Characterization of the Follicular Dendritic Cell Reservoir of Human Immunodeficiency Virus Type 1

Abstract

Throughout the natural course of human immunodeficiency virus (HIV) infection, follicular dendritic cells (FDCs) trap and retain large quantities of particle-associated HIV RNA in the follicles of secondary lymphoid tissue. We have previously found that murine FDCs in vivo could maintain trapped virus particles in an infectious state for at least 9 months. Here we sought to determine whether human FDCs serve as an HIV reservoir, based on the criteria that virus therein must be replication competent, genetically diverse, and archival in nature. We tested our hypothesis using postmortem cells and tissues obtained from three HIVinfected subjects and antemortem blood samples obtained from one of these subjects. Replication competence was determined using coculture, while genetic diversity and the archival nature of virus were established using phylogenetic and population genetics methods. We found that FDC-trapped virus was replication competent and demonstrated greater genetic diversity than that of virus found in most other tissues and cells. Antiretrovirus-resistant variants that were not present elsewhere were also detected on FDCs. Furthermore, genetic similarity was observed between FDC-trapped HIV and viral species recovered from peripheral blood mononuclear cells obtained 21 and 22 months antemortem, but was not present in samples obtained 4 and 18 months prior to the patient's death, indicating that FDCs can archive HIV. These data indicate that FDCs represent a significant reservoir of infectious and diverse HIV, thereby providing a mechanism for viral persistence for months to years.

Un virus tapi dans l’ombre : les bases moléculaires de la latence du VIH-1

“…Ce concept de réservoir a pris toute son importance peu de temps après l'introduction de la multithérapie active en 1996, quand plusieurs auteurs ont démontré la persistance du virus, qui s'était intégré de manière latente dans des cellules T CD4 + , chez des patients traités par au moins trois molécules antirétrovirales 2 (ce que l'on désigne par le terme HAART pour highly active anti retroviral therapy), ruinant alors les espoirs fondés sur l'éradication totale du virus [7][8][9]. Depuis lors, il a été montré que d'autres types cellulaires que les lymphocytes T CD4 + pouvaient servir de réservoir du VIH-1 [32] : c'est le cas des cellules de la lignée monocyte-macrophage [10] dont les cellules microgliales qui sont les macrophages résidants du système nerveux central [11], et des cellules dendritiques [12].…”

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

“…This more prolonged third decay phase has been estimated to have a half-life of around six months [43,65], although a half-life of 30 months during HAART was estimated in another study [66], and mathematical modelling studies have shown HIV:FDC interactions to persist for years, despite effective HAART [67]. Through phylogenetic analysis of the HIV that interacts with FDCs isolated from 2 out of 4 patients, the virus present was similar to the virus isolated 22 months earlier, which suggests long-term FDC sequestration of replication-competent HIV [68]. However, other studies have shown DC-SIGN being unable to protect against virion degradation, since loss of HIV infectivity was reported over a course of hours [69].…”

HIV Type-1 Latency: Targeted Induction of Proviral Reservoirs

“…These include cells in the central nervous system (CNS) [12] and male urogenital tract [13], as well as macrophages [14] and follicular dendritic cells [15]. There is also evidence that low levels of ongoing viral replication might continue even in patients receiving HAART who are clinically aviraemic and for whom plasma HIV-1 RNA levels are below the limit of detection of standard assays.…”

“…Additional reservoirs have been identified, including those in macrophages and follicular dendritic cells [14,15]. Strategies sufficient to activate latent virus in CD4 + T-cells might not be applicable to other cellular reservoirs, or pharmacological issues might limit their efficacy.…”