD25 ϩ lymphocytes do not proliferate in response to polyclonal, allogenic, or antigen-specific stimulation 8,9,17 but require activation through their T-cell receptor (TCR) to exert their suppressive function. Their anergic state could be partially reversed by IL-2 and IL-15. 9 Besides CD4 ϩ CD25 ϩ regulatory T cells, 2 other types of CD4 ϩ cells with suppressive function have been described: type 1 T regulatory (Tr1) cells 18 and T-helper 3 (Th3) cells. 19 Tr1 cells were reported to suppress the immune response via the secretion of the immunosuppressive cytokines IL-10 and transforming growth factor ␤ (TGF-␤). The mechanism by which CD4 ϩ CD25 ϩ T cells mediate suppression seems to require direct cell-cell contact. Levings et al 19 have recently demonstrated, at the clonal level, that Tr1 and CD4 ϩ CD25 ϩ T cells are distinct subsets of regulatory T cells and that the suppression mediated by CD4 ϩ CD25 ϩ T cells is partially dependent on TGF-␤.In healthy individuals, the CD4 ϩ CD25 ϩ T-cell subset represents 5% to 10% of peripheral CD4 ϩ T cells and is characterized by the constitutive expression of CD152 (CTL-associate...

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Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy

Cited by 103 publications

References 35 publications

A Splenic Marginal Zone-Like Peripheral Blood CD27⁺B220⁻B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

A Splenic Marginal Zone-Like Peripheral Blood CD27⁺B220⁻B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

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Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy

Cited by 103 publications

References 35 publications

A Splenic Marginal Zone-Like Peripheral Blood CD27+B220−B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

A Splenic Marginal Zone-Like Peripheral Blood CD27+B220−B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

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Product

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A Splenic Marginal Zone-Like Peripheral Blood CD27⁺B220⁻B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals

A Splenic Marginal Zone-Like Peripheral Blood CD27⁺B220⁻B Cell Population Is Preferentially Depleted in HIV Type 1-Infected Individuals