Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression

O’Carroll, Ina P.; Li, Fan; Kroupa, Tomáš; McShane, Erin K.; Theodore, Christophe; Yates, Elizabeth A.; Kondrup, Benjamin; Ding, Jienyu; Martin, Tyler S.; Rein, Alan; Wang, Yun‐Xing

doi:10.1016/j.jmb.2020.11.010

Cited by 14 publications

(10 citation statements)

References 78 publications

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“…Subsequently, it was indicated that in vitro experiments simulating physiological infectious doses, the expression level of global HERV-K (HML-2) in cell lines did not change significantly, but some individual HML-2 elements were significantly upregulated (Vincendeau et al, 2015;Young et al, 2018;Gray et al, 2019). This suggests that HIV-1 infection may have a selective effect on the expression of HERV-K (HML-2) in cells, and the expression of each element may vary with the infectious dose and time of infection (Contreras-Galindo et al, 2017;O'Carroll et al, 2020). In addition, as a retrovirus, HIV evolves rapidly and has comprehensive diversity.…”

Section: Introductionmentioning

confidence: 99%

Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines

Guo

et al. 2021

Front. Microbiol.

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Human endogenous retroviruses (HERVs) make up ~8% of the human genome, and for millions of years, they have been subject to strict biological regulation. Many HERVs do not participate in normal physiological activities in the body. However, in some pathological conditions, they can be abnormally activated. For example, HIV infection can cause abnormal activation of HERVs, and under different infection conditions, HERV expression may be different. We observed significant differences in HERV-K transcription levels among HIV-1 subtype-infected individuals. The transcriptional levels in the HERV-K gag region were significantly increased in HIV-1 B subtype-infected patients, while the transcriptional levels in the HERV-K pol region were significantly increased in CRF01_AE and CRF07_BC subtype-infected patients. In vitro, the transcriptional levels of HEVR-K were increased 5-fold and 15-fold in MT2 cells transfected with two different HIV-1 strains (B and CRF01_AE, respectively). However, there was no significant difference in transcriptional levels among regions of HERV-K. When MT2 cells were infected with different subtypes of HIV-1 Tat proteins (B, CRF01_AE), which is constructed by lentiviruses, and the transcription levels of HERV-K were increased 4-fold and 2-fold, respectively. Thus, different subtypes of HIV-1 have different effects on HERV-K transcription levels, which may be caused by many factors, not only Tat protein.

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Section: Introductionmentioning

confidence: 99%

Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines

Guo

et al. 2021

Front. Microbiol.

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“…Previous studies have demonstrated that ERE activity is widely changed in response to the HIV-1 lifecycle 21,22,27,29,31 and certain HIV-1 associated comorbidities 62,63 . ERE expression is also susceptible to changes the in epigenetics and immunity that are elicited during viral infections and the host response 64 .…”

Section: Discussionmentioning

confidence: 99%

“…In humans, EREs include long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and human endogenous retroviruses (HERVs) 20 . Previous studies have demonstrated that ERE activity is highly susceptible to change during infection with HIV-1 21–31 . While IFN-I signaling may activate EREs proximal to interferon stimulated genes (ISGs), other EREs, such as HERV elements, can be directly trans-activated by HIV-1 cofactors due to high sequence homology between endogenous and exogenous retroviruses 21,22,24,32,33 .…”

Section: Introductionmentioning

confidence: 99%

Endogenous Retroelement Expression in the Gut Microenvironment of People Living with HIV-1

