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J Virol 2002 Dec;76(24):12845-54
 

Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection.

Zhang ZQ, Fu TM, Casimiro DR, Davies ME, Liang X, Schleif WA, Handt L, Tussey L, Chen M, Tang A, Wilson KA, Trigona WL, Freed DC, Tan CY, Horton M, Emini EA, Shiver JW

Department of Viral Vaccine Research, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, WP16-225, West Point, PA 19486, USA. zhiqiang_zhang@merck.com

Expression of several major histocompatibility complex (MHC) class I alleles is associated with a protective effect against disease progression in both human immunodeficiency virus type 1 and simian immunodeficiency virus infection. To understand the mechanism underlying this effect, we investigated the expression of the MHC class I allele Mamu-A*01 in simian-human immunodeficiency virus (SHIV) infection, one of the major models for evaluation of AIDS vaccine candidates. We found that disease progression was significantly delayed in Mamu-A*01-positive rhesus monkeys infected with the highly pathogenic SHIV 89.6P. The delay corresponded not only to a noted Mamu-A*01-restricted dominant cytotoxic T-lymphocyte (CTL) response but also to a lower viral load in lymph nodes (LN) and, importantly, to minimal destruction of LN structure during early infection. In contrast, Mamu-A*01-negative monkeys exhibited massive destruction of LN structure with accompanying rapid disease progression. These data indicate that MHC class I allele-restricted CTL responses may play an important role in preservation of lymphoid tissue structure, thereby resulting in attenuation of disease progression in immunodeficiency virus infection.

PMID: 12438610, UI: 22326837

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J Virol 2002 Dec;76(24):12584-95
 

Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection.

Day CL, Lauer GM, Robbins GK, McGovern B, Wurcel AG, Gandhi RT, Chung RT, Walker BD

Partners AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA.

Vigorous virus-specific CD4+ T-helper-cell responses are associated with successful control of hepatitis C virus (HCV) and other human viral infections, but the breadth and specificity of responses associated with viral containment have not been defined. To address this we evaluated the HCV-specific CD4+ T-helper-cell response in HCV antibody-positive persons who lack detectable plasma viremia, and compared this response to that in persons with chronic HCV infection. Peripheral blood mononuclear cells were stimulated with HCV proteins, followed by measurement of HCV-specific CD4+ T-cell responses to a comprehensive set of overlapping HCV peptides by intracellular gamma interferon production. In three persons with resolved HCV infection studied in detail, 13 to 14 epitopes were targeted, but none was recognized by all three. The 37 defined epitopes were predominantly distributed among the HCV proteins core, NS3, NS4, and NS5. In an expanded analysis of responses to these proteins in persons with resolved infection, an average of 10 epitopes was targeted, whereas in persons with chronic viremia never was more than one epitope targeted (P < 0.001). This comprehensive analysis of the breadth and specificity of HCV-specific T-helper-cell responses indicates that up to 14 viral epitopes can be simultaneously targeted by circulating virus-specific CD4+ T helper cells in a controlled human viral infection. Moreover, these data provide important parameters for evaluation of candidate HCV vaccines, and provide rationale for immunotherapy in chronic HCV infection.

PMID: 12438584, UI: 22326811

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J Virol 2002 Dec;76(24):12483-90
 

Evidence that replication of the antitumor adenovirus ONYX-015 is not controlled by the p53 and p14(ARF) tumor suppressor genes.

Edwards SJ, Dix BR, Myers CJ, Dobson-Le D, Huschtscha L, Hibma M, Royds J, Braithwaite AW

Departments of Pathology, University of Otago, Dunedin, New Zealand.

The adenovirus mutant ONYX-015 is in phase III clinical trials as a novel antitumor therapy. Its apparent efficacy is thought to be due to its ability to replicate selectively in tumor cells defective in the signaling pathway for p53. Recent data have shown that p14(ARF), a positive regulator of p53, inhibits ONYX-015 replication in cells with a wild-type p53, a phenotype that characterizes normal cells. We, however, found that ONYX-015 activates p53 in tumor cells and in normal cells and that this can occur without p14(ARF) induction. We also show that ONYX-015 is not attenuated in cells with functional p53, whether or not p14(ARF) is expressed, and that where attenuation does occur, it is cell type specific.

