The Remarkable Stability of the Latent Reservoir for HIV-1 in Resting Memory CD4+ T Cells.

The modern era of antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infectionbegan in the mid-1990s with the introduction of 2 new classes of antiretroviral drugs, the protease inhibitors (PIs) and the nonnucleoside reverse-transcriptase inhibitors. Combinations consisting of 1 of these drugs along with 2 nucleoside analogue reverse-transcriptase inhibitors rapidly reduced plasma HIV-1 RNA levels to below the limit of detection of clinical assays [1, 2], leading to predictions that continued treatment for 2–3 years could cure the infection [3]. Although it did not prove curative, combination ART became the mainstay of HIV treatment, allowing durable control of viral replication and reversal or prevention of immunodeficiency [4]. A major reason why ART did not prove curative is the persistence of a latent form of the virus in a small population of resting memory CD4 T cells [5, 6]. In these cells, the viral genome is stably integrated into host cell DNA, but viral genes are not expressed at significant levels in part because of the absence of key host transcription factors that are recruited to the HIV prompter only after T-cell activation. The latent reservoir for HIV-1 was originally demonstrated using an assay in which resting cells from patients are activated to reverse latency [6]. Viruses released from individual latently infected cells are expanded in culture. This viral outgrowth assay (VOA) was used to demonstrate the remarkable stability of the latent reservoir [7–9]. The half-life of this pool of cells was shown to be 44 months. At this rate of decay, >70 years would be required for a pool of just 10 cells to decay completely [8, 9]. Initial studies of the decay of the latent reservoir were completed in 2003 [9]. Since that time, remarkable advances in ART have taken place, including the introduction of new classes of antiretroviral drugs, such as integrase inhibitors, and the development of simplified regimens in which multiple antiretroviral drugs are combined into a single pill that can be taken once daily [4]. In this context, an extensive and careful study of latent reservoir decay by Crooks et al [10], reported in this issue of the Journal, is of particular interest. The authors have reexamined the stability of the latent reservoir using longitudinal VOAs in a series of 37 patients, some of whom have been receiving treatment for most of the modern ART era. Despite the long duration of treatment in some patients and the changes in ART, the authors found that the decay rate of the latent reservoir is almost exactly the same as that reported in 2003. The half-life measured by Crooks et al is 43 months [10]. The fact that the decay rate measured in the present study is no different from that measured more than a decade ago confirms that the stability of the latent reservoir is not determined by treatment regimens. As long as the regimen produces a complete or near-complete arrest of new infection events, the decay of the reservoir is determined by the biology of the resting memory T cells that harbor persistent HIV-1. Pharmacodynamic studies indicate that the nonnucleoside reversetranscriptase inhibitors and PIs possess a remarkable potential to inhibit viral replication, a property that reflects an unexpected degree of cooperativity in their dose-response curves [11, 12]. At clinical concentrations, the best PIs can actually produce a 10 billion–fold inhibition of a single round of HIV-1 replication. Thus, even the early combination therapy regimens may have produced complete or near-complete inhibition of new infection events in drug-adherent patients. Subsequent improvements in ART have largely affected tolerability and convenience. Viewed in this light, the finding that the reservoir decay is constant is not surprising. The cures now being routinely achieved with direct-acting antiviral drugs Received and accepted 6 April 2015; electronically published 15 April 2015. Correspondence: Janet M. Siliciano, PhD, Johns Hopkins School of Medicine, 733 N Broadway, Miller Research Bldg 871, Baltimore, MD 21205 ([email protected]). The Journal of Infectious Diseases 2015;212:1345–7 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiv219