F-104 Non-human primate models for immunological studies of HIV eradication

Abstract

The mechanisms by which pathogenic HIV and SIV infections cause immune deficiency involve factors related to both the virus and the host immune system. Over the past few years, emphasis has been placed on the role of the chronic immune activation that is apparent during the natural history of the infection and remains as “residual” immune activation in HIV-infected individuals treated with antiretroviral therapy (ART). Several key concepts and hypotheses regarding the pathogenic role of immune activation have been generated in studies involving SIV-infected non-human primates (NHP) such as the sooty mangabeys, in which a natural, non-pathogenic infection is characterized by robust virus replication but low levels of immune activation, and Asian macaques, in which experimental infection with SIV results a progressive infection characterized by CD4+ T cell depletion, high immune activation, and simian AIDS. More recently, the SIV/NHP model has been developed and validated for studies of the HIV-associated “residual” disease under fully suppressive ART, which is characterized by persistent immune dysfunction and presence of a reservoir of latently infected cells which makes it impossible to eradicate the virus. In this presentation, I will briefly review the opportunities presented by NHP models to conduct studies that will improve our understanding of AIDS virology, immunology, and pathogenesis, with specific focus the goal of reducing the residual disease that persists in ART-treated HIV-infected individuals despite suppression of virus replication. I will discuss (1) the key pathogenic aspects of the residual immune activation observed in ART-treated HIV-infected individuals and SIV-infected macaques, (2) the role of type I interferons as both antiviral and pro-inflammatory factors, and (3) the key role played by the pattern of infected CD4+ T cell subsets as a determinant of both residual immune activation and persistent virus reservoir in the setting of ART-mediated suppression of virus replication.