In Vivo Evolution of Human Immunodeficiency Virus Type 1 toward Increased Pathogenicity through CXCR4-Mediated Killing of Uninfected CD4 T Cells

Jekle, Andreas; Keppler, Oliver T.; Clercq, Erik De; Schols, Dominique; Weinstein, Mark D.; Goldsmith, Mark A.

doi:10.1128/jvi.77.10.5846-5854.2003

Cited by 117 publications

(124 citation statements)

References 51 publications

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“…Hence, the hypothesis that gp41-mediated hemifusion results in bystander cell death may not be just an in vitro effect but also correlates with in vivo clinical findings and has implications for Enfuvirtide therapy. The nat- ural progression of HIV disease results in the selection of more pathogenic (42) and probably more fusogenic Env proteins as a selection for viral fitness. However, the use of Enfuvirtide therapy to select less fusogenic and consequently less pathogenic viruses may be beneficial to patients, even after failure of Enfuvirtide therapy to control virus replication.…”

Section: Discussionmentioning

confidence: 99%

Site-specific Mutations in HIV-1 gp41 Reveal a Correlation between HIV-1-mediated Bystander Apoptosis and Fusion/Hemifusion

Garg

Joshi

Freed

et al. 2007

Journal of Biological Chemistry

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The loss of CD4؉ T cells in HIV-1 infections is hypothesized to be caused by apoptosis of bystander cells mediated by cell surface-expressed HIV-1 Env glycoprotein. However, the mechanism by which Env mediates this process remains controversial. Specifically, the role of HIV-1 gp120 binding to CD4 and CXCR4 versus the fusion process mediated by gp41 remains unresolved. Env-induced apoptosis in bystander cells has been shown to be gp41-dependent and correlates with the redistribution of membrane lipids between Env-expressing cells and target cells (hemifusion). Using a rational mutagenesis approach aimed at targeting Env function via the gp41 subunit, we examined the role of HIV gp41 in bystander apoptosis. A mutation in the fusion domain of gp41 (V513E) resulted in a fusion-defective Env that failed to induce apoptosis. A mutation in the gp41 N-terminal helix (G547D) reduced cell fusion capacity and apoptosis; conversely, an Env mutant with a deletion of the gp41 cytoplasmic tail (Ct Del) enhanced both cell-to-cell fusion and apoptosis. Most significantly, an Env mutant containing a substitution in the loop region of gp41 (D589L) mediated transfer of lipids (hemifusion) to bystander cells but was defective in cellto-cell and to a lesser degree virus-to-cell fusion. This mutant was still able to induce apoptosis in bystander cells. Hence, we have provided the first direct evidence that gp41-mediated hemifusion is both required and sufficient for induction of apoptosis in bystander cells. These results may help to explain the mechanism of HIV-1 Env-induced T cell depletion.The mechanism by which HIV 2 induces T cell depletion leading to immunodeficiency remains unresolved. As the number of CD4 ϩ T cells lost during HIV infection far exceeds the number of infected cells (1), it is believed that HIV induces the death of uninfected bystander cells via apoptosis (2). The Env glycoprotein is a good candidate for inducing bystander cell death, as it is expressed on the surface of infected cells and can interact with bystander cells expressing the HIV receptor (CD4) and co-receptors (CXCR4/CCR5). Furthermore, because the depletion of T cells is largely restricted to CD4 ϩ cells, a role for the Env glycoprotein in either direct or indirect killing of bystander cells has been proposed (3).The Env glycoprotein of HIV consists of a CD4-and CXCR4-binding gp120 subunit and a membrane fusion-inducing gp41 subunit. Although the role of the Env glycoprotein in inducing bystander cell death is well studied, it remains controversial whether gp120 or gp41 are major players in this process. It is well established that the fusion capacity of HIV gp41 contributes to HIV-induced pathogenesis both in vitro (4) and in vivo (5, 6). However, because HIV Env-induced syncytia formation is not a universal pathogenic feature of HIV infection, it is unclear how HIV gp41 could cause depletion of CD4 ϩ cells in the absence of cell-to-cell fusion. It has been suggested that gp41-mediated autofusion may lead to the death of Env-expressing cells (7)....

