HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND) DOI Open Access
Izchel Figarola-Centurión, Martha Escoto-Delgadillo, Gracia Viviana González-Enríquez

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17566 - 17566

Published: Dec. 17, 2023

During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in observed alterations within central nervous system (CNS), mitochondrial dysfunction emerging as prominent hallmark. As result, our objective was examine expression genes associated mitophagy and biogenesis brain exposed HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections 100 ng into hippocampus Sprague-Dawley rats, followed immunoneuromagnetic cell isolation. Subsequently, we assessed gene Ppargc1a, Pink1, Sirt1-3 neurons using RT-qPCR. Additionally, understand Tert telomeric dysfunction, quantified activity Tert. Our results revealed that only Sirt3 were downregulated response presence hippocampal neurons. Interestingly, reduction experimental group, while mRNA levels remained relatively stable. These findings support compelling evidence dysregulation both which turn induces dysfunction.

Language: Английский

PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication DOI Creative Commons
Lori A. Emert‐Sedlak, Colin M. Tice, Haibin Shi

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 658 - 668.e14

Published: March 19, 2024

Language: Английский

Citations

10
Neurological impact of HIV/AIDS and substance use alters brain function and structure DOI Creative Commons
James Haorah,

Samikkannu Malaroviyam,

Hemavathi Iyappan

et al.

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 7, 2025

Human immunodeficiency virus (HIV) infection is the cause of acquired syndrome (AIDS). Combination antiretroviral therapy (cART) has successfully controlled AIDS, but HIV-associated neurocognitive disorders (HANDs) remain prevalent among people with HIV. HIV often associated substance use, which promotes transmission and viral replication exacerbates HANDs even in era cART. Thus, comorbid effects use exacerbate neuropathogenesis HANDs. Unraveling mechanism(s) this exacerbation at molecular, cell-type, brain region levels may provide a better understanding HAND persistence. This review aims to highlight specific regions cell types involved persistence includes an overview post-translational modifications, alterations microglia-specific biomarkers, possible mechanistic pathways that link epigenomic modifications functional protein microglia. The impairment microglial proteins are neural circuit function appears contribute breakdown cellular communication neurodegeneration epigenetic modification N-terminal acetylation currently understudied, discussed brief demonstrate important role infected microglia within regions. discussion also explores whether combined effective preventing or substance-use-mediated

Language: Английский

Citations

1
EcoHIV Infection of Primary Murine Brain Cell Cultures to Model HIV Replication and Neuropathogenesis DOI Creative Commons
Boe‐Hyun Kim, Wei Chao, Eran Hadas

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(5), P. 693 - 693

Published: April 27, 2024

EcoHIV is a chimeric HIV that replicates in mice CD4+ T cells, macrophages, and microglia (but not neurons), causing lasting neurocognitive impairment resembling disease people living with HIV. The present study was designed to develop EcoHIV-susceptible primary mouse brain cultures investigate the indirect effects of infection on neuronal integrity. We used two clones encoding EGFP bone marrow-derived macrophages (BMM), mixed or enriched glial cells from wild-type strains test replication efficiency, identity productively infected apoptosis replicated efficiently BMM. In cell cultures, targeted but did cause apoptosis. Instead, productive activated them impaired synaptophysin expression, dendritic density, axonal structure neurons. structural changes during were prevented by culture an antiretroviral. murine largely responsible for aspects dysfunction relevant cognitive These provide tool further neuropathogenesis its control.

Language: Английский

Citations

5
Clinical evidence of human pathogens implicated in Alzheimer’s disease pathology and the therapeutic efficacy of antimicrobials: an overview DOI Creative Commons
Celso S. G. Catumbela, Vijayasree V. Giridharan, Tatiana Barichello

et al.

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: July 26, 2023

A wealth of pre-clinical reports and data derived from human subjects brain autopsies suggest that microbial infections are relevant to Alzheimer's disease (AD). This has inspired the hypothesis increase risk or even trigger onset AD. Multiple models have been developed explain in pathogenic microbes AD patients. Although this is well accepted field, it not yet clear whether neuroinvasion a cause consequence pathological changes experienced by demented brain. Along same line, gut microbiome also proposed as modulator In review, we focus on human-based evidence demonstrating elevated abundance microbe-derived molecules hosts their interactions with hallmarks. Further, direct-purpose potential off-target effects underpinning efficacy anti-microbial treatments addressed.

Language: Английский

Citations

11
Increasing Neuroinflammation Relates to Increasing Neurodegeneration in People with HIV DOI Creative Commons
Azin Tavasoli,

Benjamin B. Gelman,

Christina M. Marra

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1835 - 1835

Published: Aug. 30, 2023

Background: HIV infection causes neuroinflammation and immune activation (NIIA) systemic inflammation (SIIA), which in turn drive neurodegeneration (ND). Cross-sectionally, higher levels of NIIA biomarkers correlate with increased ND. A more convincing confirmation would be a longitudinal demonstration. Methods: PWH the US multisite CHARTER Aging project were assessed at baseline visit after 12 years using standardized evaluations. We measured panel 14 NIIA, SIIA, ND plasma CSF two time points calculated changes from to 12-year visit. Factor analysis yielded simplified indices Results: The factor Factor1 loading on soluble tumor necrosis type-2 (sTNFR-II) neopterin, Factor2, MCP1, CD14, IL-6. SIIA CRP, D-dimer, Neopterin; Factor2 sTNFR-II. Phosphorylated tau (p-tau) Aβ42; NFL. Factor1, but not correlated increases NFL (r = 0.370, p 0.0002). Conclusions: Increases associated corresponding ND, suggesting that reducing neuro/systemic might slow or reverse neurodegeneration.

