Cell-Based Measures of Viral Persistence Are Associated With Immune Activation and Programmed Cell Death Protein 1 (PD-1)–Expressing CD4+ T cells

Hatano, Hiroyu; Jain, Vivek; Hunt, Peter W.; Lee, Tzong‐Hae; Sinclair, Elizabeth; D., Tri; Hoh, Rebecca; Martin, Jeffrey N.; McCune, Joseph M.; Hecht, Frederick M.; Busch, Michael P.; Deeks, Steven G.

doi:10.1093/infdis/jis630

Cited by 221 publications

(229 citation statements)

References 41 publications

(54 reference statements)

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“…There is growing recognition that low CD4 ϩ cell counts, despite suppressive cART, correlate with persistent immune activation (43,44). Thus, to determine whether ST levels were related to T cell immunophenotypes in patients with plasma viremia (Ͻ50 copies/ml), we analyzed the percentages of CD4 ϩ and CD8 ϩ T cells expressing markers for T cell activation (HLA-DR and CD38), immune exhaustion (PD-1), and senescence (CD57) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

Ishizaka

Sato

Nakamura

et al. 2016

J Virol

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HIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4؉ cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8 ؉ T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4؉ cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs. IMPORTANCECombination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.

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Section: Resultsmentioning

confidence: 99%

Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

Ishizaka

Sato

Nakamura

et al. 2016

J Virol

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“…Through millions of years of coexistence, HHV have developed numerous strategies to modulate the human immune response, including impeding antigen-reactive immune cells from eradicating virus-infected cells (24). It is reasonable to hypothesize that other coinfecting pathogens, like HIV, could exploit this particular immune environment to promote HIV pathogen persistence and replication, for example, through upregulation of immune-inhibitory molecules like interleukin 10 (IL-10) and programmed cell death protein 1 (PD-1), which are also involved in HIV persistence (25,26). Persistence of the HIV DNA reservoir during ART has been attributed to two possible factors, which could contribute separately or in combination.…”

Section: Discussionmentioning

confidence: 99%

Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection

Gianella

Anderson

Var

et al. 2016

J Virol

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Asymptomatic replication of human herpesviruses (HHV) is frequent in HIV-infected men and is associated with increased Tcell activation and HIV disease progression. We hypothesized that the presence of replication of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) (the most frequently detected HHV) might influence HIV DNA decay during antiretroviral therapy (ART). We investigated 607 peripheral blood mononuclear cell (PBMC) samples from 107 CMV-seropositive, HIV-infected men who have sex with men, who started ART within a median of 3 months from their estimated date of infection (EDI) and were monitored for a median of 19 months thereafter. Levels of HIV, CMV, and EBV DNA and cellular HIV RNA were measured by droplet digital PCR (ddPCR) for each time point. Using a general linear mixed-effect regression model, we evaluated associations between the presence of detectable CMV DNA and EBV DNA levels and HIV DNA decay and cellular HIV RNA levels, while adjusting for peak HIV RNA, nadir CD4؉ count, CD4/CD8 ratio, CMV IgG levels, time from EDI to ART initiation, time from ART initiation to virologic suppression, detectable CMV DNA pre-ART, and age. The presence of intermittent CMV DNA in PBMC during ART was significantly associated with slower decay of HIV DNA (P ‫؍‬ 0.011) but not with increased cellular HIV RNA transcription or more detectable 2-long terminal repeat circles. Higher levels of EBV DNA were also associated with higher levels of HIV DNA (P < 0.001) and increased unspliced cellular HIV RNA transcription (P ‫؍‬ 0.010). These observations suggest that replication of HHV may help maintain a larger HIV DNA reservoir, but the underlying mechanisms remain unclear. IMPORTANCEOver three-fourths of HIV-infected men have at least one actively replicating human herpesvirus (HHV) in their mucosal secretions at any one time. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the most common, and although it is often asymptomatic, such CMV and EBV replication is associated with higher levels of immune activation and HIV disease progression. We hypothesized that HHV-associated activation of HIV-infected CD4 ؉ T cells might lead to increased HIV DNA. This study found that detectable CMV in blood cells of HIV-infected men was associated with slower decay of HIV DNA even during antiretroviral therapy (ART) that was started during early HIV infection. Similarly, levels of EBV DNA were associated with higher levels of HIV DNA during ART. If this observation points to a causal pathway, interventions that control CMV and EBV replication may be able to reduce the HIV reservoir, which might be relevant to current HIV cure efforts.

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“…Recent studies have linked residual immune activation to HIV persistence (33)(34)(35). Thus, we sought to determine whether the IL-21-induced reduction of immune activation and inflammation impacted the level of virus persistence during ART by measuring plasma levels of SIV RNA using an ultrasensitive assay (LOD, 3 copies of SIV RNA/ml).…”

Section: Il-21 Treatment Reduces Viral Persistence In Art-treated Simentioning

confidence: 99%

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

Micci

Ryan

Fromentin

et al. 2015

Journal of Clinical Investigation

100

129

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Cell-Based Measures of Viral Persistence Are Associated With Immune Activation and Programmed Cell Death Protein 1 (PD-1)–Expressing CD4+ T cells

Cited by 221 publications

References 41 publications

Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

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