The role of bone marrow in SIV pathogenesis using the Rhesus macaque model

Abstract

CD4+ memory T cells are depleted in mucosal tissues post human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection without restoration to pre-infection levels during progressive course of disease. Bone marrow (BM) as a hematopoietic organ has been investigated for hematologic and morphologic changes during HIV infection. However, BM as a primary lymphoid tissue during HIV infection has been poorly characterized. We proposed BM was also a site of CD4+ T cell depletion driven by increased apoptosis during progressive HIV disease. We chose to investigate bone marrow changes using the premier non-human primate Rhesus macaque SIV model for the study HIV infection. We observed hematologic abnormalities of anemia, thrombocytopenia, neutropenia and eosinophilia during SIV infection mimicked HIV infection as did morphologic increased BM cellularity, loss of iron marrow storage, and increased marrow fibrosis as infection advanced to AIDS. The increased BM cellularity was characterized by increased erythroid, myeloid including dendritic cells, and lymphoid lineages in the later stages of infection. In fact, numbers of BM CD3+ T lymphocytes increased in absolute numbers and proliferation percentage during progressive SIV infection mainly composed of CD8+ T cells and fewer CD4+ T cells. Naïve and memory CD8+ T cells and CD4+ T cells were maintained in BM during SIV infection. Low numbers of SIV infected BM cells were observed including CD3+ T cells, macrophages, and other hematopoietic cells with detection of both viral RNA and DNA by polymerase chain reaction. However, less than 0.2% of CD3+ BM T cells were apoptotic determined by activated caspase 3 though overall BM cells tended to have increased rates of apoptosis in later stages of SIV. Our data revealed BM T cells were not depleted but maintained to increased during SIV disease without an increase in apoptosis. Future studies into mechanisms of bone marrow lymphocyte maintenance may reveal homeostatic mechanisms potentially disrupted in mucosal tissues during HIV and SIV infection.