Dopkins,

Fei,

Michael

et al. 2023

Preprint

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SummaryBackgroundEndogenous retroelements (EREs), including human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), comprise almost half of the human genome. HIV-1 infects a target cell already possessing ancient retroviral genetic material, and exogenous HIV-1 infection modulates the expression of cell associated EREs. Following initial HIV-1 infection, there is a rapid destruction of CD4+ cells in the gut associated lymphoid tissue (GALT). Our previous studies of the interferome in the gut suggest potential mechanisms regarding how IFNb may drive HIV-1 gut pathogenesis. As ERE activity is suggested to partake in type 1 immune responses and is incredibly sensitive to viral infections, we sought to elucidate underlying interactions between ERE expression and GALT dynamics in PLWH.MethodsERE expression profiles from bulk RNA sequencing of colon biopsies and PBMC were compared between a cohort of PLWH prior to or within 7 days of initiating antiretroviral therapy (ART) (n=19) and uninfected controls (n=13). Individual EREs were then compared with the profiling of uninfected gut CD4+ T cells activated with type 1 interferons (IFN-Is) (n=3) to elucidate potential mechanisms for their induction in PLWH.Findings59 EREs were differentially expressed in the colon of PLWH when compared to uninfected controls (Wald’s Test with Benjamin-Hochberg correction: padj < 0.05 and FC ≤ −1 or ≥ 1). Of these 59, 12 EREs were downregulated in PLWH and 47 were upregulated. Colonic expression of the ERE loci LTR19_12p13.31 and L1FLnI_1q23.1s showed significant correlations with CD8+ T Cells and dendritic cell subset frequencies in the GI tract (Spearman’s Correlation: p value < 0.05). Furthermore L1FLnI_1q23.1s showed a significant upregulation in the blood of PLWH when compared to uninfected controls (T test: p <0.05) suggesting a common mechanism of differential ERE expression in PBMC and GALT.InterpretationERE activity has been largely understudied in genomic characterizations of human pathologies. We show that the activity of certain EREs in the GI tract of PLWH is deregulated, supporting our hypotheses that their underlying activity could function as (bio)markers and potential mediators of pathogenesis in HIV-1 reservoirs.FundingNCI CA260691 (DFN) and NIAID UM1AI164559 (DFN).

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“…HIV transactivator of transcription (Tat) protein can stimulate expression of HERV-K and HERV-W in astrocytes and peripheral blood cells and that of HERV-W also indirectly via TLR4 and proinflammatory cytokine (TNFα, NF-κB) production (Uleri et al, 2014). Using mimicry, HIV rev, which mediates nuclear export of HIV messenger RNA (mRNA), also mediates the nuclear export of HERV-K mRNA, thereby promoting HERV-K translation (O'Carroll et al, 2020). Exogenous viruses can further facilitate expression of endogenous superantigens, linked in particular with the CNSaffecting autoimmune diseases (Acha-Orbea, 1992).…”

Section: Interplay Between Endogenous and Exogenous Virusesmentioning

confidence: 99%

“…Further augmentation of neurodegeneration and neuroinflammation in HAND comes from HIV and infectioninduced cytokines' (IL-6, IL-1β, TNF-α, and IFN-γ) ability to dynamically activate HERVs, such as HERV-W (Uleri et al, 2014) and HERV-K (Bhardwaj et al, 2014;O'Carroll et al, 2020). In particular, HIV induces HERV-K transcription and can trigger adaptive immune response against the HERV-K capsid protein (de Mulder et al, 2017).…”

Section: Hiv-associated Neurodegenerative Disordermentioning

confidence: 99%

Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

Römer

2021

Front. Neurosci.

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Many neurodegenerative diseases are associated with chronic inflammation in the brain and periphery giving rise to a continuous imbalance of immune processes. Next to inflammation markers, activation of transposable elements, including long intrespersed nuclear elements (LINE) elements and endogenous retroviruses (ERVs), has been identified during neurodegenerative disease progression and even correlated with the clinical severity of the disease. ERVs are remnants of viral infections in the human genome acquired during evolution. Upon activation, they produce transcripts and the phylogenetically youngest ones are still able to produce viral-like particles. In addition, ERVs can bind transcription factors and modulate immune response. Being between own and foreign, ERVs are reviewed in the context of viral infections of the central nervous system, in aging and neurodegenerative diseases. Moreover, this review tests the hypothesis that viral infection may be a trigger at the onset of neuroinflammation and that ERVs sustain the inflammatory imbalance by summarizing existing data of neurodegenerative diseases associated with viruses and/or ERVs.

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Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression

Cited by 14 publications

References 78 publications

Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines

Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines

Endogenous Retroelement Expression in the Gut Microenvironment of People Living with HIV-1

Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

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