Persistence of Infectious HIV on Follicular Dendritic Cells

Abstract

Follicular dendritic cells (FDCs) trap Ags and retain them in their native state for many months. Shortly after infection, HIV particles are trapped on FDCs and can be observed until the follicular network is destroyed. We sought to determine whether FDCs could maintain trapped virus in an infectious state for long periods of time. Because virus replication would replenish the HIV reservoir and thus falsely prolong recovery of infectious virus, we used a nonpermissive murine model to examine maintenance of HIV infectivity in vivo. We also examined human FDCs in vitro to determine whether they could maintain HIV infectivity. FDC-trapped virus remained infectious in vivo at all time points examined over a 9-mo period. Remarkably, as few as 100 FDCs were sufficient to transmit infection throughout the 9-mo period. Human FDCs maintained HIV infectivity for at least 25 days in vitro, whereas virus without FDCs lost infectivity after only a few days. These data indicate that HIV retained on FDCs can be long lived even in the absence of viral replication and suggest that FDCs stabilize and protect HIV, thus providing a long-term reservoir of infectious virus. These trapped stores of HIV may be replenished with replicating virus that persists even under highly active antiretroviral therapy and would likely be capable of causing infection on cessation of drug therapy.

Follicular Dendritic Cell-Mediated Up-Regulation of CXCR4 Expression on CD4 T Cells and HIV Pathogenesis

“…The data reported here do not demonstrate that virus tropism shifts occur in GCs, but they do provide evidence that relatively small differences in HIV coreceptor expression can influence viral infection in primary cells and suggest that this may contribute to selection of X4 variants over time. Because HIV is trapped on the FDC network early after infection and remains infectious for long periods of time (15,42), an understanding of the contributions of FDCs that lead to increased CXCR4 expression and heightened susceptibility to infection by X4 isolates of virus may be important to our ability to devise intervention strategies that effectively target this important HIV reservoir and microenvironment.…”

“…Human FDCs were isolated from tonsillar tissue as described (15). FDCenriched preparations prepared by this procedure were examined by flow cytometry and typically contain 75-90% FDCs with residual cells consisting of T and B lymphocytes.…”

“…Importantly, HIV immune complexes on FDCs are highly infectious even in the presence of high levels of neutralizing Ab (14). Our recent studies have indicated that FDCs maintain HIV infectivity in vivo for many months in the complete absence of viral infection and/or replication (15). Additionally, FDCs appear to increase the production of virus in CD4 lymphocytes (16).…”

Factor I-Mediated Processing of Complement Fragments on HIV Immune Complexes Targets HIV to CR2-Expressing B Cells and Facilitates B Cell-Mediated Transmission of Opsonized HIV to T Cells

“…HIV bound extracellularly to the follicular dendritic cells (FDC) 3 in germinal centers of lymph nodes represent by far the largest viral reservoir in HIV-infected individuals (5,6). The binding of this infectious pool of HIV in the germinal centers depends mainly on interactions of complement receptor type (CR) 2 expressed on FDC (or B cells) with C3d fragments on the viral surface (4,7).…”

Mechanism(s) promoting HIV‐1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co‐cultures

“…DC are thought to transport HIV after infection via the mucosal route to the LT, while FDC represent the major reservoir of infectious virus which harbors more than 90% of total viral load [5]. Virions in the LT are extracellularly trapped on FDC [4,6] and are thought to remain infectious in vivo for months [7,8]. The crucial role of complement fragments on HIV in the LT is highlighted by ex vivo investigations demonstrating that extracellularly bound virus can be detached from germinal centers by blocking CR2 [4].…”