Virol

Virol. macrophage cell-cell fusion assays, but was prior to reverse transcription, as determined by quantitative PCR assay for new viral DNA formation. The inhibitory effects of anti-CD63 in primary macrophages could not be explained by changes 20-Hydroxyecdysone in the levels of CD4, CCR5, or -chemokines. Infections of peripheral blood lymphocytes and certain cell lines were unaffected by treatment with anti-CD63, suggesting that this role of CD63 in HIV-1 contamination may be specific for macrophages. Human immunodeficiency computer virus (HIV-1) is known to infect several primary cell types, predominantly CD4+ T lymphocytes and macrophages. HIV-1 contamination results in a gradual decline in the number of CD4+ T cells, leading to the development of AIDS. Macrophages are of particular importance for the pathogenesis of HIV-1, as these cells contribute to viral persistence and dissemination and are likely to be the major cell type involved in mucosal transmission of the computer virus (60, 61). Furthermore, HIV-1 contamination of macrophages has been implicated as contributing to many of the clinical manifestations of AIDS (14, 17, 19, 22, 33, 40, 48, 53, 57, 60, 61). Due to the importance of macrophages in the pathogenesis of HIV-1, identification of molecular determinants of macrophage infection is relevant and may lead to novel therapies specific for this 20-Hydroxyecdysone cell type. Identification of the -chemokine receptor CCR5 as an HIV-1 coreceptor for macrophages 20-Hydroxyecdysone and T cells has led to the development of specific inhibitors of these receptors, which block HIV-1 entry (1, 6, 7, 12, 13, 18, 50, 51). Several lines of evidence, however, indicate the possible involvement of additional factors in macrophage infection. For example, neither antibodies to CCR5 nor the ligands to CCR5 inhibit infection of macrophages as efficiently as they do T cells (10, 13), suggesting that CCR5 utilization may be different in macrophages or that cofactors in addition to CCR5 may be involved in macrophage tropism. Moreover, although the -chemokine receptor CXCR4 is expressed on macrophages and some atypical HIV-1 strains can utilize this coreceptor along with CD4 for entry into macrophages, viruses that use CD4 and CCR5 (R5 or macrophagetropic strains) typically enter macrophages far more efficiently than those using CD4 and CXCR4 (X4, T-tropic, or LIN28 antibody T-cell line-adapted [TCLA] strains) (3, 10). While primary X4 strains are capable of macrophage entry, TCLA strains are unable to replicate efficiently in macrophages. It has been proposed that aspects such as receptor or coreceptor density levels (43, 52), inadequate cell surface associations between CD4 and CXCR4 (11, 26, 58), and chemokine receptor signaling (28, 55) may be important for macrophage tropism. In addition, it has been shown that TCLA strains which enter macrophages but fail to replicate may be blocked at an early postentry step (47), suggesting that postentry factors may also be important for infection of macrophages. Collectively, these studies focus primarily on answering the significant question of why TCLA strains are unable to infect macrophages. There have been fewer studies, however, evaluating whether there may be unique factors, in addition to CD4 and CCR5, that could be involved specifically in R5-mediated macrophage infection. Our laboratory has implicated the cell membrane glycoprotein CD63 as playing a potential role in HIV-1 infection of macrophages. CD63 belongs to the tetraspan transmembrane protein family (also known as the tetraspanins), whose members include CD9, CD37, CD81, CD82, CD53, and CD151. CD63 is structurally characterized by four membrane-spanning domains, resulting in two extracellular loops of unequal size and two short cytoplasmic domains which may be involved in signal transduction in some cell types (49). Although the precise function of CD63 remains unknown, it has been characterized as an activation or differentiation marker on a wide.

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