MECHANISMS OF ERADICATION OF VIRUS INFECTED MACROPHAGES

Project Details

Description

The primary targets for HIV infection are CD4+ T lymphocytes and cells of
the macrophage-monocyte lineage. Infection of T cells leads to their
destruction and profound immunosuppression, while infection of macrophage-
monocytes does not generally cause cytopathology, but may represent a
sanctuary for the virus, serving as a reservoir for HIV persistence, spread
and continual infection of T cells in the face of a significant, early
immune response against viral antigens. Macrophages are also the likely
routes of HIV infection of the central nervous system. The mechanisms by
which virus-infected macrophages evade the host immune response are
unknown. Unless they are elucidated, the pathogenesis of AIDS will not be
fully understood and the prevention or therapy of HIV infections by
immunologic means may not be achieved. The studies proposed are designed
to systematically determine the mechanisms by which retroviral infection of
macrophage lineage cells evades host immune responses and to identify the
circumstances in which host immunity can be made capable of eliminating the
infected cells. This will be approached using a novel experimental system
developed in our laboratory involving Friend virus-induced erythroleukemias
in mice. We have demonstrated that virus infection of macrophages occurs
and is a critical factor in the pathogenesis of this disease. The
conditions, the host is able to mount an immune response that eradicates
the virus infected macrophages and this leads to leukemia regression. We
have also found that CNS macrophages are productively infected with virus
in this system, and that these infected cells are absent in regressor
animals. This system thus permits identification of the factors involved
in retroviral escape from host immune responses by establishment of a
sanctuary infection in macrophages, as occurs in progressor animals.
Moreover, it uniquely permits identification of the mechanisms by which the
immune system can successfully eradicate infected macrophages and bring the
disease under control, as occurs in regressor animals. This will be
accomplished by: 1) determining if the viral and MHC antigens expressed on
infected cells of the macrophage lineage differ from those on infected
erythroid, lymphoid or fibroblastic cells; 2) determining whether
expression of viral and MHC antigens on infected macrophages is modulated
by cytokines, including GM-CSF, TNF-alpha, IFN's; and, 3) determining
whether infected macrophages differ from other infected lineages in
susceptibility to cell-mediated immune effectors.
StatusFinished
Effective start/end date3/1/912/28/95

Funding

  • National Institutes of Health
  • National Institutes of Health: $133,667.00
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.