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Journal of Virology, September 2007, p. 9693-9706, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00492-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Productive Human Immunodeficiency Virus Type 1 Infection in Peripheral Blood Predominantly Takes Place in CD4/CD8 Double-Negative T Lymphocytes

Philipp Kaiser, Beda Joos, Barbara Niederöst, Rainer Weber, Huldrych F. Günthard, Marek Fischer,^* the Swiss HIV Cohort Study

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich Rämistrasse, 100 8091 Zürich, Switzerland

Received 8 March 2007/ Accepted 27 June 2007

Human immunodeficiency virus type 1 (HIV-1) transcription is subject to substantial fluctuation during the viral life cycle. Due to the low frequencies of HIV-1-infected cells, and because latently and productively infected cells collocate in vivo, little quantitative knowledge has been attained about the range of in vivo HIV-1 transcription in peripheral blood mononuclear cells (PBMC). By combining cell sorting, terminal dilution of intact cells, and highly sensitive, patient-specific PCR assays, we divided PBMC obtained from HIV-1-infected patients according to their degree of viral transcription activity and their cellular phenotype. Regardless of a patient's treatment status, the bulk of infected cells exhibited a CD4⁺ phenotype but transcribed HIV-1 provirus at low levels, presumably insufficient for virion production. Furthermore, the expression of activation markers on the surface of these CD4⁺ T lymphocytes showed little or no association with enhancement of viral transcription. In contrast, HIV-infected T lymphocytes of a CD4^–/CD8^– phenotype, occurring exclusively in untreated patients, exhibited elevated viral transcription rates. This cell type harbored a substantial proportion of all HIV RNA⁺ cells and intracellular viral RNAs and the majority of cell-associated virus particles. In conjunction with the observation that the HIV quasispecies in CD4⁺ and CD4^–/CD8^– T cells were phylogenetically closely related, these findings provide evidence that CD4 expression is downmodulated during the transition to productive infection in vivo. The abundance of viral RNA in CD4^–/CD8^– T cells from viremic patients and the almost complete absence of viral DNA and RNA in this cell type during antiretroviral treatment identify HIV⁺ CD4^–/CD8 T cells as the major cell type harboring productive infection in peripheral blood.

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* Corresponding author. Mailing address: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich Rämistrasse, 100 8091 Zürich, Switzerland. Phone: 41 44 255 3610. Fax: 41 44 255 3291. E-mail: marek.fischer{at}usz.ch

Published ahead of print on 3 July 2007.

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Journal of Virology, September 2007, p. 9693-9706, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00492-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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