Language: Английский

Citations

11
Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era DOI Creative Commons
Cristián E. Hernández, Anna Górska, Eliseo A. Eugenín

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109236 - 109236

Published: Feb. 15, 2024

HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated the early transmigration HIV-infected monocytes across BBB a CCL2 and replication-dependent manner. However, mechanisms chronic brain damage are unknown. We demonstrate that PWH ART have elevated circulating ATP levels correlate onset cognitive impairment absence virus. Serum found most severe neurocognitive trigger transcellular migration leukocytes JAM-A LFA-1-dependent propose targeting leukocyte could reduce or prevent devastating consequences within brains ART.

Language: Английский

Citations

4
Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5 DOI Creative Commons

Chloe A. Simons,

Sarah Kim-Hellmuth,

Yun K. Hahn

et al.

ASN NEURO, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 13, 2025

People living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND), even though combination antiretroviral therapy (cART) suppresses replication. HIV-1 transactivator of transcription (HIV-1 Tat) contributes to the development HAND through neuroinflammatory and neurotoxic mechanisms. C-C chemokine 5 receptor (CCR5) is important in immune cell targeting a co-receptor for viral entry into CD4+ cells. Notably, CCR5 has been implicated cognition unrelated infection. Inhibition shown improve learning memory. To test whether involved cognitive changes HAND, we used non-infectious, transgenic model which Tat inducibly expressed. Well-powered cohorts male female mice were placed on diet containing doxycycline induce expression 8-wks. Males showed Tat-mediated deficits Barnes maze spatial memory; females no impairments. Deficits males fully reversed by antagonist, maraviroc (MVC). not found novel object recognition or contextual fear conditioning either sex. Based earlier work, hypothesized that MVC might increase brain-derived neurotrophic factor (BDNF), essential maintaining synaptodendritic function. did mBDNF proBDNF ratio males, perhaps contributing improved cognition.

Language: Английский

Citations

0
Contribution of intact viral genomes persisting in blood and tissues during ART to plasma viral rebound in SHIV-infected rhesus macaques DOI Creative Commons

César Trifone,

Corentin Richard, Amélie Pagliuzza

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 111998 - 111998

Published: Feb. 12, 2025

Persistent SIV/HIV reservoirs are the primary obstacle to a cure and source of viral rebound after ART interruption (ATI). However, anatomical remains elusive. Here, we characterized proviral landscape in blood, inguinal, axillary lymph nodes colon biopsies five SHIV-infected rhesus macaques (RMs), under for 28 weeks. From 144 near full-length (NFL) sequences obtained pre-ATI, 35% were genetically intact only 2.8% found multiple copies. Envelope plasma rebounding viruses ATI, more frequently matched pre-ATI proviruses retrieved from compared isolated blood or (4, 1, 1 pair sequences, respectively). Our results suggest that clonal expansion infected cells rare this model, persisting may be preferential upon ATI.

Language: Английский

Citations

0
SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes DOI Creative Commons

Neda Rezagholizadeh,

Gaurav Datta,

Wendie A. Hasler

et al.

Life Science Alliance, Journal Year: 2025, Volume and Issue: 8(7), P. e202503231 - e202503231

Published: May 5, 2025

Cellular senescence contributes to accelerated aging and the development of various neurodegeneration disorders including HIV-associated neurocognitive disorders. The is attributed, at least in part, CNS persistence HIV-1 transactivator transcription (Tat), an essential protein for viral that actively secreted from HIV-1–infected cells. Secreted Tat enters cells via receptor-mediated endocytosis induces endolysosome dysfunction cellular Given represents early step exogenous Tat-induced senescence, we tested hypothesis endolysosome-dependent mechanism human astrocytes. We demonstrated internalized interacts with endolysosome-resident arginine sensor SLC38A9 arginine-rich basic domain. Such interaction between leads dysfunction, enhanced LTR transactivation, senescence. These findings suggest drives highlight novel role astrocyte

Language: Английский

Citations

0
The role of tunneling nanotubes during early stages of HIV infection and reactivation: implications in HIV cure DOI Creative Commons
Silvana Valdebenito, Akira Ono, Libin Rong

et al.

NeuroImmune Pharmacology and Therapeutics, Journal Year: 2023, Volume and Issue: 2(2), P. 169 - 186

Published: Jan. 4, 2023

Abstract Tunneling nanotubes (TNTs), also called cytonemes or tumor microtubes, correspond to cellular processes that enable long-range communication. TNTs are plasma membrane extensions form tubular connect the cytoplasm of two more cells. mostly expressed during early stages development and poorly in adulthood. However, disease conditions such as stroke, cancer, viral infections HIV, proliferate, but their role is understood. function has been associated with signaling coordination, organelle sharing, transfer infectious agents HIV. Here, we describe critical HIV infection reactivation, well use for cure strategies.

Language: Английский

Citations

8