Apoptosis in HIV-Infected Individuals Is an Early Marker Occurring Independently of High Viremia

Rothen, Madeleine; Gratzl, Stephanie; Hirsch, Hans H.; Moroni, Christoph

doi:10.1089/aid.1997.13.771

Cited by 23 publications

(12 citation statements)

References 31 publications

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“…Interestingly, we found a negative correlation between HIV viral load and DC m whereas the percentage of apoptotic cells was independent of the viral load, confirming the results of previous studies [40,41]. Reduction of DC m does not lead to cell apoptosis automatically.…”

Section: Mitochondrial Membrane Potential and Cd4 Cell Countsupporting

confidence: 91%

Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV‐1 infected patients

et al. 2009

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ObjectivesInfection with HIV leads to progressive CD4 T-cell loss, resulting in AIDS. Apoptosis is the main mechanism for the loss of infected and bystander cells, but the complex interacting factors inducing and inhibiting apoptosis are not fully understood. Mitochondrial dysfunction is a pivotal step of the apoptotic cascade and can result in reduced mitochondrial membrane potential. MethodsThe mitochondrial membrane potential of peripheral blood mononuclear cells (PBMC) was measured by flow cytometry using the dye JC-1 (Molecular Probes Inc). Apoptotic cells were identified using the Annexin V assay (Becton Dickinson GmbH). ResultsThe mitochondrial membrane potential of PBMC was significantly decreased and apoptotic cell rate was increased in HIV-infected therapy-naïve patients compared with HIV-negative controls. There was a highly significant correlation between the mitochondrial membrane potential and the rate of apoptosis. CD4 cell count was correlated negatively to the apoptotic rate and positively to the mitochondrial membrane potential. ConclusionsThe JC-1 assay is a sensitive tool to detect changes of mitochondrial membrane potential associated with apoptosis in HIV-infected therapy-naïve patients. We could show in vivo that a reduction of mitochondrial membrane potential is correlated to apoptosis of PBMC, CD4 cell count and HIV viral load during HIV infection. IntroductionInfection with HIV leads to progressive CD4 T-cell death, resulting in the development of AIDS. The mechanisms triggering this CD4 T-cell death are still not understood fully, but data indicate that apoptosis plays a major role [1]. There is a correlation between the extent of apoptosis and disease progression [2,3], and highly active antiretroviral therapy is associated with a lower level of CD4 T-cell apoptosis in HIV-1 infected patients [4][5][6][7].Both infected and uninfected CD4 T-cells can die during HIV-1 infection by different cell death pathways, but HIV-1 induced bystander CD4 T-cell demise is now recognized as pivotal to the development of immunodeficiency. Chronically increased activation of the immune system may contribute directly to progressive CD4 T-cell depletion, irrespective of viral load [8,9]. Upon receiving a death signal, a cascade of molecular events resulting in the activation or inactivation of numerous cellular proteins is initiated, leading to morphological and biochemical changes such as plasma membrane blebbing, DNA fragmentation and mitochondrial dysfunction. The regulators of the apoptotic pathway exert their function primarily at the mitochondrion by either preventing or inducing mitochondrial dysfunction [10,11]. Furthermore, there is evidence that resistance to apoptosis in persistently infected cells involves direct modulation of the mitochondrial pathway [1]. The measurement of the mitochondrial membrane potential of peripheral blood mononuclear cells (PBMC) might be a useful tool to [24]. In the early stages of apoptosis, there are changes at the cell surface. One of these plasma membrane al...

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Section: Mitochondrial Membrane Potential and Cd4 Cell Countsupporting

confidence: 91%

Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV‐1 infected patients

et al. 2009

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“…Finally, the state of chronic immune activation in HIV infection has been linked to the gradual and continuous process of immune deficiency resulting from T cell depletion [44]. Although the evidence for a direct correlation between the level of viral load and cell apoptosis is still questionable [45], results on the use of highly active anti-retroviral therapy suggest a direct relationship between sustained suppression of viral replication and enhanced lymphocyte count or immune recovery [46]. Moreover, effective anti-retroviral treatment has been recently demonstrated to result in down-regulation of CD95-ligand expression on T cells, suggesting that significant reduction in virus replication could lead to a decrease in the PCD of uninfected cells [47].…”

Section: Discussionmentioning

confidence: 99%

Recombinant human IL-16 inhibits HIV-1 replication and protects against activation-induced cell death (AICD)

Idziorek

Khalife

Billaut-Mulot

et al. 1998

Clinical and Experimental Immunology

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The chemoattractant cytokine IL- 16 has been reported to suppress lymphocyte activation and to inhibit HIV-1 replication in acutely infected T cells. We have cloned and expressed human IL-16 in Escherichia coli and investigated whether the recombinant protein could regulate the level of lymphocyte apoptosis from HIV-1-infected subjects. After purification and refolding, only 2-10% of the recombinant cytokine was present in a biologically active homotetrameric form. This could explain the need for high concentrations of the bacterially derived IL- 16 to induce significant inhibition of HIV-1 replication. Addition of IL-16 to unstimulated peripheral blood mononuclear cell (PBMC) cultures from HIV-1-infected subjects did not modify the observed level of spontaneous lymphocyte apoptosis. In contrast, IL-16 added to PBMC cultures stimulated with anti-CD3, anti-CD95 or dexamethasone reduced significantly the percentage of lymphocytes undergoing AICD. This effect was found to correlate with the ability of the cytokine to decrease CD95 expression on activated CD4+ T cells. Comparative studies on PBMC from healthy individuals indicated that the regulation of apoptosis levels by IL-16 is a complex phenomenon and could depend on the nature of the activator used and/or the immune status of lymphocytes tested. The outcome of CD4 cross-linking on T cells by various ligands is discussed in the context of the observed beneficial activities of IL- 16 and its potential role in the treatment of HIV disease.

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“…3 This suggests several possibilities: (1) not all of the CD4T-cell apoptosis is driven by active viral replication or the immune response to such; or (2) the circulating CD4T cells, although the easiest to quantify, are not necessarily the most physiologically relevant compartment to gauge functional CD4T-cell loss. Both of these possibilities are supported by one early investigation of apoptosis in lymph nodes of HIV-infected persons that showed increased apoptosis compared with uninfected persons; and in that study, the majority of the apoptotic cells, defined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining positivity, were not demonstrated to be infected.…”

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Mechanisms of HIV-associated lymphocyte apoptosis: 2010

2010

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The inevitable decline of CD4T cells in untreated infection with the Human immunodeficiency virus (HIV) is due in large part to apoptosis, one type of programmed cell death. There is accumulating evidence that the accelerated apoptosis of CD4T cells in HIV infection is multifactorial, with direct viral cytotoxicity, signaling events triggered by viral proteins and aberrant immune activation adding to normal immune defense mechanisms to contribute to this phenomenon. Current antiviral treatment strategies generally lead to reduced apoptosis, but this approach may come at the cost of preserving latent viral reservoirs. It is the purpose of this review to provide an update on the current understanding of the role and mechanisms of accelerated apoptosis of T cells in the immunopathogenesis of HIV infection, and to highlight potential ways in which this seemingly deleterious process could be harnessed to not just control, but treat HIV infection.

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Apoptosis in HIV-Infected Individuals Is an Early Marker Occurring Independently of High Viremia

Cited by 23 publications

References 31 publications

Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV‐1 infected patients

Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV‐1 infected patients

Recombinant human IL-16 inhibits HIV-1 replication and protects against activation-induced cell death (AICD)

Mechanisms of HIV-associated lymphocyte apoptosis: 2010

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