Analysis Of Viral And Cellular Gene Expression During Human Cytomegalovirus Latent Infection Of Hematopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$407,545.00
Summary
Human cytomegalovirus (HCMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing HCMV disease. Like other herpesviruses, after initial infection HCMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body a ....Human cytomegalovirus (HCMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing HCMV disease. Like other herpesviruses, after initial infection HCMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and no infectious virus is made. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that viral latency and reactivation are of most medical concern, yet viral latency remains very poorly understood. This project has three major components. Firstly, we aim to continue studies which are defining what viral genes are active (ie expressed) during latent infection. Identification of these genes and determination of how they function may have profound implications to our understanding of latency. Secondly, we will examine how human cells are affected when they become latently infected. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in a single experiment. For the first time, we will be able to determine how the cell changes during latency and reactivation. The study of viral and cellular gene expression during latency may contribute to the development of drugs which interfere with the viruses ability to become latent or reactivate. Thirdly, we have preliminary results which suggest that latent HCMV may actively avoid detection by the immune system. In this project we also aim to determine the mechanism by which the virus interferes with the expression of molecules which are an essential component of our immune system.Read moreRead less
Sympathetic Control Of Cutaneous Blood Flow And Blood Pressure In Human Spinal Cord Injury
Funder
National Health and Medical Research Council
Funding Amount
$242,002.00
Summary
While spinal cord injury can cause devastating changes in the nervous system paralysis and loss of sensation relatively little is known about changes to the sympathetic nervous system. The sympathetic nervous system is intimately involved in the ongoing control of blood pressure, blood flow and temperature control. Loss of sympathetic control can occur following spinal cord injury. Interruption of descending pathways can result in partial or complete loss of sympathetic outflow from the thoracol ....While spinal cord injury can cause devastating changes in the nervous system paralysis and loss of sensation relatively little is known about changes to the sympathetic nervous system. The sympathetic nervous system is intimately involved in the ongoing control of blood pressure, blood flow and temperature control. Loss of sympathetic control can occur following spinal cord injury. Interruption of descending pathways can result in partial or complete loss of sympathetic outflow from the thoracolumbar segments. Complete decentralization can result in autonomic dysreflexia (autonomic hyperreflexia), in which sensory stimuli originating below the lesion evoke a reflex increase in sympathetic drive to the blood vessels, causing them to constrict. Because of this, blood pressure may rise suddenly and remain at such high levels that stroke and (occassionally) cardiac arrest may occur. This phenomenon, autonomic dysreflexia, is considered a medical emergency. The typical subjective signs of autonomic dysreflexia include a throbbing headache, tingling in the head or nasal congestion; sweating and flushing above the lesion are clinical signs that prompt medical staff to measure blood pressure and to locate the source of sensory irritation (usually a distended bladder or impacted colon, sometimes a pressure sore or ingrown toenail). Commonly, however, subclinical episodes go undetected, and this phenomenon of silent dysreflexia is of increasing concern. This project will develop means of assessing the integrity and state of the sympathetic nervous system below a lesion in patients with spinal cord injury and characterize the firing properties of reflexly activated sympathetic neurones.Read moreRead less
Cell Type Specific Biologic Responses To HIV Infection
Funder
National Health and Medical Research Council
Funding Amount
$636,242.00
Summary
The way in which HIV alters the internal environment of its target cells to facilitate its growth will be examined. These changes enhance its ability to gain a toehold in the human body after entering the genital tract and its persistence for life in the brain and elsewhere in the body.