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Section: Discussionmentioning

confidence: 99%

Site-specific Mutations in HIV-1 gp41 Reveal a Correlation between HIV-1-mediated Bystander Apoptosis and Fusion/Hemifusion

Garg

Joshi

Freed

et al. 2007

Journal of Biological Chemistry

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“…1,2,[8][9][10] The third proposed mechanism is excessive, ongoing immune activation caused by a high, persistent viral antigen load and leading to the activation-induced death of various uninfected immune cells, including CD4 þ T cells. 1,2,4,8,9 Evidence for the involvement of indirect mechanisms of CD4 þ T-cell killing has been provided by the identification in vivo [11][12][13][14][15][16] and ex vivo [17][18][19] of increased number of dying, uninfected immune cells, including CD4 þ T cells, both in HIV1-infected persons and in non-human primate models of pathogenic simian immunodeficiency virus (SIV) infection, that are closely related to HIV. An important question is whether HIV1 may only cause death in activated, cycling CD4 þ T cells, or also in unstimulated noncycling CD4 þ T cells, which represent at any given time point the vast majority of the CD4 þ T cells in HIV1-infected persons.…”

Section: Introductionmentioning

confidence: 99%

“…3 Because most of the viral particles produced during HIV1 infection are replication-defective, 6 but can still bind to-, and enter into-CD4 þ T cells, viral proteins present at the surface or inside the viral particles have been proposed as candidates for the killing of noncycling CD4 þ T cells in the absence of productive infection of these cells. In vitro findings have suggested that among such viral proteins, the HIV1 surface envelope (Env) constitutes a major potential candidate for the HIV1-mediated killing of CD4 þ T cells in the absence of productive infection, 16,[20][21][22][23][24][25][26] through death signaling caused by engagement of either its cell-surface receptor, CD4 [27][28][29] or, for the Env of X4-tropic HIV1 strains, of its CXCR4 coreceptor. 25,26,30,31 Incubation of noncycling, primary CD4 þ T cells with X4-tropic HIV1 viral particles has been previously reported to cause CD4 þ T-cell death, after a delay of 3-4 days.…”

Section: Introductionmentioning

confidence: 99%

“…In vitro findings have suggested that among such viral proteins, the HIV1 surface envelope (Env) constitutes a major potential candidate for the HIV1-mediated killing of CD4 þ T cells in the absence of productive infection, 16,[20][21][22][23][24][25][26] through death signaling caused by engagement of either its cell-surface receptor, CD4 [27][28][29] or, for the Env of X4-tropic HIV1 strains, of its CXCR4 coreceptor. 25,26,30,31 Incubation of noncycling, primary CD4 þ T cells with X4-tropic HIV1 viral particles has been previously reported to cause CD4 þ T-cell death, after a delay of 3-4 days. 32,33 The aims of our study were first to confirm this latter finding, and then to investigate the mechanisms involved.…”

Section: Introductionmentioning

confidence: 99%

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A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

et al. 2004

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CD4 þ T-cell death is a crucial feature of AIDS pathogenesis, but the mechanisms involved remain unclear. Here, we present in vitro findings that identify a novel process of HIV1 mediated killing of bystander CD4 þ T cells, which does not require productive infection of these cells but depends on the presence of neighboring dying cells. X4-tropic HIV1 strains, which use CD4 and CXCR4 as receptors for cell entry, caused death of unstimulated noncycling primary CD4 þ T cells only if the viruses were produced by dying, productively infected T cells, but not by living, chronically infected T cells or by living HIV1-transfected HeLa cells. Inducing cell death in HIV1-transfected HeLa cells was sufficient to obtain viruses that caused CD4 þ T-cell death. The addition of supernatants from dying control cells, including primary T cells, allowed viruses produced by living HIV1-transfected cells to cause CD4 þ Tcell death. CD4 þ T-cell killing required HIV1 fusion and/or entry into these cells, but neither HIV1 envelope-mediated CD4 or CXCR4 signaling nor the presence of the HIV1 Nef protein in the viral particles. Supernatants from dying control cells contained CD95 ligand (CD95L), and antibody-mediated neutralization of CD95L prevented these supernatants from complementing HIV1 in inducing CD4 þ T-cell death. Our in vitro findings suggest that the very extent of cell death induced in vivo during HIV1 infection by either virus cytopathic effects or immune activation may by itself provide an amplification loop in AIDS pathogenesis. More generally, they provide a paradigm for pathogen-mediated killing processes in which the extent of cell death occurring in the microenvironment might drive the capacity of the pathogen to induce further cell death.

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“…180 When HIV translates into the more advanced AIDS, CXCR4 becomes the more relevant receptor. 181 Although potent inhibitors of CXCR4 exist, their clinical utility is limited by severe side effects. Indeed, since CXCR4 or CXCL12 knockout mice are not viable, significant doubt remains over whether this pathway can be safely manipulated in the long term.…”

Section: Chemokines As Therapeutic Targetsmentioning

confidence: 99%

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

Rees¹,

Greaves²,

Baguneid

et al. 2015

Advances in Wound Care

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In Vivo Evolution of Human Immunodeficiency Virus Type 1 toward Increased Pathogenicity through CXCR4-Mediated Killing of Uninfected CD4 T Cells

Cited by 117 publications

References 51 publications

Site-specific Mutations in HIV-1 gp41 Reveal a Correlation between HIV-1-mediated Bystander Apoptosis and Fusion/Hemifusion

Site-specific Mutations in HIV-1 gp41 Reveal a Correlation between HIV-1-mediated Bystander Apoptosis and Fusion/Hemifusion

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

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