Title

Pathogenesis of Mycobacterium avium complex in the SIV/macaque model of AIDS

Date of Completion

January 2004

Keywords

Biology, Microbiology|Health Sciences, Pathology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Mycobacterium avium complex (MAC) is the most common disseminated bacterial disease in patients infected with the human immunodeficiency virus (HIV) and in Rhesus macaques (Macaca mulatta) inoculated with simian immunodeficiency virus (SIV), and is associated with profound wasting [1–5]. This work examines factors involved in the development of disseminated MAC in the acquired immunodeficiency syndrome (AIDS) as well as the pathogenesis of wasting associated with this disease. ^ Previous studies have demonstrated an increased susceptibility of macaques infected with wild-type SIVmac251 to disseminated MAC, suggesting a role of viral determinants in the progression of disseminated MAC [5–6]. Co-inoculation studies using a recombinant clone, derived from the pathogenic clone SIVmac239 and envelope from an animal with spontaneous MAC, and M. avium resulted in progressive disseminated MAC in animals inoculated with the recombinant virus. Immunohistochemistry and intracellular cytokine staining revealed increased expression of somatostatin, decreased expression of CXCR3, decreased expression of IFN-γ and TNF-α and increased expression of IL-4 in animals infected with the recombinant virus compared to immunologically normal or SIVmac239 infected animals. ^ We then examined whether disseminated M. avium is associated with disruption of the somatotropic axis in AIDS using rhesus macaques co-inoculated with SIV and M. avium. Both immunologically normal and SIV-infected macaques inoculated with mycobacteria had changes in body composition, increased growth hormone to insulin like growth factor-1 ratios, and increased serum somatostatin levels. Infection with M. avium also increased serum levels of soluble TNF receptor II (sTNFR-II), a finding that has been associated with peripheral resistance to growth hormone. ^ Next, we investigated the potential role of monocyte chemotactic protein-1 (MCP-1) in the pathogenesis of disseminated MAC. Following M. avium challenge marked elevations in serum MCP-1 levels in SIV-infected animals were detected, a finding that was duplicated in co-inoculated bronchial-alveolar macrophages. MCP-1 levels were significantly higher in SIV-infected animals than non-SIV-infected controls. Similarly morphometric analysis revealed increased MCP-1 expression in hepatic microgranulomas from SIV-infected animals. ^ Based on these findings we conclude that viral determinants within envelope are associated with aberrant granuloma formation that may have multiple effects including development of disseminated disease and disruption of the somatotropic axis. ^