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.
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