Differential Expression ofbcl-2and Susceptibility to Programmed Cell Death in Lymphocytes of HIV-1-Infected Individuals

Dobmeyer, Thomas S.; Klein, Stefan; Dobmeyer, Jürgen; Raffel, Bernhard; Findhammer, Stephan; Hoelzer, Dieter; Helm, E. B.; Rossol, Rita; Kabelitz, Dieter

doi:10.1006/clin.1997.4465

Cited by 10 publications

(6 citation statements)

References 26 publications

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“…The HIV-associated reduction in mDC Bcl-2 expression reported in the present study concurs with findings of reduced Bcl-2 expression described in T cells during HIV-1 infection (1,14,26,80,83,100), raising the possibility that a common mechanism may be responsible for predisposing both mDCs and T cells to apoptosis. Most studies addressing the effect of ART on levels of T-cell Bcl-2 expression have noted increased expression of Bcl-2 with therapy (1,4,93), although one study found that Bcl-2 expression by T cells was not altered during 6 months of ART (38).…”

Section: Discussionsupporting

confidence: 92%

“…It is also possible that the lack of differences using this measure of apoptosis simply reflects a poor correlation between assays assessing different stages of the apoptosis pathway or in those carried out on cells directly ex vivo versus following a culture period. Indeed, in an early study of T-cell apoptosis during HIV-1 infection, lower Bcl-2 expression of CD4 ϩ and CD8 ϩ T cells measured directly ex vivo did not correlate with the percentage of cells induced to undergo apoptosis in vitro (26).…”

Section: Discussionmentioning

confidence: 96%

“…Subsequent in vivo studies demonstrated apoptotic T cells and B cells within the LNs of HIV-1-infected individuals (13,74). Increased blood T-cell apoptosis has been associated with disease progression, (26,34,73,98), and the expression of markers of apoptosis is predictive of adverse clinical events (96).…”

mentioning

confidence: 99%

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Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Dillon

Friedlander

Rogers

et al. 2011

J Virol

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Reduced frequencies of myeloid and plasmacytoid dendritic cell (DC) subsets (mDCs and pDCs, respectively) have been observed in the peripheral blood of HIV-1-infected individuals throughout the course of disease. Accumulation of DCs in lymph nodes (LNs) may partly account for the decreased numbers observed in blood, but increased DC death may also be a contributing factor. We used multiparameter flow cytometry to evaluate pro-and antiapoptotic markers in blood mDCs and pDCs from untreated HIV-1-infected donors, from a subset of infected donors before and after receiving antiretroviral therapy (ART), and from uninfected control donors. Blood mDCs, but not pDCs, from untreated HIV-1-infected donors expressed lower levels of antiapoptotic Bcl-2 than DCs from uninfected donors. A subset of HIV-1-infected donors had elevated frequencies of proapoptotic caspase-3 ؉ blood mDCs, and positive correlations were observed between caspase-3 ؉ mDC frequencies and plasma viral load and CD8 ؉ T-cell activation levels. Caspase-3 ؉ mDC frequencies, but not mDC Bcl-2 expression, were reduced with viral suppression on ART. Apoptosis markers on DCs in blood and LN samples from a cohort of untreated, HIV-1-infected donors with chronic disease were also evaluated. LN mDCs displayed higher levels of Bcl-2 and lower caspase-3 ؉ frequencies than did matched blood mDCs. Conversely, LN pDCs expressed lower Bcl-2 levels than their blood counterparts. In summary, blood mDCs from untreated HIV-1-infected subjects displayed a proapoptotic profile that was partially reversed with viral suppression, suggesting that DC death may be a factor contributing to blood DC depletion in the setting of chronic, untreated HIV disease.Dendritic cells (DCs) are antigen-presenting cells (APCs) found throughout the body that are central in bridging innate and adaptive immune responses (5, 6). Immature DCs typically detect the presence of microbes through the binding of conserved molecular patterns to pattern recognition receptors (PRRs) such as C-type lectins and Toll-like receptors (TLRs) (32, 55). DCs exposed to microbial products then undergo a regulated maturation process, migrate to lymph nodes (LNs) and stimulate naive T cells and other immune cells to induce appropriate adaptive immune responses (5, 6). Although shown to be the most potent of the APCs in activating naive T cells, DCs have also recently been shown to play a crucial role in reactivating memory T cells (43,95,99) and in maintaining peripheral tolerance to self-antigens (91, 92).Human DCs can be divided into myeloid DC (mDC) and plasmacytoid DC (pDC) subsets that differ in ontogeny, phenotype, and function (19, 50, 51, 53, 54, 61, 77-79, 87, 94). Specifically, pDCs are considered to be involved in antiviral immunity, are capable of sensing viral single-stranded RNA (ssRNA) through TLR7 and bacterial CpG DNA through TLR9, and predominantly produce type I interferons (IFNs). Conversely, mDCs sense both bacterial and viral pattern motifs through a broader range of TLRs (TLR1 to TLR8) and are in...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

