The goal of this initiative is to encourage research on the mechanism of activation of HIV-1 in the lung and mechanism by which co-factors lead to increased HIV-1 associated pulmonary disease.
The mechanisms which may lead to the activation of HIV in the lung have not been clearly defined. Several factors have been proposed to influence the activation of HIV in the lung, including concurrent bacterial and viral infections, environmental exposures and cytokines and their networks. In vitro systems have shown that macrophages latently infected with HIV can be stimulated to produce infectious virus by exposure to phorbol esters, cytokines (interleukin 1, interleukin 6, TNF-alpha, TNF-ß , GM-CSF, mitogens, endotoxin) and other viruses.
This study will focus on mechanisms by which the risk factors/co-factors lead to enhanced pulmonary disease.
This study will be supported from 1996 to 2001.
HL57875 - Paul Skolnik - New England Medical Center, Boston, MA
HL57880 - Mario Stevenson - University of MA Medical School, Worcester, MA
HL57882 - Gregory Viglianti - Boston University, Boston, MA
HL57883 - Peter Barry - University of California, Davis, CA
HL57885 - Michael Coffey - University of Michigan, Ann Arbor, MI
HL57911 - Richard Kornbluth - Veterans Medical Center, San Diego, CA
HL57940 - Elizabeth Rich - Case Western Reserve University, Cleveland, OH
HL58004 - Ronald Collman - University of Pennsylvania, Philadelphia, PA
HL58005 - Maureen Goodenow - University of Florida, Gainesville, FL
HL57890 - Lynn Schnapp - Mt. Sinai School of Medicine, New York, NY
Immune mechanisms appear to contribute to the control of replication of HIV in vivo. Preliminary studies indicate that contact with CD40 ligand bearing cells stimulates macrophages to make several -chemokines that bind to the CCR5 receptor and prevent CD4+ T cells from becoming infected with HIV. How CD40L expression is impaired and the role of CD40 ligand in maintaining a balance between humoral and cellular immune responses are being investigated. Another group reported that IL-16 represses HIV-1 promoter activity. They are examining the role of retinoids and IL-16 during asymptomatic stages of HIV infection. The effects of pneumonia on the course of HIV-1 infection is being studied by other investigators. They found that pneumococcal disease and pneumococcal vaccine increase plasma HIV-1 levels and are now studying the mechanisms responsible for the increased levels of virus. This project will help determine the influence of pneumococcal disease on the progression of HIV-1 disease. A different approach to understanding the repeated infections occurring in HIV disease is to study the role of cell adhesion molecules to see how they alter viral replication. Not only is the recruitment of cells to areas of inflammation mediated by interactions between integrins (a class of adhesion molecules and extracellular matrix), but it now appears that adhesion of HIV-1 containing cells to extracellular matrix protein modulates viral replication.
The major objective of this program is to refine for use in clinical laboratories and blood banks one or more nucleic acid based techniques that will be feasible for the direct detection of blood borne viruses in donors of blood for transfusion to reduce the antibody negative window period between infectivity and detection to the shortest possible time and when possible to obviate the need for indirect antibody tests.
The assay format being refined utilizes an integrated approach in which sample preparation, amplification and detection are performed in a single tube. The assay protocol includes three sequential procedures: (I) Sample processing, viral lysis and capture of the RNAs; (ii) Amplification of viral sequences with Transcription-Mediated Amplification (TMA); and (iii) Detection of the amplicon with HPA or DKA. A major challenge for the development of screening assays for HIV and HCV is their high degree of genetic diversity. Analysis of sequences of viral strains originated in different countries allowed classification of HIV-1 in two major groups: M and O. Group M, which comprises the majority of HIV-1 isolates, can be subdivided in nine subtypes or classes: A to J. Similar studies allowed classification of HCV in ten types: 1 to 10, subdivided into at least 28 different subtypes. HIV subtype B and HCV subtypes I/1a and II/1b are the most common types in the US. The overall strategy to assure subtype detection includes: (I) selection of primers and probes targeted to conserve genomic regions; (ii) the use of double sets of primers, detection probes and capture probes; and (iii) for HIV, examine a second conserved region, LTR.
This study will be supported from 1996 to 1999.
HB67131 - John Findlay - Johnson & Johnson Clinical Diagnostics, Rochester, NY
Recent Progress
This is a newly funded grant. Results are preliminary and have not yet been published.
The objective of this program is to refine for use in clinical laboratories, blood bank laboratories, or both, one or more nucleic acid based techniques that will be feasible for the direct detection of blood borne viruses in donors of organs for transplantation to reduce the antibody negative window period between infectivity and detection to the shortest possible time.
The contract has been awarded recently and the first quarterly technical report is not available as yet.
This study will be supported from 1996 to 1999.
HB67130 - Larry Mimms - Gen-Probe, Inc., San Diego, CA
This is a newly funded grant. Results are preliminary and have not yet been published.