PMID: 12438574, UI: 22326801

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J Virol 2002 Dec;76(23):12355-9
 

Mucosal immunization with live recombinant bovine respiratory syncytial virus (BRSV) and recombinant BRSV lacking the envelope glycoprotein G protects against challenge with wild-type BRSV.

Schmidt U, Beyer J, Polster U, Gershwin LJ, Buchholz UJ

Institute of Molecular Biology, Federal Research Centre for Virus Diseases of Animals, D-17498 Insel Riems, Germany.

Recombinant bovine respiratory syncytial virus (rBRSV) and an rBRSV deletion mutant lacking the G gene (rBRSVDeltaG) were characterized in calves with respect to replication competence, attenuation, and protective efficacy as live-attenuated BRSV vaccines. Both recombinant viruses were safe and induced protection against a BRSV challenge infection. rBRSV replicated efficiently in the upper respiratory tract. Intranasal immunization with rBRSVDeltaG led to infection but not to mucosal virus replication. Neutralizing antibodies were induced by rBRSV and rBRSVDeltaG. Thus, the BRSV attachment glycoprotein G seems to be dispensable in vaccinating calves against BRSV.

PMID: 12414977, UI: 22302345

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J Virol 2002 Dec;76(23):12325-34
 

Generation of hepatitis C virus-like particles by use of a recombinant vesicular stomatitis virus vector.

Ezelle HJ, Markovic D, Barber GN

Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.

Hepatitis C virus (HCV), a major etiologic agent of hepatocellular carcinoma, presently infects approximately 400 million people worldwide, making the development of protective measures against HCV infection a key objective. Here we have generated a recombinant vesicular stomatitis virus (VSV), which expresses the HCV structural proteins, by inserting the contiguous Core, E1, and E2 coding region of HCV into the VSV genome. Recombinant VSV expressing HCV Core, E1, and E2 (VSV-HCV-C/E1/E2) grew to high titers in vitro and efficiently expressed the incorporated HCV gene product, which became fully processed into the individual HCV structural proteins. Biochemical and biophysical analysis indicated that the HCV Core, E1, and E2 proteins assembled to form HCV-like particles (HCV-LPs) possessing properties similar to the ultrastructural properties of HCV virions. Mice immunized with VSV-HCV-C/E1/E2 generated cell-mediated immune responses to all of the HCV structural proteins, and humoral responses, particularly to E2, were also readily evident. Our data collectively indicate that engineered VSVs expressing HCV Core, E1, and E2 and/or HCV-LPs represent useful tools in vaccine and immunotherapeutic strategies designed to address HCV infection.

PMID: 12414973, UI: 22302341

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JAMA 2002 Dec 11;288(22):2815-7
 

From the Centers for Disease Control and Prevention. Influenza and pneumococcal vaccination levels among persons aged > or = 65 years--United States, 2001.

PMID: 12481760, UI: 22367733

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JAMA 2002 Dec 11;288(22):2814-5
 

From the Centers for Disease Control and Prevention. Preventive-care practices among persons with diabetes--United States, 1995 and 2001.

PMID: 12481759, UI: 22367732

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Science 2002 Dec 20;298(5602):2314
 

PUBLIC HEALTH: Looking for Vaccines That Pack a Wallop Without the Side Effects.

Cohen J

[Medline record in process]
 

Since the 11 September terrorist attacks, the quest for a safer smallpox vaccine has taken on a new urgency, drawing in a number of leading labs. Science discusses a few of the new approaches being tested.

PMID: 12493891, UI: 22382072

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Science 2002 Dec 20;298(5602):2313
 

PUBLIC HEALTH: Treating Vaccine Reactions: Two Lifelines, But No Guarantees.

Enserink M

[Medline record in process]
 

In a small minority of cases, the smallpox vaccine can have horrific side effects. Unfortunately, doctors will have only limited means to help such patients when the United States resumes vaccination. Although two treatments are recommended for vaccine complications, little hard evidence supports the efficacy of either one.

PMID: 12493890, UI: 22382071

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