Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

Karlsson, Ingrid; Grivel, Jean‐Charles; Chen, Fengde; Karlsson, Anders; Albert, Jan; Fenyõ, Éva Mária; Margolis, Leonid

doi:10.1128/jvi.79.17.11151-11160.2005

Cited by 22 publications

(21 citation statements)

References 63 publications

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“…We can speculate that these viruses could have sufficient mutations in V3 to enable them to interact with CXCR4 and thereby activate bystander T cells, even if these viruses could not efficiently infect target cells via CXCR4 and thus did not have an X4 phenotype. This model of X4-like pathogenicity of R5 "late" viruses might be consistent with studies reporting increased pathogenicity in R5-infected patients during latestage disease (22,28,39).…”

Section: Our Investigation Of the Immunological And Virological Detersupporting

confidence: 76%

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Delobel

Nugeyre

Cazabat

et al. 2006

J Virol

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The reasons for poor CD4؉ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeostasis during immune reconstitution on HAART. We examined this hypothesis and the mechanisms of CD4 ؉ T-cell restoration by comparing the virological and immunological features of 15 poor and 15 good immunological responders to HAART. We found a high frequency of X4 viruses in the poor immunological responders. But the levels of intrathymic proliferation of the two groups were similar regardless of whether they were infected by R5 or X4 virus. The frequency of recent thymic emigrants in the poor immunological responders was also similar to that found in the good immunological responders, despite their reduced numbers of naïve CD4 ؉ T cells. Our data, rather, suggest that the naïve T-cell compartment is drained by a high rate of mature naïve cell loss in the periphery due to bystander apoptosis or activation-induced differentiation. X4 viruses could play a role in the depletion of naïve T cells in poor immunological responders to HAART by triggering persistent T-cell activation and bystander apoptosis via gp120-CXCR4 interactions.Highly active antiretroviral therapy (HAART) successfully controls human immunodeficiency virus type 1 (HIV-1) replication in most individuals, resulting in substantial immune restoration and decreased morbidity and mortality. However, the suppression of detectable HIV-1 viremia does not invariably result in a significant increase in CD4 ϩ T cells. Five to 15% of HIV-infected patients still have a CD4ϩ T-cell counts of Ͻ200 cells/l and are thus at risk of developing AIDS, despite being on HAART for several years (15, 23).The mechanisms responsible for these persistently low CD4 ϩ T-cell counts are not clear; they could be due to impaired reconstitution or to excessive destruction of CD4 ϩ T cells. The recovery of peripheral CD4 ϩ T-cell counts in patients on HAART depends mainly on a slow increase in naïve CD4 ϩ T cells (3). Several studies have suggested that the thymus plays a role in immune reconstitution during HIV-1 infection, even in adults (12,34,36), but the extent to which it determines the regeneration of the peripheral CD4 ϩ T-cell pool in patients on HAART remains unclear. Analyses of thymic activity are hampered by the difficulty of directly measuring thymic output. Most studies have measured the signaljoint (sj) T-cell receptor (TCR) excision circle (TREC) in blood T cells. This surrogate marker of thymic activity is a byproduct of the TCR␦ locus rearrangement within the TCR␣ locus (␦Rec-J␣ rearrangement) that occurs during thymopoiesis (5,11,12,36,44). However, TRECs persist in recen...

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Section: Our Investigation Of the Immunological And Virological Detersupporting

confidence: 76%

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Delobel

Nugeyre

Cazabat

et al. 2006

J Virol

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“…Ϫ subsets was that CD4 ϩ cells are the target cells for HIV-1, and both CD4 and CCR5 are downregulated on cells after infection with HIV-1 (6,22,48). The percentages of CCR5 ϩ CD4 ϩ T cells and concentrations of CCR5 receptors on the surfaces of CD4 ϩ T-cell subsets were significantly related to concentrations of virus within the subsets; log 10 HIV-1 RNA/10 5 cells increased 0.54 (95% CI, 0.33 to 0.74) for each 10% increase in the percentage of CCR5 (Fig.…”

