Evaluation of the human herpesvirus 8 DNA load in blood and Kaposi's sarcoma skin lesions from AIDS Patients on highly active antiretroviral therapy

Boivin, Guy; Gaudreau, Annie; Routy, Jean‐Pierre

doi:10.1097/00002030-200009080-00004

Cited by 56 publications

(39 citation statements)

References 17 publications

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“…For a KS tumor mass to expand under such conditions, continuous (re)infection of such KSHV-negative cells by infectious virus produced by lytic replication would be required to sustain high levels of latency in the tumor. This is consistent with clinical studies showing that progression to advanced KS is linked to high KSHV viral loads (69)(70)(71). Our findings encourage the view that a principal role of HIV-induced immune depletion in KS pathogenesis may be to cause the host to lose control of lytic KSHV replication.…”

Section: Discussionsupporting

confidence: 91%

Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis

Grundhoff¹,

Ganem²

2004

J. Clin. Invest.

227

240

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Section: Discussionsupporting

confidence: 91%

Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis

Grundhoff¹,

Ganem²

2004

J. Clin. Invest.

227

240

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“…Interestingly, KS spindle-like cells can be detected in the PBMC fraction of peripheral blood of HIV-positive patients with or at risk for KS, a possible explanation for the multifocal nature of this disease (7). However, the third subject with progressing KS had fewer than 1 HHV-8 genome per 6 million PBMCs, consistent with prior observations that KS lesions are not always associated with high virus levels in PBMCs (4,5,16). In sum, while there is an association in our data and in data from others, peripheral blood virus load is much less tightly linked to pathogenesis for HHV-8 and KS than for EBV and PTLD.…”

Section: Hhv-8 Genome and Infected-cell Frequencies In Pbmcssupporting

confidence: 88%

“…When measured as net HHV-8 genome copy numbers per bulk quantity of PBMCs, the frequency of HHV-8 genomes in KS subjects with a positive PCR result ranged from 12 to 1,090 copies per 10 6 PBMCs (median of 244), in agreement with other studies that used quantitative PCR (3,4,26). In EBVinfected individuals with PTLD, these virus genome loads would be considered low (29).…”

Section: Hhv-8 Genome and Infected-cell Frequencies In Pbmcssupporting

confidence: 86%

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Evidence for both Lytic Replication and Tightly Regulated Human Herpesvirus 8 Latency in Circulating Mononuclear Cells, with Virus Loads Frequently below Common Thresholds of Detection

Martró

Cannon²,

Dollard³

et al. 2004

J Virol

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To address whether human herpesvirus 8 (HHV-8) DNA in peripheral blood mononuclear cells (PBMCs) might be the product of latent or lytic infection and to shed light on sporadic detection of HHV-8 DNA in individuals seropositive for the virus, we studied the frequency of infected cells, total virus load, and virus load per infected cell in PBMCs from men coinfected with HHV-8 and human immunodeficiency virus (HIV), some of whom had Kaposi's sarcoma. The low frequencies of infected cells detected (fewer than one per million cells in some individuals) suggest that the prevalence of the virus in circulating leukocytes was underestimated in previous studies that employed more conventional sampling methods (single, small-volume specimens). Mean virus loads ranged from 3 to 330 copies per infected PBMC; these numbers can represent much higher loads in individual lytically infected cells (>10 3 genomes/cell) in mixtures that consist predominantly of latently (relatively few genomes) infected cells. The presence in some subjects of high HHV-8 mean genome copy numbers per infected cell, together with viral DNA being found in plasma only from subjects with positive PBMCs, supports earlier suggestions that the virus can actively replicate in PBMCs. In some individuals, mean virus loads were less than 10 genomes per infected cell, suggesting a tightly controlled purely latent state. HHV-8 genome copy numbers are substantially higher in latently infected cells derived from primary effusion lymphomas; thus, it appears that HHV-8 is able to adopt more than one latency program, perhaps analogous to the several types of Epstein-Barr virus latency.

