ALVEOLAR MACROPHAGES AND DEFENSE OF THE LUNG IN AIDS

Project: Research project

Description

Human immunodeficiency virus type 1 (HIV-1), a lentivirus etiologically
linked to AIDS and related disorders, infects principally CD4+ T-
lymphocytes and cells in the monocyte/macrophage lineage. In infected
individuals, virus is found in peripheral blood monocytes/macrophage
(PBMM), alveolar macrophage (AM), as well as in monocyte-related cells
in the bone marrow, brain, and skin. The simian immunodeficiency virus
isolated from Asian macaques, designated SIVmac, is a T-lymphocytopathic
lentivirus that is genetically related to HIV-1 and HIV-2. SIVmac
replicates in CD4+ lymphocytes and in cells in the monocyte/macrophage
lineage. This virus causes a fatal AIDS-like disease in susceptible
macaques. The hypothesis for the current proposal is that SIV mac
infection of AM plays an important role in important role in
pathogenesis. Infected monocyte/macrophage may account for viral
persistence (and/or latency), and the cell activation state may
influence the extent of viral replication and, ultimately, disease
progression. The research in this proposal will evaluate the
involvement of AM in SIV-infected animals (Specific Aims 1 to 3). This
information will lay a basis for elucidating molecular mechanisms
regulating cell activation and viral replication in AM (Specific Aims 4
and 5). SPECIFIC AIM 1: Optimal conditions will be established for recovery,
characterization, and maintenance of rhesus macaque AM and PBMM in
tissue culture systems. SPECIFIC AIM 2: AM and PBMM from SIV-infected
macaques progressing through various disease stages will be tested in
functional assays and cell surface markers will be characterized.
SPECIFIC AIM 3: Replication of SIV will be monitored in AM and PBMM
from infected macaques who progress from a healthy state to a fatal
AIDS-like disease. The effects of cell activation on SIV replication
will be analyzed and a role for macrophage in viral persistence (and/or
latency) will be investigated. SPECIFIC AIM 4: An in vitro infection
system for AM will be developed to analyze directly the effects of SIV
on macrophage functions and to evaluate the role of cell activation on
viral infection. SPECIFIC AIM 5: Transient expression assays will be
performed with AM and macrophage tumor cell lines to elucidate molecular
mechanisms regulating expression of both viral and macrophage genes. This proposal will examine the effects of SIV infection on AM in
macaques with the goal of gaining a better understanding of the role of
AM in individuals infected with HIV-1. Emphasis is directed at
analyzing the consequences of viral infection on macrophage functions
related to defense of the lung. With respect to pathogenesis, results
of these investigations may reveal whether viral infection directly
disrupts AM and PBMM or whether indirect mechanisms lead to cellular
dysfunctions.
StatusFinished
Effective start/end date7/1/896/30/94

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Alveolar Macrophages
Acquired Immunodeficiency Syndrome
Macrophages
Lung
Monocytes
HIV-1
Macaca
Virus Diseases
Viruses
T-Lymphocytes
Virus Activation
Lentivirus
HIV-2
Viral Genes
Infection
Tumor Cell Line
Macaca mulatta
Research Design
Bone Marrow
Maintenance

ASJC

  • Medicine(all)