This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Human Immunodeficiency Virus (HIV) infection is associated with a progressive depletion of CD4+ T-cells whose extent predicts development of AIDS. Recently, it was shown that pathogenic HIV and simian immunodeficiency virus (SIV) infections of humans and macaques, respectively, are associated with an early, severe and largely irreversible loss of memory CD4+ T-cells in mucosal tissues 1-6. As such, a model has been proposed whereby this loss of mucosal CD4+ T-cells is a key determinant of progression to AIDS 7-10. Important insights into the pathogenesis of HIV infection have been provided by studies of non-pathogenic SIV infection of natural hosts, such as the sooty mangabeys. In marked contrast to pathogenic lentiviral infections, natural SIV infection of mangabeys is not associated with an AIDS-like disease despite many years of infection with a highly replicating virus. The absence of disease in mangabeys has been attributed to the preservation of peripheral CD4+ T-cell homeostasis. Here we show that, in fact, both chronic 'natural' and acute 'experimental' SIV infections of mangabeys are characterized by a severe depletion of memory CD4+ T-cells from the intestinal and respiratory mucosa. However, in contrast to pathogenic HIV/SIV infections, the depletion of MALT CD4+ T-cells in mangabeys occurs in the context of low levels of immune activation and can be reverted by suppressing virus replication. In all, these results indicate that a profound depletion of MALT-associated CD4+ T cells is not sufficient per se to induce disease progression in a natural host, thus emphasizing the role of other immunological abnormalities (e.g., chronic immune activation and dysfunction of non-CD4+ cells) in the pathogenesis of AIDS. These data provide a rationale for exploring new, immune-based approaches, in addition to standard antiretroviral therapy, in the clinical management of HIV-infected patients.
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