Interactions Between HIV And Mycobacterial Infections Of Macrophages Mediated By Changes In Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$119,625.00
Summary
HIV-AIDS and tuberculosis are two of the worlds most important diseases. HIV-AIDS is the fourth leading killing disease worldwide and tuberculosis is the leading opportunistic infection in patients with AIDS particularly in the developing world. Both microbes infect the same cell type, the macrophage, which is widely distributed throughout the body, particularly in lymph nodes and lung. Recent studies in humans have shown that HIV and TB like organisms stimulate each others growth. This study us ....HIV-AIDS and tuberculosis are two of the worlds most important diseases. HIV-AIDS is the fourth leading killing disease worldwide and tuberculosis is the leading opportunistic infection in patients with AIDS particularly in the developing world. Both microbes infect the same cell type, the macrophage, which is widely distributed throughout the body, particularly in lymph nodes and lung. Recent studies in humans have shown that HIV and TB like organisms stimulate each others growth. This study uses the immense power of DNA microarrays, based on the identification of almost all genes by the human genome project, to decipher the interactions between the two microbes. By following up new leads indicated by the microarrays, the way in which the microbes manipulate the macrophage to enhance their own growth and that of the other can be eventually deciphered. This will provide new strategies for future interventions. New drugs are urgently needed for both microbes.Read moreRead less
Viral And Host Cell Gene Expression During The Establishment And Maintenance Phases Of Human Cytomegalovirus Latency
Funder
National Health and Medical Research Council
Funding Amount
$149,250.00
Summary
Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing CMV disease. Like other herpesviruses, after initial infection CMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and ....Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing CMV disease. Like other herpesviruses, after initial infection CMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and no infectious virus is made. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that viral latency and reactivation are of most medical concern, yet viral latency remains very poorly understood. The overall aim of these studies is to provide a much better understanding of how CMV latency is established and maintained, with the ultimate goal of making advances for the design of anti-viral therapies to disrupt these processes. This project has three major components: Firstly, we aim to identify and characterise viral gene expression during the establishment of latency and these findings will have profound implications to our understanding of latency. Secondly, we will examine how human cells are affected when they become latently infected. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in a single experiment. For the first time, we will be able to determine how the cell changes during the establishment and maintenance phases of latency. Thirdly, we will apply microarray technologies to determine how human cell genes are altered in response to the expression of individual viral genes that are active during the latent phase of infection.Read moreRead less
The Effect Of Exogenous Hormones, Smoking And HPV On The Incidence Of Screen Detected Pre-invasive Cervical Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$1,201,168.00
Summary
Cervical cancer is one of the leading causes of cancer death in women internationally. About 15,000 women are detected in NSW annually as having pre-invasive cervical cancer (cervical intraepithelial neoplasia (CIN) grade I, II or III). Infection with certain high risk human papillomaviruses is known to be necessary for the development of cervical cancer. In addition, recent long term exposure to smoking and to hormonal contraception are two new factors considered as independent risk factors for ....Cervical cancer is one of the leading causes of cancer death in women internationally. About 15,000 women are detected in NSW annually as having pre-invasive cervical cancer (cervical intraepithelial neoplasia (CIN) grade I, II or III). Infection with certain high risk human papillomaviruses is known to be necessary for the development of cervical cancer. In addition, recent long term exposure to smoking and to hormonal contraception are two new factors considered as independent risk factors for the disease. Hormone replacement therapy (HRT) preparations taken around the menopause are a similar composition to hormonal contraceptives, (oestrogen and progestogen), therefore women on HRT may also be at increased risk. No comprehensive study exists internationally to measure the relative importance of these exogenous hormones on the development of pre-invasive cervical cancer in a way that is of public health relevance (e.g. recent long-term use of oral contraceptives and time since stopped, and among smokers and non-smokers). No Australian data are available on the proportion of women who are current users of hormonal contraceptives or HRT. No local prevalence data on the major high risk HPV subtypes (e.g. 16, 18, 33, 45) are available for Australia to describe its distribution and to inform the cervical screening program and future vaccine initiatives. The NSW Pap Test Register holds the screening history of all women on the cervical screening program, hence this is an ideal source for recruiting a representative sample into a study. We wish to conduct a large study of ~2600 NSW women using the NSW Pap Test Register to measure the relative importance of hormones, smoking and HPV infection on the development of CIN II or III.Read moreRead less
The Role Of Chemokines In Establishing HIV Latency
Funder
National Health and Medical Research Council
Funding Amount
$372,049.00
Summary
Although antiviral therapy is effective in controlling HIV, therapy must be continued life-long because the virus cannot be cleared from long lived infected CD4+ T cells that are silently or latently infected. In this proposal we will explore the mechanism of how HIV can enter these resting CD4+ T-cells and establish long lived latent infection. Understanding this process may potentially lead to new strategies to cure HIV infection.