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

Ishizaka, Aya; Sato, Hidenori; Nakamura, Hitomi; Koga, Michiko; Kimura, Tadashi; Hosoya, Norimasa; Koibuchi, Tomohiko; Nomoto, Akio; Kawana-Tachikawa, Ai; Mizutani, Taketoshi

doi:10.1128/jvi.03158-15

Cited by 33 publications

(28 citation statements)

References 54 publications

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“…There are many blocks, including lack of components of p-TEFb (i.e. low cyclin T 1 levels in resting T cells), chromatin block, etc., that may be playing various inhibitory roles; however, a lack of true transcriptional inhibitors in cART mixture may be one reason for accumulation of HIV-1 coding and non-coding transcripts in cells, which eventually find their ways into exosomes (this work) (57,75). It may also alternatively be possible that one or more components of the cART (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…We next tested the variability of viral RNA transcripts in cells latently infected with HIV-1 as well as in the extracellular environments. Patients receiving antiretroviral therapy for a long time may have low or undetectable genomic viral RNA; however, few data exist to date describing the presence of short RNA transcripts in these patients (56,57). To test whether various HIV-1 transcripts are present in cells and extracellular vesicles circulating in the plasma of aviremic patients, we utilized a number of well-characterized samples from the Women's Interagency HIV Study (WIHS), specifically from four HIV-1-infected patients under various cART treatments, as indicated in Fig.…”

Section: Various Rna Transcripts Are Present In Latently Hiv-1-infectmentioning

confidence: 99%

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Exosomes from uninfected cells activate transcription of latent HIV-1

Barclay

Schwab

DeMarino

et al. 2017

Journal of Biological Chemistry

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HIV-1 infection causes AIDS, infecting millions worldwide. The virus can persist in a state of chronic infection due to its ability to become latent. We have previously shown a link between HIV-1 infection and exosome production. Specifically, we have reported that exosomes transport viral proteins and RNA from infected cells to neighboring uninfected cells. These viral products could then elicit an innate immune response, leading to activation of the Toll-like receptor and NF-κB pathways. In this study, we asked whether exosomes from uninfected cells could activate latent HIV-1 in infected cells. We observed that irrespective of combination antiretroviral therapy, both short- and long-length viral transcripts were increased in wild-type HIV-1-infected cells exposed to purified exosomes from uninfected cells. A search for a possible mechanism for this finding revealed that the exosomes increase RNA polymerase II loading onto the HIV-1 promoter in the infected cells. These viral transcripts, which include trans-activation response (TAR) RNA and a novel RNA that we termed TAR-, can then be packaged into exosomes and potentially be exported to neighboring uninfected cells, leading to increased cellular activation. To better decipher the exosome release pathways involved, we used siRNA to suppress expression of ESCRT (endosomal sorting complex required for transport) proteins and found that ESCRT II and IV significantly control exosome release. Collectively, these results imply that exosomes from uninfected cells activate latent HIV-1 in infected cells and that true transcriptional latency may not be possible , especially in the presence of combination antiretroviral therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Various Rna Transcripts Are Present In Latently Hiv-1-infectmentioning

confidence: 99%

Exosomes from uninfected cells activate transcription of latent HIV-1

Barclay

Schwab

DeMarino

et al. 2017

Journal of Biological Chemistry

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“…In patients on cART with undetectable viremia, HIV transcript loads correlate negatively with the CD4 T cell count (257) and positively with lymphoproliferative responses to HIV p24 antigen (258). Activa-tion stimulates transcription of persistent virus (257). These data suggest that defective proviruses might also produce antigens even if they do not produce replication-competent viruses.…”

Section: Discussionmentioning

confidence: 67%

“…Cell-associated HIV RNA load, which reflects the level of viral transcription, including abortive transcription, also correlates with immune activation in untreated patients, patients on cART, and natural controllers (204,255,256,257). In patients on cART with undetectable viremia, HIV transcript loads correlate negatively with the CD4 T cell count (257) and positively with lymphoproliferative responses to HIV p24 antigen (258). Activa-tion stimulates transcription of persistent virus (257).…”

Section: Discussionmentioning

confidence: 99%

“…In antiretroviral-treated adults, total HIV DNA in resting CD4 T cells is strongly associated with CD4 and CD8 T cell activation, whereas there is no association between cell activation and integrated DNA or IUPM coculture results (254). Cell-associated HIV RNA load, which reflects the level of viral transcription, including abortive transcription, also correlates with immune activation in untreated patients, patients on cART, and natural controllers (204,255,256,257). In patients on cART with undetectable viremia, HIV transcript loads correlate negatively with the CD4 T cell count (257) and positively with lymphoproliferative responses to HIV p24 antigen (258).…”

Section: Discussionmentioning

confidence: 99%

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Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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