Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
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Edited* by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved December 18, 2013 (received for review October 8, 2013)
Significance
We show that HIV continues to replicate in the lymphatic tissues of some individuals taking antiretroviral regimens considered fully suppressive, based on undetectable viral loads in peripheral blood, and that one mechanism for persistent replication in lymphatic tissues is the lower concentrations of the antiretroviral drugs in those tissues compared with peripheral blood. These findings are significant because they provide a rationale and framework for testing the efficacy of new agents and combinations of drugs that will fully suppress replication in lymphatic tissues. More suppressive regimens could improve immune reconstitution, as well as provide the effective regimens needed for functional cure and eradication of infection.
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.
Footnotes
↵1Deceased March 26, 2013.
- ↵2To whom correspondence should be addressed. E-mail: schacker{at}umn.edu.
Author contributions: C.V.F., C.R., M.S., D.C.D., A.T.H., and T.W.S. designed research; C.V.F., K.S., S.W.W., M.R., J.G.C., G.J.B., A.K., A.T., T.E.S., J.A., K.P., M.S., D.C.D., A.T.H., and T.W.S. performed research; C.V.F., K.S., S.W.W., D.C.D., and A.T.H. contributed new reagents/analytic tools; C.V.F., S.W.W., C.R., A.S.P., A.T.H., and T.W.S. analyzed data; and C.V.F., C.R., J.G.C., G.J.B., A.K., A.S.P., D.C.D., A.T.H., and T.W.S. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318249111/-/DCSupplemental.
Freely available online through the PNAS open access option.
HIV replication due to low drug levels
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