Contribution of Follicular Dendritic Cells to the 3rd Phase Decay
After initiation of highly active antiretroviral therapy, plasma HIV RNA declines to levels undetectable by clinical assays. Using a single copy assay, it has been shown that HIV viremia persists at very low levels in most patients. In fact, plasma viremia decline follows 4 phases. A new study raises the possibility that the third phase decay could originate from virions trapped at the surface of follicular dendritic cells.
The study of Zhang and Perelson published in the Journal of Virology (1) uses mathematical modeling and focuses on the third phase decay of plasma viremia on HAART.
It is already recognized that the first phase decay, with a short half-life of 1-2 days, corresponds to the loss of activated infected CD4+ T cells. The second phase decay, with a half-life of 2-4 weeks has been attributed of long-lived infected cells such as resting CD4+ T cells and macrophages. The cellular compartments responsible for decay phases 3 and 4 have not been identified.
Phase 3 has a half-life of about 39 weeks, and phase 4 is quite flat (figure).
Using a mathematical model and applying it to published data from patients, the authors show that follicular dendritic cells (FDC) may serve as compartment 3.
FDC can bind reversibly virions on their surface and slowly release them back to the circulation. On HAART, abundant virions remain trapped for a prolonged period of time serving as an HIV reservoir that hinders HIV eradication.
The trapping importance varies according to variations in FDC surface receptor density and in the number of FDC binding sites per virion. Due to the significant variance of plasma viremia levels between patients, the time range of the third phase is expected to vary strongly between individual patients.
To prove the role of FDC in the third phase decay and the fact that they can remain a source for manay years, the authors suggest some in vivo experiments in non-human primate models by the use of drugs able to block formation of the bond between terminal C3 fragments and CR2 (on FDC) by binding to one or the other protein.
The authors also discuss which compartment is the main contributor to the fourth phase of decay. One possible source is latently-infected CD4+ T cells.
Zhang J, Perelson AS. Contribution of follicular dendritic cells to persistent HIV viremia. J Virol 2013; published ahead of print on May 8
Key words: HIV cure, HIV eradication, HIV persistence, HIV reservoirs, HIV viremia