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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 6; pp. 2307 - 2312
• Main Authors: Fletcher, Courtney V., Staskus, Kathryn, Wietgrefe, Stephen W., Rothenberger, Meghan, Reilly, Cavan, Chipman, Jeffrey G., Beilman, Greg J., Khoruts, Alexander, Thorkelson, Ann, Schmidt, Thomas E., Anderson, Jodi, Perkey, Katherine, Stevenson, Mario, Perelson, Alan S., Douek, Daniel C., Haase, Ashley T., Schacker, Timothy W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.02.2014; National Acad Sciences
• Subjects: Adolescent; Adult; Anti-HIV Agents - pharmacokinetics; Antiretroviral agents; Antiretroviral drugs; Antivirals; Biological Sciences; Blood; Cells; Child; Child, Preschool; Correlation analysis; drugs; Female; Half-Life; HIV; HIV 1; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Ileum; Lymph nodes; Lymphoid tissue; Lymphoid Tissue - metabolism; Male; Ribonucleic acid; RNA; T lymphocytes; therapeutics; Tissues; virion; Virions; Virus Replication; Viruses; Young Adult; pharmacokinetics; drug levels; FDC network
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1318249111

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.