Title

Immunopathologic changes in the intestine of SIV-infected rhesus macaques (Macaca mulatta)

Date of Completion

January 2006

Keywords

Health Sciences, Pathology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

In patients infected with human immunodeficiency virus (HIV), wasting, diarrhea, and intestinal malabsorption are frequent manifestations of the disease that often occur in the absence of opportunistic infections. Similar observations have been made in nonhuman primates infected with simian immunodeficiency viruses (SIVs). To examine the pathogenesis of HIV infection on the gastrointestinal (GI) tract, we used the SIV/macaque model of AIDS. In particular we focused on the acutely enteropathogenic molecular clone SIVmac239/YEnef, derived from SIVmac239. This virus causes marked, multifocal inflammation associated with blunting and fusion of intestinal villi between day 7 and 12 postinoculation (pi). The intestinal lesions are characterized by increased numbers of CD3+ T lymphocytes, macrophages, and CD20+ B lymphocytes admixed with variable numbers of neutrophils. The increase in T cells corresponds with increases in IL-2 expression in CD3+ lymphocytes in the lamina propria. In the sites of inflammation many Ki-67+ proliferating cells are present. Some, but not all are CD3+ indicating proliferation of T cells with other cell types. ^ Although lymphocyte proliferation is a significant component of the lesions with maximal Ki-67+ cells between day 7 and 14 pi, SIV-positive cells are present in the intestine prior to evidence of lymphocyte proliferation. Coincident with the presence of SIV-positive cells in the lamina propria of the small intestine day 3-7 pi, increased numbers of α4β7+ cells are present suggesting lymphoid recruitment is also important in lesion development. ^ To address the role of lymphocyte recruitment an antibody blocking experiment was performed using a monoclonal antibody to the intestinal lymphocyte homing receptor α4β7. On the 9th day pi the animals were euthanized. Three of the animals that received anti-α4β7 did not develop diarrhea, but did develop a skin rash and peripheral lymph node enlargement consistent with systemic infection with SIV. In contrast two animals that received irrelevant antibodies developed diarrhea. Histologic evaluation of intestine reveals that animals receiving the antibody to α4β7 had mild or no lesions compared to those receiving the irrelevant antibody. Preliminary data support the hypothesis that intestinal lymphocyte homing is important in the development of the lesions and that it occurs prior to lymphocyte proliferation. ^

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