Viruses and the Brain—A Relationship Prone to Trouble

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 203 - 203

Published: Jan. 31, 2025

Neurological disorders, some of which are associated with viral infections, growing due to the aging and expanding population. Despite strong defenses central nervous system, viruses have evolved ways breach them, often result in dire consequences. In this review, we recount various by different can enter CNS, describe consequences such invasions. Consequences may manifest as acute disease, encephalitis, meningitis, or long-term effects, neuromuscular dysfunction, occurs poliomyelitis. We discuss evidence for involvement causation well-known chronic neurodegenerative diseases, Alzheimer's Parkinson's amyotrophic lateral sclerosis, multiple well vascular dementia elderly. also approaches currently available control a few neural infections. These include antivirals that effective against human immunodeficiency virus herpes simplex virus, vaccines valuable controlling rabies poliomyelitis flavivirus There is an urgent need better understand, at molecular level, how contribute and, especially, neurological diseases develop more precise therapies.

Language: Английский

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HIV-1 Vpr Functions in Primary CD4+ T Cells

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 420 - 420

Published: March 9, 2024

HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it poised exert various biological effects on the host cell upon delivery. In this way, contributes towards establishment of a successful infection, as evidenced by extent which depends factor achieve full pathogenicity vivo. Although HIV infects types organism, CD4+ T cells are preferentially targeted since they highly permissive productive concomitantly bringing about hallmark immune dysfunction that accompanies spread. The last several decades have seen unprecedented progress unraveling activities possesses at molecular scale, increasingly underscoring importance viral component. Nevertheless, remains controversial whether some these advances bear vivo relevance, commonly employed cellular models significantly differ from primary lymphocytes. One prominent example “established” ability induce G2 cycle arrest, with enigmatic physiological relevance infected objective review discoveries their context illustrate mechanisms whereby supports infection cells, whilst identifying findings require validation physiologically relevant models.

Language: Английский

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HIV-1 Vpr alters cellular transcription by targeting the PAF1 complex

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

ABSTRACT Innate immunity represents the first line of defence against viral infections, and successful pathogens like HIV-1 have evolved mechanisms to bypass these barriers. The PAF1 complex (PAF1c) has emerged as a key regulator antiviral innate immune responses, inhibiting replication various viruses, including HIV-1. While its role in transcription regulation is well documented, little known about how PAF1c inhibits circumvents this activity. Here we demonstrate that Vpr induces rapid transient downmodulation shortly after infection, process correlates with significant transcriptomic changes within host cell. Transcriptomic profiling reveals knockdown mirrors many gene expression induced by indicating antagonism means which may modulate favour replication. Further, show loss leads suppression interferon-stimulated genes (ISGs) several restriction factors. Overall, evidence supports emerging broad transcriptional program, but also suggests specific anti-HIV activity countered Vpr.

Language: Английский

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HIV capsids: orchestrators of innate immune evasion, pathogenesis and pandemicity

Journal of General Virology, Journal Year: 2025, Volume and Issue: 106(1)

Published: Jan. 13, 2025

Human immunodeficiency virus (HIV) is an exemplar virus, still the most studied and best understood a model for mechanisms of viral replication, immune evasion pathogenesis. In this review, we consider earliest stages HIV infection from transport virion contents through cytoplasm to integration genome into host chromatin. We present holistic virus-host interaction during pivotal stage infection. Central process capsid. The last 10 years have seen transformation in way understand capsid structure function. review key discoveries our latest thoughts on as dynamic regulator innate chromatin targeting. also accessory proteins Vpr Vpx because they are incorporated particles where collaborate with capsids manipulate defensive cellular responses argue that effective regulation uncoating immunity define pandemic potential pathogenesis, how comparison different lineages can reveal what makes lentiviruses special.

Language: Английский

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Identification of the Inducible HIV reservoir in Tonsillar, Intestinal and Cervical Tissue Models of HIV Latency

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Abstract HIV persists in diverse tissues, with distinct cellular reservoirs presenting a major barrier to cure and requiring targeted therapeutic strategies address this heterogeneity. Here, we developed tissue models of latency using human tonsillar, intestinal cervicovaginal tissues. These revealed differential infection across CD4 + T cell subpopulations, ART partially restoring cells reducing intact DNA. follicular helper (T FH CD69+ CCR7- ) were the primary inducible reservoir tonsils, while tissue-resident memory RM CD49a+ dominated intestine. Identification markers for that CD69, CD45RO, PD-1 shared CXCR5 tonsils CD49a intestine served as tissue-specific markers. Furthermore, different reversal agents (LRAs) found Histone Deacetylase Inhibitors (HDACis) failed induce any tissue, SMAC mimetic AZD5582 was effective only resident-memory subpopulation intestine, IL15 exhibited broadest reactivation potential tissues subsets. recapitulate key aspects providing insights into reservoir’s composition informing its elimination.

Language: Английский

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SIV-specific neutralizing antibody induction following selection of a PI3K drive-attenuated nef variant

eLife, Journal Year: 2025, Volume and Issue: 12

Published: March 3, 2025

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required NAb induction, driver molecular signatures predisposing induction still remain largely unknown. Here we describe SIV-specific following a interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening seventy difficult-to-neutralize SIV mac239 -infected macaques found nine NAb-inducing animals, with seven selecting specific CD8 + T-cell escape mutation in nef before induction. This Nef-G63E reduced excess Nef interaction-mediated B-cell maturation-limiting PI3K/mammalian target rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential perturbation cognate Envelope-specific cells, suggestive polarized contact-dependent transfer corroborating maturation post-mutant selection up Results collectively exemplify pattern extrinsically reciprocal human PI3K gain-of-function antibody-dysregulating disease indicate that harnessing the PI3K/mTORC2 axis may facilitate against viruses including HIV/SIV.

