Human immune-deficiency virus (HIV) is a negative-stranded RNA virus that infects human CD4+ T cells leading to replication and cell death. Although infection is incurable, anti-retroviral treatment (ART) can control infection and partially restore the host's CD4+ T cells Despite this success, the virus persists at low levels within lymph nodes suggesting a host reservoir located in the follicular region. More specifically, viral RNA is identified not-only witin CD4 T cells but in follicles and strikingly co-localizes with follicular dendritic cells (FDC). How virus is retained for extensive periods in humans by FDC is not known. FDC are stromal derived and they are required for formation and maintenance of the B cell follicles and for recruitment of CD4+ T follicular helper cells (TFH), the primary target cell of HIV. Recently, we reported that FDC take-up immune complexes via the CD21 receptor and periodically cycle the complexes to the cell surface. Our central hypothesis is that HIV is retained by a similar pathway as immune complexes and that the infectious virus periodically cycles to the FDC surface where it can infect TFH. We will test this hypothesis in the following three aims:
AIM 1. Test the hypothesis that FDC (human and non-human primate) endocytose complement-opsonized lentivirus via CD21 and periodically cycle viral complex to the surface.
AIM 2. Test hypothesis that FDC isolated from infected individuals transmit infectious virus to CD4+ T cells in vitro and infection can be blocked with a decoy human CD21 receptor.
AIM 3. Test efficacy of soluble human CD21 receptor in blockade of SIV retention by FDC and naive B cells in non-human primates. Milestones: The focus for years 1 & 2 (R21 period) is on Aims 1 & 2. The first major milestone is to identify retention of HIV virus by FDC isolated from humans infected with the virus. The second major milestone is the finding that treatment of HIV-infected FDC with a soluble CD21-Ig fusion protein blocks transmission of the virus to non-infected human CD4 T cells in vitro. The third major milestone is that finding that FDC isolated from SIV -infected non-human primates also retain virus and that treatment with sCD21-Ig blocks its transmission to monkey T cells.
Aim 3 will be initiated as the R33 Section of the grant if approved by NIAID for years 3-5. The fourth major milestone is demonstration that blockade of C3d-ligand binding to CD21 receptor on FDC and B cells disrupts retention of SIV by FDC in vivo.
Human immune deficiency virus (HIV) is a life threatening viral disease of the immune system for which there is no cure. While drug treatment can reduce viral burden and increase survival of CD4 T cells, the virus persists in the host through a reservoir. We propose follicular dendritic cells within lymph node follicles retain infectious viru where it can infect CD4 T cells as they traffic into the follicles. We will use a novel therapeutic approach to displace or strip the virus from the FDC to reduce infection in human FDC in vitro and in non- human primates infected with a simian immune deficiency virus.
