Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells

Ma, Meihui; Nath, Andavindra

doi:10.1128/jvi.71.3.2495-2499.1997

Cited by 184 publications

(58 citation statements)

References 29 publications

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“…Tat 1-72 was produced as previously described (Khurdayan et al, 2004;Self et al, 2003;Prendergast et al, 2002;Gurwell et al, 2001;Ma and Nath, 1997). Briefly, the tat gene encoding the first 72 amino acids (tat 1-72 ) was amplified from HIVBRU obtained from Richard Gaynor though the AIDS repository at the NIH and inserted into an E. coli vector (PinPoint Xa-2; Promega, Madison, WI).…”

Section: Materials and Methods Chemicals And Drugssupporting

confidence: 84%

Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function

Wallace

Dodson

Nath³

et al. 2005

Synapse

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Postmenopausal women who are infected with HIV are at risk for experiencing dementia and Parkinson's-like symptoms associated with low levels of estrogen. Neurotoxic damage leading to these symptoms may involve HIV-associated proteins gp120 and/or tat(1-72) (tat). Our hypothesis is that 17beta-Estradiol (E(2)) is an effective agent for protection against gp120/tat-induced damage associated with increased oxidative stress, with particular focus on peroxynitrite-induced oxidative stress. We used SK-N-SH cells and striatal synaptosomes from Sprague-Dawley rats as model systems to assess neuroprotection by E(2). Cells coincubated with SIN-1(3-morpholinosydnonimine) or tat and gp120, together or separately, significantly increased oxidative stress on the SK-N-SH cells, as indicated by the increase in the levels of dichlorofluorescein (DCFH) fluorescence. These data suggest that a component of tat and gp120 neurotoxicity may be due to increased oxidative stress. Coincubation with E(2) attenuated tat- and gp120-induced increase in fluorescence. Coincubation with progesterone had no effect on tat-induced fluorescence, whereas coincubation with the E(2) antagonist ICI 182,780 and E(2) completely prevented the effects observed with E(2) alone. Both gp120 and tat decreased [(3)H] dopamine uptake into striatal synaptosomes by decreasing the V(max) of the dopamine transporter (DAT). Pretreatment of synaptosomes with E(2) (100 nM) partially reversed this reduction. In conclusion, E(2) appears to be effective for preventing the oxidative stress and loss of DAT function associated with gp120/tat neurotoxicity.

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Section: Materials and Methods Chemicals And Drugssupporting

confidence: 84%

Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function

Wallace

Dodson

Nath³

et al. 2005

Synapse

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“…Low concentrations of tat are neurotoxic, high concentrations neuroprotective [61,79,81,84,85] Internalized and located in the nucleus of neurons in-vitro [70].…”

Section: Tatmentioning

confidence: 99%

“…tat-induced transactivation of the HIV-1 long terminal repeat promoter is essential for viral gene expression and replication [69]. tat released by HIV-1-infected cells [17], and extracellular tat can be taken up by human fetal astrocytes and neurons in vitro and is rapidly localized into the nucleus [70]. Thus, theoretically tat might interact with neurons intracellularly as well as via molecules and receptors at the plasma membrane.…”

Section: Interactions Of Tat With Neuronsmentioning

confidence: 99%

Interactions of human immunodeficiency virus‐1 proteins with neurons: possible role in the development of human immunodeficiency virus‐1‐associated dementia

Bovenkamp

Nottet

Pereira

2002

Eur J Clin Investigation

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Human immunodeficiency virus-1 (HIV-1)-associated dementia is a severe neurological complication of HIV-1 infection that affects 15-20% of the patients in the late stages of acquired immunodeficiency syndrome. HIV-1-associated dementia is most probably a consequence of HIV-1 infection of the brain rather than of an opportunistic pathogen. The exact mechanism by which the virus causes this disorder, however, is not completely understood. A number of HIV-1 proteins have been shown to be released from HIV-1-infected cells and / or to be present in the extracellular milieu in the HIV-1-infected brain. Moreover, these proteins have been shown to posses neurotoxic and / or neuromodulatory features in vitro . This review describes the possible direct interactions of the HIV-1 proteins gp120, gp41, vpr, tat, rev, vpu and nef with neurons, which might play a role in the development of HIV-1-associated dementia in vivo .Keywords Acquired immunodeficiency, human immunodeficiency virus-1-associated dementia, human immunodeficiency virus-1 proteins, neurons, neurotoxicity.

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“…Recombinant Tat1-72 and Tat1-101 were produced in our laboratory. Details of Tat production and purification have been published (22,28). Briefly, since Tat is a nonglycosolated protein, we inserted the genes into an E. coli vector, PinPoint Xa-2 (Promega, Madison, WI, USA), which allowed expression of Tat as a fusion protein naturally biotinylated at the NH 2 terminus.…”

Section: Tatmentioning

confidence: 99%

“…Reagents including Tat, MMPs, and MMP inhibitors were added to the wells as appropriate. For this assay, Tat1-101 was used because it enters astrocytic cells more efficiently than Tat1-72 (28). Transactivation of the LTR leads to increased expression of the green fluorescent protein, and this was measured using a fluorescent plate reader (Molecular Dynamics) with excitation at 488 nM and emission at 507 nM.…”

Section: Tat Transactivation Activitymentioning

confidence: 99%

Interaction of HIV Tat and matrix metalloproteinase in HIV neuropathogenesis: a new host defense mechanism

Rumbaugh¹,

Turchan–Cholewo

Galey³

et al. 2006

FASEB j.

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Tat, the HIV transactivating protein, and matrix metalloproteinases (MMPs), a family of extracellular matrix (ECM) endopeptidases, have been implicated in the pathogenesis of HIV-associated dementia. However, the possibility that MMPs interact with viral proteins has remained unexplored. We therefore treated mixed human fetal neuronal cultures with recombinant Tat and select MMPs. Neurotoxicity was determined by measuring mitochondrial membrane potential and neuronal cell death. Previous studies have shown that Tat and MMP independently cause neurotoxicity. Surprisingly, we found the combination of Tat and MMP produced significant attenuation of neurotoxicity. To determine whether there was a physical interaction between Tat and MMP, we used protein electrophoresis and Western blot techniques, and found that MMP-1 can degrade Tat. This effect was blocked by MMP inhibitors. Furthermore, MMP-1 decreased Tat-mediated transactivation of the HIV long terminal repeat region, and this functionality was restored when MMP-1 activity was inhibited. These results suggest that the decrease in Tat-induced neurotoxicity and HIV transactivation is due to Tat's enzymatic cleavage by MMP-1. The direct interaction of human MMPs with viral proteins has now been demonstrated, with resultant modulation of Tat-mediated neurotoxicity and transactivation. This study elucidates a unique viral-host interaction that may serve as an innate host defense mechanism.

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Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells

Cited by 184 publications

References 29 publications

Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function

Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function

Interactions of human immunodeficiency virus‐1 proteins with neurons: possible role in the development of human immunodeficiency virus‐1‐associated dementia

Interaction of HIV Tat and matrix metalloproteinase in HIV neuropathogenesis: a new host defense mechanism

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