Transgenic dissection of HIV genes involved in lymphoid depletion.

Tinkle, Brad T.; Ueda, Hiroyuki; Ngo, Lien T.; Luciw, Paul A.; Shaw, Katharina S.; Rosen, Craig A.; Jay, Gilbert

doi:10.1172/jci119518

Cited by 20 publications

(9 citation statements)

References 45 publications

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“…9,[41][42][43][44][45][46] It is reasonable to conclude that DNC plays a mechanistic role in mitochondrial defects from thymidine analog-based HAART. Intramitochondrial abundance of phosphorylated and unphosphorylated native nucleo- sides and NRTIs affects inhibition mtDNA replication at the level of the nucleotide substrate.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Lewis

Haase

Miller

et al. 2005

Laboratory Investigation

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Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3 0 azido-3 0 -deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs. Keywords: deoxynucleotide; NRTI; AIDS; antiretroviral; mitochondrial import; DNC; cardiac; HIV The inner mitochondrial membrane contains transport proteins to move molecules into and out of the matrix. Members of the mitochondrial carrier family of proteins contain three conserved tandemrepeated sequences (B100 residues with two hydrophobic transmembrane a-helices and a hydrophilic segment thought to be an extramembranous loop 1 ). One of these proteins functions as a deoxynucleotide carrier (DNC) to import phosphorylated precursors of mitochondrial (mt-) DNA synthesis and has been characterized. 1-3 Toxicity to mitochondria from antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) is an established side effect of AIDS therapy that limits effective treatment (reviewed in Lewis et al 4 ). Alternative combinations that are NRTI-sparing may be effective if toxicity is a significant clinical problem (reviewed in Joly et al 5 ).Since DNC provides a route for mitochondrial uptake of NRTIs including zidovudine (3 0 azido-3 0 -deoxythymidine or AZT) and stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T), its role in mitochondrial NRTI import and toxicity was addressed in vivo using transgenic mice (TG) and HAART treatment. One HAART regimen included NRTIs (with either an AZT or D4T 'backbone'). A second NRTI-sparing regimen was administered in parallel as a control.DNC ov...

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Section: Discussionmentioning

confidence: 99%

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Lewis

Haase

Miller

et al. 2005

Laboratory Investigation

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“…Several experimental animal models of HIV are associated with vascular abnormalities. Transgenic mice carrying a replication-defective HIV-1 provirus with expression restricted to SMCs were shown to develop extensive vasculopathy, characterized by intimal thickening, significant luminal narrowing, and thrombotic occlusion (49). A severe arteriopathy, also characterized by intimal thickening, luminal narrowing, and thrombosis, was seen in macaques infected with simian immunodeficiency virus (SIV) (50).…”

Section: Discussionmentioning

confidence: 99%

Human Vascular Smooth Muscle Cells Possess Functional CCR5

Schecter¹,

Calderon²,

Berman³

et al. 2000

Journal of Biological Chemistry

117

100

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CC chemokine receptors are important modulators of inflammation. Although CC chemokine receptors have been found predominantly on leukocytes, recent studies have suggested that vascular smooth muscle cells respond to CC chemokines. We now report that human smooth muscle cells express CCR5, a co-receptor for human immunodeficiency virus. CCR5 mRNA was detectable by RNA blot hybridization in human aortic and coronary artery smooth muscle cells. The cDNA generated by reverse transcription-polymerase chain reaction from aortic smooth muscle cells had 100% identity throughout the entire coding region with the CCR5 cloned from THP-1 cells. By immunohistochemistry, CCR5 and the CCR5 ligand, macrophage inflammatory protein-1␤ (MIP-1␤), were detected in smooth muscle cells and macrophages of the atherosclerotic plaque. In smooth muscle cell culture, MIP-1␤ induced a significant increase in intracellular calcium concentrations, which was blocked by an antibody to CCR5. In addition, MIP-1␤ caused a calcium-dependent increase in tissue factor activity. Tissue factor is the initiator of coagulation and is thought to play a key role in arterial thrombosis. These data suggest that human arterial smooth muscle cells express functional CCR5 receptors and MIP-1␤ is an agonist for these cells.

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“…Taken together, these findings argue against a direct in vivo role of HIV-1 in the development of mesangial hyperplasia. In contrast with this notion, Tinkle et al [59,60] generated HIV-1 Tg mice carrying a replication-defective HIV-1 provirus with selective deletion of the gag, pol , and env genes, which develop glomerulosclerosis and vasculopathy. These mice show restricted expression of HIV non-structural genes in lymphoid, mesangial, and vascular smooth muscle cells, and develop hyperplasia of mesangial and vascular smooth muscle cells in association with the recruitment of inflammatory cells [59,60].…”

Section: Mesangial Hyperplasiamentioning

confidence: 99%

“…In contrast with this notion, Tinkle et al [59,60] generated HIV-1 Tg mice carrying a replication-defective HIV-1 provirus with selective deletion of the gag, pol , and env genes, which develop glomerulosclerosis and vasculopathy. These mice show restricted expression of HIV non-structural genes in lymphoid, mesangial, and vascular smooth muscle cells, and develop hyperplasia of mesangial and vascular smooth muscle cells in association with the recruitment of inflammatory cells [59,60]. These findings, however, have not been explored in detail, and it is not clear whether they were induced by HIV-1 genes expressed in mesangial/smooth muscle cells or by cytokines released by infiltrating cells.…”

Section: Mesangial Hyperplasiamentioning

confidence: 99%

A 20-year history of childhood HIV-associated nephropathy

Ray

Rakusan

et al. 2004

Pediatr Nephrol

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In 1984, physicians in New York and Miami reported HIV-infected adult patients with heavy proteinuria and rapid progression to end-stage renal disease. These patients showed large edematous kidneys with a combination of focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. This renal syndrome, named HIV-associated nephropathy (HIVAN), was found predominantly in African Americans. Subsequent studies confirmed the presence of HIVAN in children, who frequently develop nephrotic syndrome in association with FSGS and/or mesangial hyperplasia with microcystic tubular dilatation. Since then, substantial progress has been made in our understanding of the etiology and pathogenesis of HIVAN. This article reviews 20 years of research into the pathogenesis of HIVAN and discusses how these concepts could be applied to the treatment of children with HIVAN. HIV-1 infection plays a direct role in the pathogenesis of childhood HIVAN, at least partially by affecting the growth and differentiation of glomerular and tubular epithelial cells and enhancing the renal recruitment of infiltrating mononuclear cells and cytokines. An up-regulation of renal heparan sulfate proteoglycans seems to play a relevant role in this process, by increasing the recruitment of heparin-binding growth factors (i.e., FGF-2), chemokines, HIV-infected cells, and viral proteins (i.e., gp120, Tat). These changes enhance the infectivity of HIV-1 in the kidney and induce injury and proliferation of intrinsic renal cells. Highly active anti-retroviral therapy (HAART) appears to be the most promising treatment to prevent the progression of childhood HIVAN. Hopefully, in the near future, better education, prevention, and treatment programs will lead to the eradication of this fatal childhood disease.

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Transgenic dissection of HIV genes involved in lymphoid depletion.

Cited by 20 publications

References 45 publications

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Human Vascular Smooth Muscle Cells Possess Functional CCR5

A 20-year history of childhood HIV-associated nephropathy

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