Induction of rapid and extensive beta-chemokine synthesis in macrophages by human immunodeficiency virus type 1 and gp120, independently of their coreceptor phenotype.
Human immunodeficiency virus type 1 (HIV-1) interacts with its target cells through CD4 and a coreceptor, generally CCR5 or CXCR4. Macrophages display CD4, CCR5, and CXCR4 that are competent for binding and entry of virus. Virus binding also induces several responses by lymphocytes and macrophages that can be dissociated from productive infection. We investigated the responses of macrophages to exposure to a series of HIV-1 species, R5 species that productively infect and X4 species that do not infect macrophages. We chose to monitor production of several physiologically relevant factors within hours of treatment to resolve virally induced effects that may be unlinked to HIV-1 production. Our novel findings indicate that independently of their coreceptor phenotype and independently of virus replication, exposure to certain R5 and X4 HIV-1 species induced secretion of high levels of macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, RANTES, and tumor necrosis factor alpha. However two of the six R5 species tested, despite efficient infection, were unable to induce rapid chemokine production. The acute effects of virus on macrophages could be mimicked by exposure to purified R5 or the X4 HIV-1 envelope glycoprotein gp120. Depletion of intracellular Ca(2+) or inhibition of protein synthesis blocked the chemokine induction, implicating Ca(2+)-mediated signal transduction and new protein synthesis in the response. The group of viruses able to induce this chemokine response was not consistent with coreceptor usage. We conclude that human macrophages respond rapidly to R5 and X4 envelope binding by production of high levels of physiologically active proteins that are implicated in HIV-1 pathogenesis.
Choe
W
W
Division of Molecular Virology, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, New York 10019, USA.
Volsky
D J
DJ
Potash
M J
MJ
D002118:Calcium / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D010641:Phenotype; D015728:Receptors, HIV / Q000502:physiology*; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019742:Chemokines, CC; D015699:HIV Envelope Protein gp120; D015728:Receptors, HIV; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium