Ronald S. Veazey

Early Immunologic Events in Mucosal and Systemic Lymphoid Tissues after Intrarectal Inoculation with Simian Immunodeficiency Virus

The pathogenesis of human immunodeficiency virus transmission via the rectal route remains poorly understood. By use of the simian immunodeficiency virus (SIV)-rhesus macaque model and intrarectal inoculation with pathogenic SIVmac251, a significant increase was found in the percentage of CD11b(+) monocyte lineage cells expressing HLA-DR and/or B7-2 in local and peripheral immune inductive sites, but not in mucosal effector sites, as early as 7 days after inoculation and up to 50 days after inoculation. Moreover, at 21 and 50 days after inoculation, not only the gut but also the lung mucosa were depleted of CD4(+) T cells, which suggests that early loss of CD4(+) T cells may be a common feature of mucosal effector sites. These data suggest that, after intrarectal inoculation with SIV, early activation occurs within the monocyte lineage cell population at immunologic inductive sites, which is followed by a loss of CD4(+) T cells at local and distant mucosal effector sites.

Simian Immunodeficiency Virus (SIV)-Specific CTL Are Present in Large Numbers in Livers of SIV-Infected Rhesus Monkeys

The immunopathogenesis of AIDS-associated hepatitis was explored in the SIV/rhesus monkey model. The livers of SIV-infected monkeys showed a mild hepatitis, with a predominantly CD8+ T lymphocyte infiltration in the periportal fields and sinusoids. These liver-associated CD8+ T cells were comprised of a high percentage of SIV-specific CTL as defined by MHC class I/Gag peptide tetramer binding and Gag peptide epitope-specific lytic activity. There was insufficient viral replication in these livers to account for attracting this large number of functional virus-specific CTL to the liver. There was also no evidence that the predominant population of CTL were functionally end-stage cells trapped in the liver and destined to undergo apoptotic cell death in that organ. Interestingly, we noted that liver tetramer-binding cells showed an increased expression of CD62L, an adhesion molecule usually only rarely expressed on tetramer-binding cells. This observation suggests that the expression of specific adhesion molecules by CTL might facilitate the capture of these cells in the liver. These results demonstrate that functional SIV-specific CD8+ T cells are present in large numbers in the liver of chronically SIV-infected monkeys. Thus, the liver may be a trap for virus-specific cytotoxic T cells.

Differential Effects of Simian Immunodeficiency Virus Infection on Immune Inductive and Effector Sites in the Rectal Mucosa of Rhesus Macaques

The rectal mucosa, a region involved in human immunodeficiency virus/simian immunodeficiency virus (SIV) infection and transmission, contains immune inductive sites, rectal lymphoid nodules (RLN), and effector sites, the lamina propria (LP). This study was designed to evaluate cell populations involved in rectal mucosal immune function in both RLN and LP, by immunocytochemical analysis of rectal mucosa from 11 SIV-infected (2 to 21 months postinfection) and five naive rhesus macaques. In the rectum, as previously observed in other intestinal regions, CD4(+) cells were dramatically reduced in the LP of SIV-infected macaques, but high numbers of CD4(+) cells remained in RLN indicating maintenance of T cell help in inductive sites. Cells expressing the mucosal homing receptor alpha4beta7 were dramatically decreased in the RLN and LP of most SIV-infected macaques. The RLN of both naive and SIV-infected macaques contained high numbers of CD68 + MHC-II+ macrophages and cells expressing the co-stimulatory molecules B7-2 and CD40, as well as IgM + MHCII+ and IgM + CD40+ B cells, indicating maintenance of antigen presentation capacity. The LP of all three macaques SIV-infected for 2 months contained many B7-2+ cells, suggesting increased activation of antigen-presenting cells. LP of SIV-infected rectal mucosa contained increased numbers of IgM+ cells, confirming previous observations in small intestine and colon. The data suggest that antigen-presentation capacity is maintained in inductive sites of SIV-infected rectal mucosa, but immune effector functions may be altered.

Induction of Disseminated Mycobacterium avium in Simian AIDS Is Dependent upon Simian Immunodeficiency Virus Strain and Defective Granuloma Formation

Mycobacterium avium complex (MAC) is the most common disseminated bacterial disease in patients infected by the human immunodeficiency virus. Although murine models of disseminated MAC exist, they are primarily based on underlying genetic susceptibilities and cannot adequately address the complex interactions that occur between host, mycobacteria, and immunosuppressive lentivirus. To address this problem we have developed an experimental system to co-inoculate rhesus macaques with the simian immunodeficiency virus (SIV) and a clinical M. avium isolate that results in a disease virtually identical to that observed in human cases. Using this experimental system we have found that the development of disseminated MAC is dependent on viral strain. Animals co-infected with SIVmac251 and M. avium developed progressive disease, whereas control animals and animals inoculated with closely related viruses (SIVmac239 and SIVmac239MER) developed self-limiting infections. The ability of animals infected with SIVmac239 or SIVmac239MER to eliminate mycobacterial disease was independent of viral load and CD4 T-cell number but was correlated with the size and composition of microgranulomas. This work establishes a novel primate model of disseminated MAC in the context of immunosuppressive lentiviral infection and advances our understanding of why human immunodeficiency virus-infected patients are remarkably sensitive to the development of mycobacterial disease.