Infection of B Cell Follicle-Resident Cells by Friend Retrovirus Occurs during Acute Infection and Is Maintained during Viral Persistence

B cell follicles of the spleen and lymph nodes are immune privileged sites and serve as sanctuaries for infected CD4(+) cells in HIV infection. It is assumed that CD8(+) T cell responses promote the establishment of the reservoir, as B cell follicles do not permit CD8(+) T cell entry. Here we analyzed the infected cell population in the Friend retrovirus (FV) infection and investigated whether FV can similarly infect follicular cells. For analysis of FV-infected cells, we constructed a recombinant FV encoding the bright fluorescent protein mWasabi and performed flow cytometry with cells isolated from spleens, lymph nodes and bone marrow of FV-mWasabi-infected mice. Using t-stochastic neighbor embedding for data exploration, we demonstrate how the target cell population changes during the course of infection. While FV was widely distributed in erythrocytes, myeloid cells, B cells, and CD4(+) T cells in the acute phase of infection, the bulk viral load in the late phase was carried by macrophages and follicular B and CD4(+) T cells, suggesting that FV persists in cells that are protected from CD8(+) T cell killing. Importantly, seeding into follicular cells was equally observed in CD8(+) T cell-depleted mice and in highly FV-susceptible mice that mount a very weak immune response, demonstrating that infection of follicular cells is not driven by immune pressure. Our data demonstrate that infection of cells in the B cell follicle is a characteristic of the FV infection, making this murine retrovirus an even more valuable model for development of retrovirus immunotherapy approaches.