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 Blood, 2 July 2009, Vol. 114, No. 1, pp. 85-94.
Prepublished online as a Blood First Edition Paper on May 12, 2009; DOI 10.1182/blood-2008-12-194845.

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IMMUNOBIOLOGY

HIV-1–infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase

Andrew N. Harman1, Marianne Kraus2, Chris R. Bye1, Karen Byth1, Stuart G. Turville1, Owen Tang1, Sarah K. Mercier1, Najla Nasr1, Josh L. Stern1, Barry Slobedman1, Christoph Driessen2, and Anthony L. Cunningham1

1 Centre for Virus Research, Westmead Millennium Institute, Sydney, Australia; and 2 Experimental Oncology, Department of Oncology/Hematology, Cantonal Hospital, St Gallen, Switzerland

Dendritic cells (DCs) play a key role in the pathogenesis of HIV infection. HIV interacts with these cells through 2 pathways in 2 temporal phases, initially via endocytosis and then via de novo replication. Here the transcriptional response of human DCs to HIV-1 was studied in these phases and at different stages of the virus replication cycle using purified HIV-1 envelope proteins, and inactivated and viable HIV-1. No differential gene expression was detected in response to envelope. However, more than 100 genes were differentially expressed in response to entry of viable and inactivated HIV-1 in the first phase. A completely different set of genes was differentially expressed in the second phase, predominantly in response to viable HIV-1, including up-regulation of immune regulation genes, whereas genes encoding lysosomal enzymes were down-regulated. Cathepsins B, C, S, and Z RNA and protein decreased, whereas cathepsin L was increased, probably reflecting a concomitant decrease in cystatin C. The net effect was markedly diminished cathepsin activity likely to result in enhanced HIV-1 survival and transfer to contacting T lymphocytes but decreased HIV-1 antigen processing and presentation to these T cells.


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