Roles and functions of HIV-1 Tat protein in the CNS: an overview

Bagashev, Asen; Sawaya, Bassel E.

doi:10.1186/1743-422x-10-358

Cited by 109 publications

(98 citation statements)

References 138 publications

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“…Depending on the viral subtype, it consists of 86–101 amino acids. The cysteine-rich region of Tat is responsible for the transcriptional activity of the virus (reviewed in [96]). Tat is secreted from HIV-infected cells and acts on surrounding cells, affecting their function and causing toxicity.…”

Section: Role Of Hiv-1 Proteins In Neurotoxicitymentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

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Section: Role Of Hiv-1 Proteins In Neurotoxicitymentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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“…ART curtails HIV replication; however, there is a paradoxical increase in the prevalence of HIV-associated neurocognitive disorders (HAND) (Bagashev and Sawaya 2013), which include a group of syndromes that range from undetectable neurocognitive impairments to severe forms of encephalitis/dementia (Gannon et al 2011). A commonly accepted explanation for HAND is the inability of various ART regimens to pass through the blood–brain barrier (BBB), thus rendering the brain a viral sanctuary (Bagashev and Sawaya 2013).…”

Section: Extracellular Tatmentioning

confidence: 99%

“…A commonly accepted explanation for HAND is the inability of various ART regimens to pass through the blood–brain barrier (BBB), thus rendering the brain a viral sanctuary (Bagashev and Sawaya 2013). HIV-1 does not infect neurons; therefore while still debated, neurotoxicity has been postulated to be mediated by extracellular Tat upon its direct passage through the BBB or after secretion from infected glia cells (Li et al 2009).…”

Section: Extracellular Tatmentioning

confidence: 99%

“…Tat has been proposed to mediate neurotoxicity by several mechanisms: induction of oxidative stress (Romani et al 2010), BBB damage (Bagashev and Sawaya 2013; Li et al 2009; Strazza et al 2011), up-regulation of genes such as monocyte chemoattractant protein-1 (MCP-1), TNF-α, and metalloprotease 9 (Li et al 2009; Romani et al 2010), its chemotaxic function (Li et al 2009), inhibition of autophagy in macrophages (Van Grol et al 2010), and activation of N-methyl-D-aspartate receptors (Campbell and Loret 2009; Li et al 2009). Tat’s basic domain and cysteine-rich region could play an important role in these neurotoxic effects (Li et al 2009), and patients infected with HIV-1 subtype C, containing a mutation in Tat’s cysteine region, tend to have less prevalence of HAND (Li et al 2009).…”

Section: Extracellular Tatmentioning

confidence: 99%

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Targeting HIV Transcription: The Quest for a Functional Cure

Mousseau

Mediouni

Valente

2015

The Future of HIV-1 Therapeutics

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Antiretroviral therapy (ART) potently suppresses HIV-1 replication, but the virus persists in quiescent infected CD4+T cells as a latent integrated provirus, and patients must indefinitely remain on therapy. If ART is terminated, these integrated proviruses can reactivate, driving new rounds of infection. A functional cure for HIV requires eliminating low-level ongoing viral replication that persists in certain tissue sanctuaries and preventing viral reactivation. The HIV Tat protein plays an essential role in HIV transcription by recruiting the kinase activity of the P-TEFb complex to the viral mRNA’s stem–bulge–loop structure, TAR, activating transcriptional elongation. Because the Tat-mediated transactivation cascade is critical for robust HIV replication, the Tat/TAR/P-TEFb complex is one of the most attractive targets for drug development. Importantly, compounds that interfere with transcription could impair viral reactivation, low-level ongoing replication, and replenishment of the latent reservoir, thereby reducing the size of the latent reservoir pool. Here, we discuss the potential importance of transcriptional inhibitors in the treatment of latent HIV-1 disease and review recent findings on targeting Tat, TAR, and P-TEFb individually or as part of a complex. Finally, we discuss the impact of extracellular Tat in HIV-associated neurocognitive disorders and cancers.

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“…Tat can cross the blood brain barrier and causes HIV-associated neurocognitive disorder (HAND) 52 . Because of its abundant functional roles in HIV-1 replication and pathogenesis, Tat is a promising target for antiviral therapy.…”

Section: Trans-activator Of Transcription (Tat)mentioning

confidence: 99%

Combating human immunodeficiency virus replication by gene therapy

Rustanti¹

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A mutant HIV-1 Tat protein termed Nullbasic has a strong antiviral activity via three independent mechanisms that disrupts; 1) reverse transcription of the viral RNA genome into a DNA copy, 2) HIV-1 Rev protein function required for unspliced and singly spliced viral mRNA transport from the nucleus and 3) HIV-1 transcription by RNA Polymerase II.The Nullbasic protein is derived from the HIV-1 subtype B strain BH10 and has only been tested against other HIV-1 subtype B strains. Using a gammaretroviral vector as a gene delivery system, fusion forms of Nullbasic, Nullbasic-mCherry and Nullbasic-ZSGreen1,

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Roles and functions of HIV-1 Tat protein in the CNS: an overview

Cited by 109 publications

References 138 publications

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Targeting HIV Transcription: The Quest for a Functional Cure

Combating human immunodeficiency virus replication by gene therapy

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