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Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Dillon

Friedlander

Rogers

et al. 2011

J Virol

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“…An increased oxidative stress condition has been repeatedly described in chronically HIV-1-infected patients, based on: elevated extracellular and intracellular ROS levels [46][47][48][49][50][51][52][53], systemic reduction in glutathione (GSH) and thioredoxin concentrations [54], disturbance of mitochondrial membrane potential [55], and changes in expression and activation status of cell death receptors [56], which may lead to host cell death [52,57]. An increased HIV-1 replication, induced by ROS, has been observed in reservoir cells [58].…”

Section: Ros and Hiv-1 Infectionmentioning

confidence: 99%

Immune Modulators of HIV Infection: The Role of Reactive Oxygen Species

Salmen¹,

Berrueta²

2012

J Clin Cell Immunol

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A continue loss of CD4 + T lymphocytes, immune response dysfunction and chronic immune activation (IA) are hallmarks of untreated chronic HIV-1 infection. ROS and the subsequent oxidative stress have been connected with chronic activation of the immune system, viral replication, immune dysfunction, programmed cell death, and neurological damage, all considered to be major contributing issues in HIV-1 diseases progression. It has been demonstrated that HAART partially restore the antioxidant capacity by suppressing HIV, and it has been suggested that antioxidant therapy in combination with HAART could protect the blood brain barrier from oxidative stressinduced damage. Several mechanisms have been proposed to explain how HIV could modulate ROS generation and several HIV proteins have been shown to modulate ROS production. This review is intended to highlight the role played by ROS as modulators of the immune system during the course of HIV infection, which could explain its contribution to disease progression, opening the scope to new strategies for drug design and future treatment.

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“…The findings in human cells infected with HIV-1 are consistent with our data. Although susceptibility to activation-induced apoptosis was found to correlate with Bcl2 expression in human T cells (42), death of HIV-1-infected T cells was found by other groups to be independent of Bcl2 (13,39,63).…”

mentioning

confidence: 99%

The Nef-Mediated AIDS-Like Disease of CD4C/Human Immunodeficiency Virus Transgenic Mice Is Associated with Increased Fas/FasL Expression on T Cells and T-Cell Death but Is Not Prevented in Fas-, FasL-, Tumor Necrosis Factor Receptor 1-, or Interleukin-1β-Converting Enzyme-Deficient or Bcl2-Expressing Transgenic Mice

Priceputu

Rodrigue

Chrobák

et al. 2005

J Virol

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CD4؉ -and CD8 ؉ -T-cell death is a frequent immunological dysfunction associated with the development of human AIDS. We studied a murine model of AIDS, the CD4C/HIV transgenic (Tg) mouse model, to assess the importance of the apoptotic pathway in human immunodeficiency virus type 1 (HIV-1) pathogenesis. In these Tg mice, Nef is the major determinant of the disease and is expressed in immature and mature CD4 Moreover, the double-Tg mice from a cross between the Bcl2/Wehi25 and CD4C/HIV Tg mice showed no major protection against disease. These results represent genetic evidence for the dispensable role of Fas, FasL, ICE, and TNFR-1 on the development of both T-cell loss and organ disease of these Tg mice. They also provide compelling evidence on the lack of protection by Bcl2 against Tg CD4؉ -T-cell death. In view of the high resemblance between numerous phenotypes observed in the CD4C/HIV Tg mice and in human AIDS, our findings are likely to be relevant for the human disease.

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Differential Expression ofbcl-2and Susceptibility to Programmed Cell Death in Lymphocytes of HIV-1-Infected Individuals

Cited by 10 publications

References 26 publications

Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Immune Modulators of HIV Infection: The Role of Reactive Oxygen Species

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Differential Expression ofbcl-2and Susceptibility to Programmed Cell Death in Lymphocytes of HIV-1-Infected Individuals

Cited by 10 publications

References 26 publications

Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3+Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3+Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Immune Modulators of HIV Infection: The Role of Reactive Oxygen Species

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Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study