Date Published: December 1, 2015
Publisher: Public Library of Science
Author(s): Balthasar A. Heesters, Madelene Lindqvist, Parsia A. Vagefi, Eileen P. Scully, Frank A. Schildberg, Marcus Altfeld, Bruce D. Walker, Daniel E. Kaufmann, Michael C. Carroll, Michael Emerman.
Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans.
Anti-retroviral therapy (ART) is capable of suppressing plasma viral load to undetectable levels and in many cases results in restoration of circulating CD4 T cell counts to near normal values. Despite the success of ART, when treatment is halted the virus rebounds suggesting the presence of a long lived reservoir . Despite low viremia of circulating blood, the CD4 T cells in the LNs appear to undergo continuing infection suggesting a local source of virus. For example, characterization of lymph node (LN) biopsies of HIV infected patients undergoing ART by in situ hybridization (ISH) and immunohistochemistry (IHC) identify infected CD4 T cells [2–4]; and recent studies identify T follicular helper (TFH) cells as a major target of HIV [5,6]. Further support for LNs as a major site for continued infection of CD4 T cells was reported recently in non-human primates. Simian Immunodeficiency Virus (SIV) rapidly seeds the reservoir in LNs even before detectable systemic viremia . Together, these observations suggest that cells in lymphoid organs, which are not reflected in systemic measures of viral load, are among the first to become infected and constitute the initial reservoir.
Despite the success of ART in reducing HIV viral loads and partial restoration of circulating CD4 T cells, cessation of the drugs results in acute viral rebound, suggesting the importance of a viral reservoir [40,41]. While it is generally held that latently infected CD4 T cells are a major reservoir for HIV, there is growing evidence that LNs are partly refractory to ART and include one of the earliest seeded reservoirs [7,42]. Analysis of LNs in HIV infected subjects using in situ RNA hybridization and immunohistochemistry specific for HIV have identified a dendritic pattern of viral deposition that co-localize with FDC in the B cell follicles . These observations along with others showing that FDC extracts are positive for infectious HIV , raised the question whether FDC harbor infectious HIV virus and if so how is the virus retained? To address these questions, FDCs were isolated from LNs that were surgically removed from seven infected subjects undergoing long term ART and three non-infected healthy donors. All subjects had low to undetectable plasma viral loads.