A novel HIV-1 transgenic rat model of childhood HIV-1–associated nephropathy

Ray, Patricio E.; Li, Xuehui; Robinson, Louis R.; Reid, William; Xu, Li; Owens, Jennie W.; Jones, Odell; Denaro, Frank; Davis, Harry; Bryant, Joseph

doi:10.1046/j.1523-1755.2003.00028.x

Cited by 63 publications

(64 citation statements)

References 44 publications

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“…The transgenic Tg26 mouse expressed seven of 15 HIV-1 gene products and developed proteinuria and collapsing FSGS with extensive tubulointerstitial damage that resembles the disease that is seen in humans (64). A similar rat model that replicates the phenotype of a transgenic mouse has also been developed (65,66). These experiments convincingly demonstrated that the HIV-1 gene products are important in the pathogenesis of HIVAN.…”

Section: Genetic Susceptibility and Hivansupporting

confidence: 50%

Genetic Susceptibility, HIV Infection, and the Kidney

Kiryluk

Martino

Gharavi

2007

Clinical Journal of the American Society of Nephrology

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In recent years, the sequencing of mammalian and microbial genomes has provided the opportunity to study how genetic variation in the host and pathogen influence the course of infectious disease. In the case of HIV-1 infection, such studies have led to identification of key viral proteins that determine pathogenicity, immune evasion, or drug resistance. In addition, candidate gene association studies have uncovered a large number of host genetic variants that influence the outcome of infection and some organ-specific complications. HIV-associated nephropathy (HIVAN) is a pathologically distinct complication of HIV infection. Interindividual variability in incidence, skewed ethnic distribution, and familial aggregation of HIVAN with other forms of ESRD have suggested genetic susceptibility as a major contributing factor. This article reviews the host genetic factors that influence the course of HIV-1 infection and discusses murine models that have increased the understanding of HIVAN pathogenesis and demonstrated the role of genetic background on determination of disease.

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Section: Genetic Susceptibility and Hivansupporting

confidence: 50%

Genetic Susceptibility, HIV Infection, and the Kidney

Kiryluk

Martino

Gharavi

2007

Clinical Journal of the American Society of Nephrology

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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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“…Soluble gp120 can induce apoptosis in lymphocytes, 12 but also in neurones, [24][25][26][27] cardiomyocytes, 17,28 kidney epithelial cells 29,30 and hepatocytes. 31 These potent cytotoxic effects have been implicated in the HIV-1-induced lymphodepletion, HIV-associated dementia (also called HIV encephalitis or neuro-AIDS), AIDS-cardiomyopathy, as well as AIDS associated nephropathy and hepatopathy.…”

Section: Cell Killing By Soluble Gp120mentioning

confidence: 99%

Mechanisms of apoptosis induction by the HIV-1 envelope

et al. 2005

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The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by a cornucopia of distinct mechanisms. A soluble Env derivative, gp120, can kill cells through signals that are transmitted by chemokine receptors such as CXCR4. Cell surface-bound Env (gp120/gp41), as present on the plasma membrane of HIV-1-infected cells, can kill uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by at least three different mechanisms.

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A novel HIV-1 transgenic rat model of childhood HIV-1–associated nephropathy

Cited by 63 publications

References 44 publications

Genetic Susceptibility, HIV Infection, and the Kidney

Genetic Susceptibility, HIV Infection, and the Kidney

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

Mechanisms of apoptosis induction by the HIV-1 envelope

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