HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

Jones, R. Brad; Garrison, Keith; Mujib, Shariq; Mihajlovic, Vesna; Aidarus, Nasra; Hunter, Diana V.; Martin, Eric S.; John, Vivek M.; Zhan, Wenbin; Faruk, Nabil F.; Gyenes, Gábor; Sheppard, Neil C.; Priumboom-Brees, Ingrid M.; Goodwin, David A.; Chen, Lianchun; Rieger, Melanie; Muscat-King, Sophie; Loudon, Peter T.; Stanley, Cole; Holditch, Sara J.; Wong, Jody; Clayton, Kiera; Duan, Erick H.; Song, Haihan; Xu, Yingxin; SenGupta, Devi; Tandon, Ravi; Sacha, Jonah B.; Brockman, Mark A.; Benko, Erika; Kovacs, Colin; Nixon, Douglas F.; Ostrowski, Mario

doi:10.1172/jci64560

Cited by 84 publications

(104 citation statements)

References 39 publications

(40 reference statements)

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“…However, whether the expression of HERVs drive tumorigenesis or are the result of the aberrant gene expression in cancers is still undetermined [11]. Further, HERV proteins are not normally detected in healthy human tissues but were detectable following HIV-1 infection in primary human donor cells [19]. Importantly, we do not observe remarkably increased expression of the HERVs with the HDAC inhibitors vorinostat, panobinostat or romidepsin in the context of HIV-1 infection nor in uninfected cells.…”

Section: Discussionmentioning

confidence: 56%

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences. Results:In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells. Conclusions:We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies.

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Section: Discussionmentioning

confidence: 56%

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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“…Interestingly, upon examination of proviruses that are activated by Tat treatment, we observed that some do not contain viable 5=-LTR promoter regions (i.e., the promoters have large regions missing or are truncated or mutated). It is known that proviruses and solo LTRs can be transcribed as part of other cellular transcription units if they are integrated into them (52,86); thus, HERV sequences may arise from the sense strand, the antisense strand, or both depending on where active promoters are present. However, while cellular promoters close to sequences upstream of these proviruses might mediate their activation, we do not have any evidence for that, and further analyses to test this are being assessed.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53). Compared to healthy individuals, HIV-1-infected individuals show high levels of HERV-K (HML-2) RNA, DNA, protein, and viral particles in their plasma (45,47,48,50).…”

mentioning

confidence: 99%

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Gonzalez-Hernandez

Cavalcoli

Sartor

et al. 2014

J Virol

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Approximately 8% of the human genome is made up of endogenous retroviral sequences. As the HIV-1 Tat protein activates the overall expression of the human endogenous retrovirus type K (HERV-K) (HML-2), we used next-generation sequencing to determine which of the 91 currently annotated HERV-K (HML-2) proviruses are regulated by Tat. Transcriptome sequencing of total RNA isolated from Tat-and vehicle-treated peripheral blood lymphocytes from a healthy donor showed that Tat significantly activates expression of 26 unique HERV-K (HML-2) proviruses, silences 12, and does not significantly alter the expression of the remaining proviruses. Quantitative reverse transcription-PCR validation of the sequencing data was performed on Tattreated PBLs of seven donors using provirus-specific primers and corroborated the results with a substantial degree of quantitative similarity. IMPORTANCEThe expression of HERV-K (HML-2) is tightly regulated but becomes markedly increased following infection with HIV-1, in part due to the HIV-1 Tat protein.The findings reported here demonstrate the complexity of the genome-wide regulation of HERV-K (HML-2) expression by Tat. This work also demonstrates that although HERV-K (HML-2) proviruses in the human genome are highly similar in terms of DNA sequence, modulation of the expression of specific proviruses in a given biological situation can be ascertained using next-generation sequencing and bioinformatics analysis.

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“…virus to increase the frequency of infected CD4 T cells in our assay as described previously (36)(37)(38). We cultured our cells in 0.5 ng/ml IL-7 to promote survival of the CD4 T; at this low dose, IL-7 did not augment the expression of surface activation markers (Supplemental Figure 2).…”

Section: Experimental Overview and Generation Of Latently Hiv-1-infecmentioning

confidence: 99%

“…For this experiment only, CD4 T cells were stimulated with anti-CD3 and anti-CD28 antibodies and IL-2 for 2 days prior to infection to support robust HIV-1 infection (38). Infection of activated CD4 T cells, which are more susceptible to HIV-1 infection than resting CD4 T cells, was abrogated in the presence of HAART.…”

Section: Experimental Overview and Generation Of Latently Hiv-1-infecmentioning

confidence: 99%

Pharmacologic HIV-1 Nef blockade promotes CD8 T cell–mediated elimination of latently HIV-1–infected cells in vitro

Mujib¹,

Saiyed

Fadel

et al. 2017

JCI Insight

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HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

Cited by 84 publications

References 39 publications

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Pharmacologic HIV-1 Nef blockade promotes CD8 T cell–mediated elimination of latently HIV-1–infected cells in vitro

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