Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Courtney V. Fletcher, Kathryn Staskus, Stephen W. Wietgrefe, Meghan Rothenberger, Cavan Reilly, Jeffrey G. Chipman, Greg J. Beilman, Alexander Khoruts, Ann Thorkelson, Thomas E. Schmidt, Jodi Anderson, Katherine Perkey, Mario Stevenson, Alan S. Perelson, Daniel C. Douek, Ashley T. Haase, Timothy W. Schacker

Research output: Contribution to journalArticle

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Abstract

Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.

Original languageEnglish (US)
Pages (from-to)2307-2312
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number6
DOIs
StatePublished - Feb 11 2014

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Keywords

  • Drug levels
  • FDC network
  • Pharmacokinetics

ASJC Scopus subject areas

  • General

Cite this

Fletcher, C. V., Staskus, K., Wietgrefe, S. W., Rothenberger, M., Reilly, C., Chipman, J. G., Beilman, G. J., Khoruts, A., Thorkelson, A., Schmidt, T. E., Anderson, J., Perkey, K., Stevenson, M., Perelson, A. S., Douek, D. C., Haase, A. T., & Schacker, T. W. (2014). Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proceedings of the National Academy of Sciences of the United States of America, 111(6), 2307-2312. https://doi.org/10.1073/pnas.1318249111