Section: Ccr5 Expression On Cd4mentioning

confidence: 99%

HLA-DR⁺CD38⁺CD4⁺T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

Meditz

Haas

Folkvord

et al. 2011

J Virol

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“…However, in 50% of patients there is no switch in coreceptor usage, and although the presence of X4 tropic virus has been associated with poor prognosis in patients, it is evident that the coreceptor switch is not absolutely essential for progression to AIDS (63). Nevertheless, the selection of more pathogenic CCR5 utilizing HIV has been documented.…”

Section: Discussionmentioning

confidence: 99%

HIV ENV Glycoprotein-mediated Bystander Apoptosis Depends on Expression of the CCR5 Co-receptor at the Cell Surface and ENV Fusogenic Activity

Joshi

Nyakeriga

Ravi

et al. 2011

Journal of Biological Chemistry

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HIV-1 infections lead to a progressive depletion of CD4 cells culminating in AIDS. The coreceptor usage by HIV varies from CCR5 (R5) tropic early in infection to CXCR4 (X4) tropic in later infections. Although the coreceptor switch from R5 to X4 tropic HIV is well associated with progression to AIDS, the role of CCR5 in disease progression especially in patients infected exclusively with R5 isolates throughout the disease remains enigmatic. To better understand the role of CCR5 and R5 tropic HIV envelope in AIDS pathogenesis, we asked whether the levels of CCR5 and/or HIV Env-mediated fusion determine apoptosis of bystander cells. We generated CD4 ؉ T cell lines expressing varying levels of CCR5 on the cell surface to show that CCR5 expression levels correlate with bystander apoptosis induction. The mechanism of apoptosis involved caspase-3 activation and mitochondrial depolarization and was dependent on gp41 fusion activity as confirmed by fusion-restricted gp41 point mutants and use of the fusion inhibitor T20. Interestingly, lower levels of CCR5 were able to support virus replication in the absence of bystander apoptosis. Our findings suggest that R5 HIV-1-mediated bystander apoptosis is dependent on both CCR5 expression levels as well as fusogenic activity of the Env glycoprotein.For viral entry, HIV-1 utilizes CD4 as receptor and one of the chemokine receptors as coreceptors, the most common ones being CXCR4 (X4) and CCR5 (R5) (1-3). It is well known that R5 tropic viruses predominate during the initial establishment of infection as they are transmitted with greater efficiency (4 -6), whereas the X4 viruses emerge later during the disease and are associated with rapid progression to AIDS (7,8). The progressive increase in virulence in vivo during the late stages of disease is attributed in many cases to a coreceptor switch from CCR5 tropic to CXCR4 tropic HIV (9 -11). Although in approximately half of the HIV infections the virus switches coreceptor usage to CXCR4, and there are several hypotheses to explain this phenomenon (12-15), the mechanism by which R5 tropic HIV isolates lead to AIDS remains poorly defined especially in patients that remain solely infected with R5 isolates throughout the disease.Although HIV selectively infects CD4 ϩ cells, the relatively few infected cells in vivo do not account for the extensive depletion of CD4 cells. This has led to the idea that the virus is able to kill uninfected bystander CD4 ϩ cells (16) (24,25). In support of this observation, we and others showed that the fusion process mediated by the gp41 subunit of HIV envelope may be critical in bystander killing (26 -28). Furthermore, through mutagenesis studies, we demonstrated that hemifusion (incomplete fusion accompanied by partial mixing of apposing cell membranes) induced by gp41 subunit is the major mechanism for HIV Env-mediated bystander T cell apoptosis (29). The fusion of biological membranes mediated by HIV Env, specifically in the case of R5 tropic viruses, is dependent on the expression level of CCR5 cor...

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Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

Cited by 22 publications

References 63 publications

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

HLA-DR⁺CD38⁺CD4⁺T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

HIV ENV Glycoprotein-mediated Bystander Apoptosis Depends on Expression of the CCR5 Co-receptor at the Cell Surface and ENV Fusogenic Activity

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Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

Cited by 22 publications

References 63 publications

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

HLA-DR+CD38+CD4+T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo

HIV ENV Glycoprotein-mediated Bystander Apoptosis Depends on Expression of the CCR5 Co-receptor at the Cell Surface and ENV Fusogenic Activity

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HLA-DR⁺CD38⁺CD4⁺T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNAInVivo