Transgenic Mouse Model of Ethanol as a Cofactor in HIV Disease

Prakash, Om; Joshi, Bharat; Zhang, P; Aw, Tak Yee; Teng, Steven; Ali, Manzoor; Shellito, Judd E.; Nelson, Shakira M.

doi:10.1111/j.1530-0277.1998.tb04015.x

Cited by 11 publications

(9 citation statements)

References 36 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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“…Chronic consumption of alcohol can alter various functions of the immune system, including both humoral and cell-mediated processes (8,38). It has been suggested that exposure to EtOH may both increase susceptibility to HIV infection and stimulate HIV replication in previously infected cells and also alter cytokines that increase HIV-1 replication from a quiescent state (7,9,22,(71)(72)(73). Exposure to EtOH can also cause devastating complications and neuronal damage in the brains of AIDS patients (49), resulting in the development of HIV-1-associated dementia (HAD) (25).…”

Section: Coculturing Of Infected T Cells With Neurons or Neurons Expomentioning

confidence: 99%

“…For example, ethanol (EtOH) has been shown to increase tumor necrosis factor alpha-stimulated HIV-1 long terminal repeat-induced transcription in Jurkat T cells (22). Similarly, the HIV-1 regulatory protein Tat, in combination with EtOH, induced synergistic neutrophil dysfunction in transgenic mice (72). Our laboratory has shown that EtOH can cause extensive perturbations within CNS-based cells (1,19).…”

mentioning

confidence: 97%

Cholesterol-Depleting Statin Drugs Protect Postmitotically Differentiated Human Neurons against Ethanol- and Human Immunodeficiency Virus Type 1-Induced Oxidative Stress In Vitro

Acheampong

Parveen

Mengistu

et al. 2007

J Virol

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The AIDS-related dementia characterized by cognitive dysfunction, motor neuron disease, coordination abnormalities, and other neurological signs and symptoms develops in many human immunodeficiency virus type 1 (HIV-1)-infected individuals (17, 58). The molecular mechanisms involved in these HIV-1-associated dysfunctions of the central nervous system (CNS) remain incompletely explained and controversial (42,45). Studies have demonstrated that although the major reservoirs for productive infection within the CNS of HIV-1-infected individuals are microglia and monocytes/macrophages, infection of other CNSbased cell types, such as microvascular endothelial cells and neurons, also appears to occur (44,57,92). The role of lymphocytes in AIDS dementia has also been described previously (59,67,68). Of note, viral replication in cerebrospinal fluid is considered to be a marker for the severity of AIDS-related neurodegeneration (16,20). The CNS tissues are protected from the periphery by a structure known as blood-brain barrier (BBB), which limits the passage of solutes as well as infections into the brain (10). The tight junctions of brain microvascular endothelial cells strengthen the functional impermeability of BBB. Under certain pathological conditions, the BBB becomes compromised, providing access for infections/infected cells into the brain (64). The passage of HIV-1 entry into the brains of AIDS patients in vivo is not quite clear and is supposed to involve both free viruses and virally infected cells (4,89,91).HIV-1-infected individuals are under chronic oxidative stress, and antioxidants have proved to ameliorate infectionassociated oxidative stress. (81, 84). Oxidative stress involves

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“…Furthermore, ethanol during murine AIDS increased the production of IL-4 and IFN-␥ in thymocytes [97] as well as IL-5 and IL-10, and TNF-␣ in splenocytes [96]. Finally, the oxidative damage, bone marrow toxicity, and functional polymorphonuclear neutrophil defects produced by the HIV regulatory protein, tat, in transgenic mice appears to be enhanced by ethanol exposure [98], a result consistent with the hypothesis that ethanol exposure might enhance the progression of HIV infection [98].…”

Section: Ethanol Effects On Brain Immune System Function and The Prmentioning

confidence: 96%

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

Tyor

Middaugh

1999

Journal of Leukocyte Biology

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Transgenic Mouse Model of Ethanol as a Cofactor in HIV Disease

Cited by 11 publications

References 36 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

Cholesterol-Depleting Statin Drugs Protect Postmitotically Differentiated Human Neurons against Ethanol- and Human Immunodeficiency Virus Type 1-Induced Oxidative Stress In Vitro

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

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