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HIV Neuropathogenesis

Mahar Fatima, Bharat Prajapati, Kanza Saleem, Rina Kumari, Chitra Mohindar Singh Singal, Pankaj Seth
Astroglia are indispensable component of the tripartite synapse ensheathing innumerous soma and synapses. Its proximity to neurons aids the regulation of neuronal functions, health and survival through dynamic neuroglia crosstalk. Susceptibility of astrocyte to HIV-1 infection and subsequent latency culminates in compromised neuronal health. The viral protein HIV-1 transactivator of transcription (Tat) is neurotoxic. HIV-1 Tat is detected in brain of AIDS patients even in cases where viral load is non-detectable due to successful HAART therapy...
October 20, 2016: Glia
Deanna Saylor, Arun Venkatesan
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by the human neurotropic polyomavirus JC (JCV). The disease occurs virtually exclusively in immunocompromised individuals, and, prior to the introduction of antiretroviral therapy, was seen most commonly in the setting of HIV/AIDS. More recently, however, the incidence of PML in HIV-uninfected persons has increased with broader use of immunosuppressive and immunomodulatory medications utilized in a variety of systemic and neurologic autoimmune disorders...
November 2016: Current Infectious Disease Reports
Naveen K Vaidya, Ruy M Ribeiro, Alan S Perelson, Anil Kumar
Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses...
September 2016: PLoS Computational Biology
Michael J Corley, Christian Dye, Michelle L D'Antoni, Mary Margaret Byron, Kaahukane Leite-Ah Yo, Annette Lum-Jones, Beau Nakamoto, Victor Valcour, Ivo SahBandar, Cecilia M Shikuma, Lishomwa C Ndhlovu, Alika K Maunakea
Monocytes/macrophages contribute to the neuropathogenesis of HIV-related cognitive impairment (CI); however, considerable gaps in our understanding of the precise mechanisms driving this relationship remain. Furthermore, whether a distinct biological profile associated with HIV-related CI resides in immune cell populations remains unknown. Here, we profiled DNA methylomes and transcriptomes of monocytes derived from HIV-infected individuals with and without CI using genome-wide DNA methylation and gene expression profiling...
2016: Scientific Reports
Kenneth Williams, Andrew Lackner, Jaclyn Mallard
Non-human primate models of AIDS and neuroAIDS are the premiere model of HIV infection of the CNS and neuropathogenesis. This review discusses current SIV infection models of neuroAIDS emphasizing findings in the last two years. Consistent in these findings is the interplay between host factors that regulate immune responses to virus and viral replication. Several rapid models of AIDS with consistent CNS pathogenesis exist, each of which modulates by antibody treatment or viruses that cause rapid immune suppression and replicate well in macrophages...
August 2016: Current Opinion in Virology
Thangavel Samikkannu, Venkata S R Atluri, Madhavan P N Nair
HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF...
2016: Scientific Reports
Will Dampier, Gregory C Antell, Benjamas Aiamkitsumrit, Michael R Nonnemacher, Jeffrey M Jacobson, Vanessa Pirrone, Wen Zhong, Katherine Kercher, Shendra Passic, Jean W Williams, Tony James, Kathryn N Devlin, Tania Giovannetti, David J Libon, Zsofia Szep, Garth D Ehrlich, Brian Wigdahl, Fred C Krebs
Even in the era of combination antiretroviral therapies used to combat human immunodeficiency virus type 1 (HIV-1) infection, up to 50 % of well-suppressed HIV-1-infected patients are still diagnosed with mild neurological deficits referred to as HIV-associated neurocognitive disorders (HAND). The multifactorial nature of HAND likely involves the HIV-1 accessory protein viral protein R (Vpr) as an agent of neuropathogenesis. To investigate the effect of naturally occurring variations in Vpr on HAND in well-suppressed HIV-1-infected patients, bioinformatic analyses were used to correlate peripheral blood-derived Vpr sequences with patient neurocognitive performance, as measured by comprehensive neuropsychological assessment and the resulting Global Deficit Score (GDS)...
July 11, 2016: Journal of Neurovirology
Christina E Khodr, Lihua Chen, Sonya Dave, Lena Al-Harthi, Xiu-Ti Hu
Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons...
October 2016: Neurobiology of Disease
Jennifer L McGuire, Alexander J Gill, Steven D Douglas, Dennis L Kolson
The complement system (C1q/C3) is a key mediator of synaptic pruning during normal development. HIV inappropriately induces C1q and C3 production in the brain, and reduces neuronal complement inhibition. HIV may thus alter neural connectivity in the developing brain by excessively targeting synapses for elimination. The resultant pattern of neuronal injury may fundamentally alter neurodevelopmental and cognitive processes differentially across ages. This study aimed to (1) measure the association between the cerebrospinal fluid (CSF) complement factors (C1q/C3) and a marker of neuronal injury (NFL) in HIV+ subjects; (2) quantify the differences in CSF C1q/C3 between HIV+ youth and older adults; and (3) define the relationship between CSF C1q/C3 and cognitive impairment in each age group...
June 6, 2016: Journal of Neurovirology
Prasun K Datta, Satish Deshmane, Kamel Khalili, Salim Merali, John C Gordon, Chiara Fecchio, Carlos A Barrero
HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages...
September 2016: Cell Cycle
Vidya Sagar, Venkata Subba Rao Atluri, Sudheesh Pilakka-Kanthikeel, Madhavan Nair
The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis. Symptoms of HIV-associated neurocognitive disorders (HAND) are noticed in many AIDS patients. At least 50 % of HIV diagnosed cases show one or other kind of neuropathological signs or symptoms during different stages of disease progression...
