Abstract

This is a revised version of a competitive renewal application for continuing studies on HIV-1 infection in macrophages. The investigators have observed that nominally lymphotrophic (LT) viruses can infect macrophages which, in turn, can transmit the infection back to lymphocytes despite abnormal Gag-Pol processing of the LT virus produced in macrophages. A unique contract-dependent mechanism is proposed to account for this mode of transmission. In the proposal, Aim 1 will examine the structure, mode of entry, and cytopathic effects of LT virus transmitted from macrophages to T lymphocytes.
Aim 2 will employ alveolar macrophages (AM) from AIDS patients to test transmission and cytopathogenic activity for T lymphocytes. An attempt will be made to generate HVS-transformed AM capable of transmitting endogenous primary HIV-1.
Aim 3 will study the relative synthesis of Gag-Pol versus Gag, as well as intracellular localization and modification of Gag-Pol, and the localization of virion budding. Co-infection of monocyte-derived macrophages (MDM) with LT and MT viruses will test for protease dysfunction or inhibition Vaccinia virus vectors will be used to assess the role of ENV in regulating Gag-Pol expression in a virus-free system.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043628-10
Application #
6125895
Study Section
Special Emphasis Panel (ZRG5-ARRA (03))
Project Start
1989-07-01
Project End
2000-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
10
Fiscal Year
2000
Total Cost
$254,815
Indirect Cost

  Institution

Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
623216371
City
New York
State
NY
Country
United States
Zip Code
10019

  Publications

Gendelman, H E; Persidsky, Y; Ghorpade, A et al. (1997) The neuropathogenesis of the AIDS dementia complex. AIDS 11 Suppl A:S35-45
Kotler, M; Simm, M; Zhao, Y S et al. (1997) Human immunodeficiency virus type 1 (HIV-1) protein Vif inhibits the activity of HIV-1 protease in bacteria and in vitro. J Virol 71:5774-81
Limoges, J; Persidsky, Y; Bock, P et al. (1997) Dexamethasone therapy worsens the neuropathology of human immunodeficiency virus type 1 encephalitis in SCID mice. J Infect Dis 175:1368-81
Canki, M; Potash, M J; Bentsman, G et al. (1997) Isolation and long-term culture of primary ocular human immunodeficiency virus type 1 isolates in primary astrocytes. J Neurovirol 3:10-5
Volsky, D J; Simm, M; Shahabuddin, M et al. (1996) Interference to human immunodeficiency virus type 1 infection in the absence of downmodulation of the principal virus receptor, CD4. J Virol 70:3823-33
Schmidtmayerova, H; Nottet, H S; Nuovo, G et al. (1996) Human immunodeficiency virus type 1 infection alters chemokine beta peptide expression in human monocytes: implications for recruitment of leukocytes into brain and lymph nodes. Proc Natl Acad Sci U S A 93:700-4
Nottet, H S; Flanagan, E M; Flanagan, C R et al. (1996) The regulation of quinolinic acid in human immunodeficiency virus-infected monocytes. J Neurovirol 2:111-7
Simm, M; Pekarskaya, O; Volsky, D J (1996) Synthesis of full-length viral DNA in CD4-positive membrane vesicles exposed to HIV-1. A model for studies of early stages of the hiv-1 life cycle. J Biol Chem 271:28266-70
Simm, M; Chao, W; Pekarskaya, O et al. (1996) Genetic variability and function of the long terminal repeat from syncytium-inducing and non-syncytium-inducing human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 12:801-9
Persidsky, Y; Limoges, J; McComb, R et al. (1996) Human immunodeficiency virus encephalitis in SCID mice. Am J Pathol 149:1027-53

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