Language: Английский

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HIV-1 accessory protein Vpr possesses a cryptic p300-dependent transcription-promoting activity that is blocked by histone deacetylases in CD4⁺T cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Antiretroviral therapy (ART) has dramatically improved the clinical prognosis for people with HIV and prevents transmission. However, ART does not cure infection because of a persistent, latent reservoir in long-lived cells such as central memory CD4 + T (T CM ) cells. Eliminating or preventing formation will require better understanding HIV-1 latency establishment. We others have recently shown that host cell factors histone deacetylases (HDACs) are critical cellular allow entry into latency. Whether HDACs interact specific viral to regulate establishment, however, is unknown. To examine role individual accessory proteins, we constructed panel reporter strains, each expressing single protein, examined them primary T-cell model. Interestingly, found HDAC inhibitor (HDACi) vorinostat potently enhances effect protein Vpr promoting expression infected cells, suggesting possesses cryptic transcription-promoting activity restricted by HDACs. This was dependent on p300-binding domain inhibited selective p300 acetyltransferase inhibitor. also resulted significant increase proportion phenotype. Furthermore, observed were more resistant Vpr-induced apoptosis/cell death than other subtypes, indicating during selects proviruses Overall, these findings suggest plays an important shaping results, part, from HDAC-mediated restriction Vpr’s activity. Understanding how shape establishment aid development new latency-targeting therapies. Author Summary Although antiretroviral effective at treating HIV, remains elusive. The obstacle presence latently which virus persists despite therapy. Recent work sizable fraction this forms near time initiated, it may be possible prevent some forming. prevention enters latency, including gene silenced. therefore sought interaction between proteins turning off that, whereas turns expression, block Second, leads relative type harbors virus. Our silencing persistence certain types developing approaches targeting

Language: Английский

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Heat shock protein 90 is a chaperone regulator of HIV-1 latency

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(4), P. e1012524 - e1012524

Published: April 1, 2025

An estimated 32 million people live with HIV-1 globally. Combined antiretroviral therapy suppresses viral replication but interruption results in rebound from a latent reservoir mainly found memory CD4+ T cells. Treatment is therefore lifelong and not curative. Eradication of this requires hematopoietic stem cell transplantation hemizygous or homozygous ΔCCR5 donors, which broadly applicable. Alternative cure strategies include the pharmacological reactivation latently infected cells to promote their immune-mediated clearance, induction deep latency. latency multifactorial linked activation status cell. Hence perturb latency, multiple pathways need be simultaneously targeted without affecting function. Hsp90 has been shown regulate although knowledge on limited. Because promotes proper folding numerous cellular proteins required for gene expression, we hypothesized that might master regulator We tested hypothesis using polyclonal Jurkat model ex-vivo primary that, model, mediated by T-cell receptor, phorbol esters, TNF-α, inhibition FOXO-1, agonists TLR-7 TLR-8. In cells, regulates expression induced stimulation receptor presence IL-7/IL-15 FOXO-1 inhibitor. Chemical abrogated NF-kB, NFAT AP-1 signal transduction pathways. Within population, CDRA45+ CCR7+ “naïve” CD45RA- CCR7- “effector memory” were most sensitive inhibition, did phenotype state. Our indicate can potentially strategies.

Language: Английский

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HIV-1 Vpr causes separate cell cycle arrests in G2 and M that activate alternative DNA damage pathways

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 2, 2024

Abstract Vpr is a conserved primate lentiviral accessory protein that induces cell cycle arrest in G2. The precise mechanism of this and its benefit to viral replication unknown. Here, we show addition G2 arrest, from HIV-1/SIVcpz HIV-2 lineages separately induce mitotic through the spindle assembly checkpoint, contrast other proteins only cause arrest. was mediated solely by ATR (ataxia telangiectasia Rad3 related) activity caused elevated cellular dNTP levels. required ATM (ataxia-telangiectasia mutated) as well resulted formation HIV-1 Vpr-induced ultra-fine anaphase bridges. Moreover, ectopic expression DNA structure-specific endonuclease, MUS81, prevented but not Importantly, virion-incorporated sufficient changes within 12h post-infection, implying these events early stages HIV infection. Author Summary an found lentiviruses. Like retroviral proteins, it absolutely for thought overcome factor negatively regulates most well-documented effect This has been linked activation damage response (DDR) pathway there are conflicting reports literature behind this. some lentiviruses, fact, two separate blocks, M, require different DDR pathways. Other Furthermore, degradation one reported target Vpr, specifically M indicates all functions helps explain contradictory published results. Additionally, able changes, including levels, 12 hours infection suggesting enhance events.

Language: Английский

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SIV-specific neutralizing antibody induction following selection of a PI3K drive-attenuated nef variant

Published: Feb. 13, 2025

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus-host B cell interaction appears to be basally required NAb induction, driver molecular signatures predisposing induction still remain largely unknown. Here we describe SIV-specific following a interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening seventy difficult-to-neutralize SIV mac239 -infected macaques found nine NAb-inducing animals, with seven selecting specific CD8 + T-cell escape mutation in nef before induction. This Nef-G63E reduced excess Nef interaction-mediated B-cell maturation-limiting PI3K/mammalian target rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential perturbation cognate Envelope-specific cells, suggestive polarized contact-dependent transfer corroborating maturation post-mutant selection up Results collectively exemplify pattern extrinsically reciprocal human PI3K gain-of-function antibody-dysregulating disease, indicate that harnessing the PI3K/mTORC2 axis may facilitate against viruses including HIV/SIV.

Language: Английский

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