Role of HIV-1 Vpr in AIDS pathogenesis: relevance and implications of intravirion, intracellular and free Vpr

Tungaturthi, Parithosh K.; Sawaya, Bassel E.; Singh, Satya P.; Tomkowicz, Brian; Ayyavoo, Velpandi; Khalili, Kamel; Collman, Ronald G.; Amini, Shohreh; Srinivasan, Alagarsamy

doi:10.1016/s0753-3322(02)00328-1

Cited by 51 publications

(38 citation statements)

References 26 publications

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“…Vpr is important for transport of the pre-integration complex, nuclear localization, induction of cell cycle arrest in G2, transactivation of the HIV-1 LTR and other cellular promoters. [72][73][74][75][76] Vpr is found in the serum and the CSF of HIV-1-infected patients. 77 In HIV-infected patients with neurological dysfunction, CSF levels of Vpr are elevated, suggesting an involvement of Vpr in AIDS-related neurological disorders.…”

Section: Neurotoxic Viral Proteinsmentioning

confidence: 99%

Cell death in HIV dementia

2005

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Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/ or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients.

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Section: Neurotoxic Viral Proteinsmentioning

confidence: 99%

Cell death in HIV dementia

2005

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“…8 The purified Vpr has been shown to have transactivational and cytotoxic properties in CD4 þ T cells and neurons, respectively. [8][9][10] Such results suggest that Vpr's cellular effects can manifest through various mechanisms including entry of free Vpr into uninfected, activated CD4 þ T cells for destruction. Accordingly, we review the questions surrounding the biochemical mechanism of Vpr-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism

et al. 2005

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The destruction of CD4 þ T cells and eventual induction of immunodeficiency is a hallmark of the human immunodeficiency virus type 1 infection (HIV-1). However, the mechanism of this destruction remains unresolved. Several auxiliary proteins have been proposed to play a role in this aspect of HIV pathogenesis including a 14 kDa protein named viral protein R (Vpr). Vpr has been implicated in the regulation of various cellular functions including apoptosis, cell cycle arrest, differentiation, and immune suppression. However, the mechanism(s) involved in Vprmediated apoptosis remains unresolved, and several proposed mechanisms for these effects are under investigation. In this review, we discuss the possibility that some of these proposed pathways might converge to modulate Vpr's behavior. Further, we also discuss caveats and future directions for investigation of the interesting biology of this HIV accessory gene.

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“…As HIV Vpr circulates freely in plasma, 3 paracrine effects from this retroviral accessory protein could impact cell function (including cardiomyocyte function) in AIDS. Based on data herein, it may be reasonable to suggest that circulating Vpr of sufficient concentration could cause deleterious effects on the cardiomyocyte in analogous ways to observed Vpr effects on immunocytes (defined by others 8,9 ).…”

Section: Discussionmentioning

confidence: 99%

“…1 Early in the epidemic, extracellular Vpr was found at high levels in serum of AIDS patients, 2 and reflected disease. Since Vpr is cell permeable, it is reasonable to suggest that Vpr could have functional implications in diverse cell types, 3 including terminally differentiated cardiomyocytes. 4 In mononuclear cells, Vpr causes G2/M cell cycle arrest and apoptosis.…”

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confidence: 99%

HIV viral protein R causes atrial cardiomyocyte mitosis, mesenchymal tumor, dysrhythmia, and heart failure

Lewis

Miller

Haase

et al. 2005

Laboratory Investigation

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HIV viral protein R (Vpr) affects the immunocyte cell cycle and circulates as free polypeptide in plasma of AIDS patients. Effects of Vpr on cardiomyocytes were explored using transgenic mice (TG) with Vpr targeted to cardiomyocytes by the a-myosin heavy-chain promoter. TG and WT littermate hearts were evaluated histopathologically, ultrastructurally, molecularly via RNA microarray analysis and quantitative RT-PCR, and functionally by cardiac magnetic resonance imaging (MRI) and electrocardiograms (ECG). Six hemizygous lines were created (Vpr a,b,c,d,e,h ). Vpr RNA was expressed exclusively in myocardium and Vpr mRNA expression correlated with phenotypic changes. Vpr b exhibited the highest expression and mortality. TGs developed congestive heart failure (E8 weeks), abnormal cardiomyocyte nuclei and mitoses (E12 weeks), and became moribund (E20 weeks) with atrial mesenchymal tumors. MRI revealed four-chamber dilation, defective contraction, and atrial masses. Pathologically, cardiomegaly and atrial mesenchymal tumors occurred (E16-20 weeks). ECGs showed prolonged R-R, Q-T, and P-R intervals (E12 weeks). RNA encoding collagen and bone morphogenic protein 4, 6, and 7 were increased. Vpr targeted to cardiomyocytes caused defective contractility and atrial tumors. Since some Vpr cardiomyocytic effects resemble those found in terminally differentiated immunocytes, some pathogenetic mechanisms may be shared at the subcellular level.

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Role of HIV-1 Vpr in AIDS pathogenesis: relevance and implications of intravirion, intracellular and free Vpr

Cited by 51 publications

References 26 publications

Cell death in HIV dementia

Cell death in HIV dementia

Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism

HIV viral protein R causes atrial cardiomyocyte mitosis, mesenchymal tumor, dysrhythmia, and heart failure

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