Maternal-Fetal Interactions Affect Growth of Human Immunodeficiency Virus Type 1 Transgenic Mice

Franks, Roberta; Ray, Patricks E; Babbott, Cecelia C; Bryant, Joseph; Notkins, Abner Louis; Santoro, Thomas J.; Klotman, Paul E.

doi:10.1203/00006450-199501000-00012

Cited by 11 publications

(7 citation statements)

References 53 publications

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“…Similar results have been reported in several HIV-1 transgenic studies, 60,61,76 as well as HIV-infected children and adults. [77][78][79][80] Although the mechanisms are currently unknown, a multifactorial etiology seems likely.…”

Section: Discussionsupporting

confidence: 78%

Neuropathologies in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Tat Protein under the Regulation of the Astrocyte-Specific Glial Fibrillary Acidic Protein Promoter and Doxycycline

Kim

Liu

Ruan

et al. 2003

The American Journal of Pathology

228

308

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The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycline (Dox)-inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together dem-

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Section: Discussionsupporting

confidence: 78%

Neuropathologies in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Tat Protein under the Regulation of the Astrocyte-Specific Glial Fibrillary Acidic Protein Promoter and Doxycycline

Kim

Liu

Ruan

et al. 2003

The American Journal of Pathology

228

308

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“…To determine whether apoptosis was caused by alterations in cytokines that are known to affect apoptosis or by a direct effect of HIV-1 gene expression, we cultured kidneys ex vivo. Whole organ culture can only be accomplished in fetal tissue and we have previously shown transgene expression during fetal development (33). Day 12 fetal kidneys from transgenic and normal fetuses were grown in culture for 7 d and developed normally.…”

Section: Resultsmentioning

confidence: 99%

“…Pups from three pregnant Tg26 heterozygotes were obtained and two litters (15 pups total) were used for in situ hybridization and one litter (eight pups) was used for electron microscopy. DNA was extracted from the remainder of each fetus and used for Southern blot analysis to identify transgenic and nontransgenic fetuses as previously described (33). Each kidney was placed in a separate 35-mm tissue culture dish with ME/ Ham F12 plus 10% FBS and cultured for 7 d (34).…”

Section: Methodsmentioning

confidence: 99%

Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression.

Bruggeman¹,

Dikman²,

Meng³

et al. 1997

J. Clin. Invest.

227

155

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HIV-associated nephropathy (HIVAN) is a progressive glomerular and tubular disease that is increasingly common in AIDS patients and one of the leading causes of end stage renal disease in African Americans. A major unresolved issue in the pathogenesis of HIVAN is whether the kidney disease is due to renal cell infection or a "bystander" phenomenon mediated by systemically dysregulated cytokines. To address this issue, we have used two different experimental approaches and an HIV-1 transgenic mouse line that develops a progressive renal disease histologically similar to HIVAN in humans. In the murine model, kidney tissue expresses the transgene and in heterozygous adults, renal disease develops shortly thereafter. We demonstrate by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labeling assay that similar to the disease in humans, apoptosis of renal tubular epithelial cells is a component of the molecular pathogenesis. To determine whether apoptosis is due to transgene expression or environmental factors, we treated fetal kidney explants (normal and transgenic) with UV light to induce transgene expression. Apoptosis occurred in transgenic but not normal littermates after stimulation of transgene expression. To confirm a direct effect of HIV expression on the production of HIVAN, we transplanted kidneys between normal and transgenic mice. HIVAN developed in transgenic kidneys transplanted into nontransgenic littermates. Normal kidneys remained disease free when transplanted into transgenic littermates. Thus, the renal disease in the murine model is intrinsic to the kidney. Using two different experimental approaches, we demonstrate a direct effect of transgene expression on the development of HIVAN in the mouse. These studies suggest that in humans, a direct effect of HIV-1 expression is likely the essential cause of HIVAN, rather than an indirect effect of cytokine dysregulation. ( J. Clin. Invest. 1997. 100:84-92.)

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“…Heterozygous Tg26 mice exhibit normal appearance and near normal growth but develop nephropathy and hyperproliferative skin lesions (e.g., papillomas) in adult life. Homozygous Tg26 mice are normal in appearance and weight at birth but develop debilitating cachexia and diffuse scaling of the skin and die within 3 to 4 weeks after birth (10,(17)(18)(19). Previously, it was shown that treatment of newborn homozygous Tg26 mice with human chorionic gonadotropin (hCG) prevented death, reduced skin lesions, and resulted in near normal growth (7).…”

mentioning

confidence: 99%

Elevated Levels of Tumor Necrosis Factor Alpha (TNF-α) in Human Immunodeficiency Virus Type 1-Transgenic Mice: Prevention of Death by Antibody to TNF-α

Devadas

Notkins

2002

J Virol

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Homozygous human immunodeficiency virus type 1 (HIV-1)-transgenic mice (Tg26) appear normal at birth but die within 3 to 4 weeks. The skin of these animals shows diffuse scaling and high-level expression of both HIV-1 mRNA and gp120. Previous experiments showed that treatment with human chorionic gonadatropin (hCG) prevented death and the expression of HIV-1 mRNA and gp120. The present experiments were initiated to study the role of tumor necrosis factor alpha (TNF-␣) in HIV-1-induced pathology. Examination of the sera of Tg26 mice revealed a 50-fold increase in TNF-␣ levels compared to those in nontransgenic mice. Treatment with antibody to TNF-␣ prevented death, resulted in near normal growth, and produced a marked decrease in skin lesions and a profound reduction in the expression of HIV-1 mRNA and gp120. Both TNF-␣ antibody and hCG reduced TNF-␣ levels in sera by approximately 75%. We conclude that TNF-␣ contributes in a major way to HIV-1-induced pathology in transgenic mice and that both hCG and antibody to TNF-␣ prevent the development of pathology by suppressing the level of TNF-␣.

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Maternal-Fetal Interactions Affect Growth of Human Immunodeficiency Virus Type 1 Transgenic Mice

Cited by 11 publications

References 53 publications

Neuropathologies in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Tat Protein under the Regulation of the Astrocyte-Specific Glial Fibrillary Acidic Protein Promoter and Doxycycline

Neuropathologies in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Tat Protein under the Regulation of the Astrocyte-Specific Glial Fibrillary Acidic Protein Promoter and Doxycycline

Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression.

Elevated Levels of Tumor Necrosis Factor Alpha (TNF-α) in Human Immunodeficiency Virus Type 1-Transgenic Mice: Prevention of Death by Antibody to TNF-α

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