An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction

Reid, William; Sadowska, Mariola; Denaro, Frank; Rao, Srinivas S.; Foulke, James S.; Hayes, Nandini V. L.; Jones, Odell; Doodnauth, D.; Davis, Harry; Sill, Anne; O’Driscoll, Peter; Huso, David L.; Fouts, Timothy; Lewis, George K.; Hill, M.; Kamin-Lewis, Roberta; Wei, Catherine; Ray, Patricio E.; Gallo, Robert C.; Reitz, Marvin S.; Bryant, Joseph

doi:10.1073/pnas.161290298

Cited by 326 publications

(430 citation statements)

References 26 publications

(26 reference statements)

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“…These observations are similar to those noted in the brains of AIDS patients and provide evidence of a critical role of Tat protein in HIV-1 neuropathogenesis (32). Furthermore, HIV-1 transgenic rats that develop HIVrelated pathology and immunologic dysfunction were also generated (39). These transgenic rats contain a gag-pol-detected HIV-1 provirus regulated by the viral promoter.…”

Section: Discussionsupporting

confidence: 78%

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

Avraham

Jiang

Lee

et al. 2004

The Journal of Immunology

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The blood-brain barrier (BBB) is a network formed mainly by brain microvascular endothelial cells (BMECs). The integrity of the BBB is critical for brain function. Breakdown of the BBB is commonly seen in AIDS patients with HIV-1-associated dementia despite the lack of productive HIV infection of the brain endothelium. The processes by which HIV causes these pathological conditions are not well understood. In this study we characterized the molecular mechanisms by which Tat mediates its pathogenic effects in vitro on primary human BMECs (HBMECs). Tat treatment of HBMECs stimulated cytoskeletal organization and increased focal adhesion sites compared with control cells or cells treated with heat-inactivated Tat. Pretreatment with Tat Abs or with the specific inhibitor SU-1498, which interferes with vascular endothelial growth factor receptor type 2 (Flk-1/KDR) phosphorylation, blocked the ability of Tat to stimulate focal adhesion assembly and the migration of HBMECs. Focal adhesion kinase (FAK) was tyrosine-phosphorylated by Tat and was found to be an important component of focal adhesion sites. Inhibition of FAK by the dominant interfering mutant form, FAK-related nonkinase, significantly blocked HBMEC migration and disrupted focal adhesions upon Tat activation. Furthermore, HIV-Tat induced permeability changes in HBMECs in a time-dependent manner. Tat also impaired BBB permeability, as observed in HIV-1 Tat transgenic mice. These studies define a mechanism for HIV-1 Tat in focal adhesion complex assembly in HBMECs via activation of FAK, leading to cytoskeletal reorganization and permeability changes.

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Section: Discussionsupporting

confidence: 78%

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

Avraham

Jiang

Lee

et al. 2004

The Journal of Immunology

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“…A majority of researchers in this field, however, emphasize the importance of FDC and the GC reaction in maintaining serological memory (44,48,49). In this context, it should be pointed out that HIV-1 transgenic rats harboring an HIV genome deleted in p24 generate enlarged GCs in lymphatic tissues, morphologically almost indistinguishable from those in HIV-1 infected individuals (52). Consequently, we have focused our efforts on studies of p17 and Env persistence in GCs of LNs.…”

Section: Discussionmentioning

confidence: 99%

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Popovič

Tenner-Rácz

Pelser

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

151

125

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Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120͞gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 ؋ 10 3 to 6.3 ؋ 10 5 copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant with in situ hybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV1p17, -p24, and -gp120͞gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are discussed in relation to HIV-1 persistence in infected individuals and the potential role of chronic antigenic stimulation by the deposited structural proteins in GCs for AIDS-associated B cell malignancies.

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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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An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction

Cited by 326 publications

References 26 publications

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

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

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