Viral Dynamics in Human Immunodeficiency Virus Type 1 Infection

Extracellular amyloid β peptides (Aβs) have long been thought to be a primary cause of Alzheimer's disease (AD). Now, detection of intracellular neuronal Aβ1–42 accumulation before extracellular Aβ deposits questions the relevance of intracellular peptides in AD. In the present study, we directly address whether intracellular Aβ is toxic to human neurons. Microinjections of Aβ1–42 peptide or a cDNA-expressing cytosolic Aβ1–42 rapidly induces cell death of primary human neurons. In contrast, Aβ1–40, Aβ40–1, or Aβ42–1 peptides, and cDNAs expressing cytosolic Aβ1–40 or secreted Aβ1–42 and Aβ1–40, are not toxic. As little as a 1-pM concentration or 1500 molecules/cell of Aβ1–42 peptides is neurotoxic. The nonfibrillized and fibrillized Aβ1–42 peptides are equally toxic. In contrast, Aβ1–42 peptides are not toxic to human primary astrocytes, neuronal, and nonneuronal cell lines. Inhibition of de novo protein synthesis protects against Aβ1–42 toxicity, indicating that programmed cell death is involved. Bcl-2, Bax-neutralizing antibodies, cDNA expression of a p53R273H dominant negative mutant, and caspase inhibitors prevent Aβ1–42-mediated human neuronal cell death. Taken together, our data directly demonstrate that intracellular Aβ1–42 is selectively cytotoxic to human neurons through the p53–Bax cell death pathway.

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Selective cytotoxicity of intracellular amyloid β peptide1–42 through p53 and Bax in cultured primary human neurons

p53 in neuronal apoptosis.

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease

OBJECTIVE Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals. The aim of the study was to compare the main features of HCC in HIV-seropositive individuals with those in to HIV-negative patients. PATIENTS AND METHODS All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study as cases. HCC cases that occurred in the province of Brescia, North Italy, in the period 1995-1998 and all cases reported at the Italian Liver Cancer Project were enrolled as controls. All data were collected using a standardized case report form. The main clinical and epidemiological characteristics of patients with HCC and their survival were compared between HIV-positive and uninfected subjects. RESULTS Forty-one HIV-infected subjects with HCC were identified. Multivariate analysis adjusted for age and sex identified an association between HIV infection and HCV infection [odds ratio (OR), 11; P = 0.005], and infiltrating tumours and/or extranodal metastasis at presentation (OR = 11.8; P < 0.001). HIV infection was independently associated with shorter survival (hazard ratio, 1.63; P = 0.015). CONCLUSIONS HCC in HIV-infected patients is mainly associated with underlying chronic hepatitis C and has a more aggressive clinical course. Thus, preventative strategies (including the treatment of hepatitis C) should be implemented in the management of HIV/HCV-coinfected patients.

Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.

The finding that intracellular expression of the beta-amyloid protein (Abeta) under a neuron-specific promoter led progressively to degeneration and death of neurons in the brains of transgenic mice provides a unique opportunity to utilize this animal model to both understand the mechanism that underlies neuronal cell death and define the complexity of events which may ensue. We observed a correlation between Abeta accumulation in selective neurons and activation of p53, a protein that has been implicated in the induction of apoptosis. Histological and immunohistochemical evaluations of adjacent brain sections suggest that expression of p53 is accompanied by nuclear DNA fragmentation. In certain regions with marked neuronal cell death, extracellular deposition of A(beta) became evident, together with the local activation of astrocytes. Interestingly, the neuritic structures underlying the Abeta deposits showed altered synaptophysin immunoreactivity and morphologic evidence for damage. This transgenic mouse model suggests that intracellular generation of the Abeta protein not only leads to the death of the neuron but may also functionally impair neighboring neurons as well. It further offers a mechanism whereby neuritic plaques may be derived.

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Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice.

Patients with the acquired immunodeficiency syndrome are at risk to develop a variety of different cancers. Based on epidemiological data, Kaposi's sarcoma and non-Hodgkin's lymphoma have been clearly associated with infection by the human immunodeficiency virus (HIV). Additional cancers such as basal cell and squamous cell carcinomas, melanoma, and hepatocellular carcinoma have also been reported to be associated with a diagnosis of acquired immunodeficiency syndrome. A direct causal role of HIV has yet to be established for any of these cancers. We now report that transgenic mice carrying the HIV tat gene develop a high incidence of hepatocellular carcinoma after a long latency and that these changes in the liver are likely to be initiated by extrahepatic growth signals from the tat expressing cells in these mice. We predict that as acquired immunodeficiency syndrome patients begin to respond to therapy and show prolonged survival, such “secondary” malignancies induced by HIV will become increasingly prevalent.

Liver Cancer in Transgenic Mice Carrying the Human Immunodeficiency Virus tat Gene

There is substantial clinical evidence for the development of vascular disorders in human immunodeficiency virus (HIV)-infected individuals, particularly in the form of vasculitis. Transgenic mice carrying a replication-defective HIV-1 provirus with selective deletion of the gag, pol, and env genes developed extensive vasculopathy. Restricted expression of HIV nonstructural genes in smooth muscle cells was accompanied by the migration and proliferation of these cells in blood vessels of all sizes and at different body sites. The frequent infiltration observed in the hypertrophic vessel walls occurred predominantly in the adventitia and was composed of primarily T cells and occasionally plasma cells. The intimal thickening generated significant luminal narrowing in some vessels, and the restricted blood flow led to ischemia in the affected tissues. Interestingly, the endothelium did not appear to support HIV gene expression or be involved in the pathological process. This transgenic model provides an opportunity to dissect the mechanism underlying HIV-associated vasculopathy.

Human immunodeficiency virus-associated vasculopathy in transgenic mice.

Transgenic mice carrying an HIV provirus, with selective deletion of all three structural genes, developed extensive lymphoid depletion which was detected not only in the spleen and lymph nodes but also in the thymus Mice with a high level of HIV gene expression developed acute disease which resulted in premature death, and mice with a low level of viral transcripts developed chronic disease with long-term survival Neither HIV replication nor the envelope glycoprotein (gp120) was required for T cell depletion Despite abundant viral gene expression early in life, cell death did not become evident until about the time of full lymphoid maturation, suggesting that thymopoiesis was not affected The more mature T cells in the peripheral lymphoid organs and in the thymic medulla were less sensitive to the apoptotic process than the immature T cells in the thymic cortex Gradual depletion of the T cell compartment in the peripheral lymphoid organs was intimately accompanied by the reciprocal expansion of the B cell compartment, resulting in the almost complete replacement of T lymphocytes with B immunoblasts in lymph nodes Unlike T cells, which showed abundant HIV gene expression, B cells did not The transgenic approach may help identify the HIV nonstructural gene(s) responsible for immune deficiency and help facilitate dissection of its role in inducing apoptosis

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Transgenic dissection of HIV genes involved in lymphoid depletion.

CHAPTER 19 – Analysis of Transgene Expression

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