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“…Several studies have shown an association of DNA positivity and higher levels of HHV-8 DNA in blood and tissues with development of KS and other HHV-8-related diseases. [52][53][54][55][56] We hypothesize that such viral replication may boost CD8 ϩ T-cell responses against HHV-8 lytic cycle proteins. This T-cell reactivity in turn acts to quell viral replication and prevent development of disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of an HLA A*0201–restricted CD8+T-cell epitope for the glycoprotein B homolog of human herpesvirus 8

Wang

Huang

Rappocciolo

et al. 2002

Blood

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IntroductionHuman herpesvirus 8 (HHV-8; also termed Kaposi sarcomaassociated herpesvirus) is a gammaherpesvirus that is considered to be the causative agent of Kaposi sarcoma (KS), body cavity B-cell lymphoma, and multicentric Castleman disease. 1 T-cell immunity is thought to play an important role in control of HHV-8 infection and these associated diseases. [2][3][4][5] In this regard, we 2,3 and others 4 have demonstrated that major histocompatibility complex (MHC) class I-restricted, CD8 ϩ cytotoxic T lymphocytes (CTLs), and interferon ␥ (IFN-␥) responses are detectable in peripheral blood mononuclear cells (PBMCs) of HHV-8 ϩ individuals using recombinant vaccinia viruses expressing HHV-8 lytic and latent cycle proteins. These anti-HHV-8 T-cell responses are lower during human immunodeficiency virus type 1 (HIV-1) infection and may be involved in prevention of KS and other HHV-8-associated diseases.Support for the potential role of CD8 ϩ T-cell immunity in control of HHV-8 infection comes from several studies on immune control of acute and persistent infections with 2 other gammaherpesviruses, specifically, Epstein-Barr virus (EBV) and murine herpesvirus 68 (MHV-68). 6-10 Although EBV latency proteins can induce strong CD8 ϩ T-cell responses, 11 lytic cycle proteins are considered as major CD8 ϩ T-cell targets in both acute and persistent EBV infections. 12 Immunodominant epitopes restricted to different HLA class I alleles, which are important for our understanding of viral immunopathogenesis and development of appropriate vaccines, 13 have been determined for peptides derived from EBV structural proteins gp350 and gp85, and immediate-early (IE) and early proteins such as BZLF1, BRLF1, and BMLF1. [6][7][8][9] Compared to latency proteins, the frequency of CD8 ϩ T lymphocytes specific for peptides derived from lytic cycle proteins is higher in PBMCs of healthy virus carriers. 14 CD8 ϩ CTLs have also been demonstrated to secrete IFN-␥ in response to EBV lytic cycle antigens in seropositive individuals. 15 During primary EBV infectious mononucleosis, up to 60% of CD8 ϩ T cells circulating in blood are EBV-specific. 16 Furthermore, by use of a peptide-tetramer complex, Tan et al 17 have directly visualized from 0.5% to 6.6% of CD8 ϩ T blood cells in virus carriers that are specific for a single BMLF-1 epitope.In MHV-68 infection, lytic cycle proteins also induce CD8 ϩ T cell responses. 10,18,19 T cells specific for peptides derived from lytic cycle proteins dominate the acute phase of MHV-68 infection. 10,19 Moreover, vaccination with immunodominant CD8 ϩ T-cell epitopes derived from lytic cycle proteins of MHV-68 significantly reduces viral titers and the level of infected cells during acute infection. 20 We have tested CD8 ϩ T-cell reactivity to peptides derived from 5 HHV-8 lytic cycle proteins based on a prediction model for the HLA A*0201 motif in HHV-8-infected subjects to determine immunodominant epitopes to the virus. We chose HLA A*0201 because it is prevalent in a large percentage of the white populat...

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Evaluation of the human herpesvirus 8 DNA load in blood and Kaposi's sarcoma skin lesions from AIDS Patients on highly active antiretroviral therapy

Abstract: There is a strong relationship between the tumour burden and the HHV-8 viral load in KS skin lesions of subjects with AIDS, reinforcing the causal link between this herpesvirus and AIDS-related KS.

Cited by 56 publications

References 17 publications

Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis

Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis

Evidence for both Lytic Replication and Tightly Regulated Human Herpesvirus 8 Latency in Circulating Mononuclear Cells, with Virus Loads Frequently below Common Thresholds of Detection

Identification of an HLA A*0201–restricted CD8+T-cell epitope for the glycoprotein B homolog of human herpesvirus 8

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