Abstract
The neuronal damage characteristic of HIV-1-mediated CNS diseases is inflicted by HIV-1 infected brain macrophages. Several steps of viral replication, including assembly and budding, differ between macrophages and T cells; it is likely that cell-specific host factors mediate these differences. We previously defined Annexin 2 (Anx2) as an HIV Gag binding partner in human monocyte-derived macrophages (MDMs) that promotes proper viral assembly. Anx2, a calcium-dependent membrane-binding protein that can aggregate phospholipid-containing lipid rafts, is expressed to high levels in macrophages, but not in T lymphocytes or the 293T cell line. Here, we use bimolecular fluorescence complementation in the 293T cell model to demonstrate that Anx2 and HIV-1 Gag interact at the phosphatidylinositol (4,5) bisphosphate-containing lipid raft membrane domains at which Gag mediates viral assembly. Furthermore, we demonstrate that Anx2 expression in 293T cells increases Gag processing and HIV-1 production. These data provide new evidence that Anx2, by interacting with Gag at the membranes that support viral assembly, functions in the late stages of HIV-1 replication.
Highlights
Direct infection of the brain by HIV-1 causes the AIDSdefinining illness HIV-associated dementia (HAD) as well as a spectrum of motor and cognitive disorders [1,2]
We previously reported that Annexin 2 (Anx2) and Gag co-precipitated when co-transfected into 293T cells [9]
Chertova et al (2006) recently reported that Anx2 is incorporated into virions produced by HIV-1 infected monocyte-derived macrophages (MDMs), evidence that in these cells viral assembly occurs at membranes on which this protein is concentrated [49,50]
Summary
Direct infection of the brain by HIV-1 causes the AIDSdefinining illness HIV-associated dementia (HAD) as well as a spectrum of motor and cognitive disorders [1,2]. Several aspects of HIV replication differ in macrophages from the more extensively studied CD4+ T cells, including the coreceptor used for entry, the mechanisms regulating nuclear import and viral transcription, and the cellular location of assembly and budding (reviewed in [8]). As these cells serve vastly different functions in the immune response, it is likely that many of the differences in viral replication are due to differential protein expression and regulation between the two cell types. We recently undertook studies to identify macrophage-specific proteins that function in HIV-1 assembly and budding [9]
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