2016: Molecular Brain
Fabián J Vázquez-Santiago, Vanessa Rivera-Amill
In the era of combined antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) account for 40 to 56% of all HIV(+) cases. During the acute stage of HIV-1 infection (<6 months), the virus invades and replicates within the central nervous system (CNS). Compared to peripheral tissues, the local CNS cell population expresses distinct levels of chemokine receptors, which levels exert selective pressure on the invading virus. HIV-1 envelope (env) sequences recovered from the brains and cerebrospinal fluid (CSF) of neurocognitively impaired HIV(+) subjects often display higher nucleotide variability as compared to non-impaired HIV(+) subjects...
October 2015: Journal of Neuroinfectious Diseases
Neha Vartak-Sharma, Shruthi Nooka, Anuja Ghorpade
Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, all hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington's disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging...
April 14, 2016: Progress in Neurobiology
Karina Villalba, Jessy G Dévieux, Rhonda Rosenberg, Jean Lud Cadet
HIV-infected individuals continue to experience neurocognitive deterioration despite virologically successful treatments. While the cause remains unclear, evidence suggests that HIV-associated neurocognitive disorders (HAND) may be associated with neurobehavioral dysfunction. Genetic variants have been explored to identify risk markers to determine neuropathogenesis of neurocognitive deterioration. Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life and HIV risk-taking behaviors...
2016: Genetics Research International
Luca Sardo, Priyal R Vakil, Weam Elbezanti, Anas El-Sayed, Zachary Klase
BACKGROUND: Long term infection with HIV-1, even in the context of therapy, leads to chronic health problems including an array of neurocognitive dysfunctions. The viral Tat protein has previously been implicated in neuropathogenesis through its effect on astrocytes. Tat has also been shown to inhibit the biogenesis of miRNAs by inhibiting the activity of the cellular Dicer protein in an RNA dependent fashion. Whether there is a mechanistic connection between the ability of HIV-1 Tat to alter miRNAs and its observed effects on cells of the central nervous system has not been well examined...
2016: Retrovirology
Tony James, Michael R Nonnemacher, Brian Wigdahl, Fred C Krebs
It is increasingly evident that the human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) has a unique role in neuropathogenesis. Its ability to induce G2/M arrest coupled with its capacity to increase viral gene transcription gives it a unique role in sustaining viral replication and aiding in the establishment and maintenance of a systemic infection. The requirement of Vpr for HIV-1 infection and replication in cells of monocytic origin (a key lineage of cells involved in HIV-1 neuroinvasion) suggests an important role in establishing and sustaining infection in the central nervous system (CNS)...
August 2016: Journal of Neurovirology
Joanne K Marcario, Gurudutt Pendyala, Mariam Riazi, Kandace Fleming, Janet Marquis, Shannon Callen, Steven J Lisco, Stephen C Fowler, Paul D Cheney, Shilpa J Buch
The abuse of opiates such as morphine in synergy with HIV infection not only exacerbates neuropathogenesis but significantly impacts behavioral attributes in HIV infected subjects. Thus, the goal of the current study was to characterize behavioral perturbations in rhesus macaques subjected to chronic morphine and SIV infection. Specifically, we assessed three behavioral tasks: motor skill (MS), forelimb force (FFT) and progressive ratio (PR) tasks. After collecting baseline control data (44 weeks) and data during the morphine-only dependency period (26 weeks), a subset of animals were productively infected with neurovirulent strains of SIVmac (R71/E17) for an additional 33 weeks...
June 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Anjana Yadav, Michael R Betts, Ronald G Collman
HIV-1-associated neurocognitive disorder (HAND) remains a persistent problem despite antiretroviral therapy (ART), largely a result of continued inflammation in the periphery and the brain and neurotoxin release from activated myeloid cells in the CNS. CD14+CD16+ inflammatory monocytes, expanded in HIV infection, play a central role in the pathogenesis of HAND and have parallels with monocyte-dependent inflammatory mechanisms in atherosclerosis. Statins, through their HMG-CoA reductase inhibitor activity, have pleiotropic immunomodulatory properties that contribute to their benefit in atherosclerosis beyond lipid lowering...
March 28, 2016: Journal of Neurovirology
Matias Jaureguiberry-Bravo, Rebecca Wilson, Loreto Carvallo, Joan W Berman
BACKGROUND: HIV-1 enters the CNS within two weeks after peripheral infection and results in chronic neuroinflammation that leads to HIV associated neurocognitive disorders (HAND) in more than 50% of infected people. HIV enters the CNS by transmigration of infected monocytes across the blood brain barrier. Intravenous drug abuse is a major risk factor for HIV-1 infection, and opioids have been shown to alter the progression and severity of HAND. Methadone and buprenorphine are opioid derivates that are used as opioid maintenance therapies...
March 24, 2016: Current HIV Research
Shaily Malik, Eliseo A Eugenin
BACKGROUND: One of the major complications of Human Immunodeficiency Virus (HIV) infection is the development of HIV-Associated Neurocognitive Disorders (HANDs) in approximately 50-60% of HIV/AIDS patients. Despite undetectable viral loads in the periphery owing to highly active anti-retroviral therapy, neuroinflammation and neurocognitive impairment are still prevalent in HIV/AIDS patients. Several studies indicate that the central nervous system (CNS) abnormalities observed in HIV infected individuals are not a direct effect of viral replication in the CNS, rather these neurological abnormalities are associated with amplification of HIV pathogenesis by unknown mechanisms...
March 24, 2016: Current HIV Research
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