Viral and host determinants of HIV-1-mediated CD4+ T-cell infection and depletion in human lymphoid tissue: The role of viral coreceptor preference and CD4+ T-cell phenotype (Immune deficiency).

다국어 초록 (Multilingual Abstract)

The central feature of human immunodeficiency virus type 1 (HIV-1) disease is the depletion of CD4<super>+</super> T-cells. The course of disease in HIV-1-infected individuals is determined by incompletely understood interactions between the virus and the host. The primary goal of this study was to examine how cellular entry, as determined by viral coreceptor preference, sets the stage for HIV-1-mediated depletion of CD4<super>+</super> T-cells. To accomplish this, we utilized a lymphoid histoculture system that recapitulated key aspects of HIV-1 infection <italic>in vivo</italic>. We inoculated human tonsil or spleen histocultures with a panel of paired HIV-1 strains that were isogenic except for envelope determinants that controlled coreceptor preference and measured the depletion of CD4<super>+</super> T-lymphocytes. We found that CXCR4-dependent HIV-1 strains depleted CD4<super>+</super> T-cells aggressively while CCR5-dependent strains depleted these cells only mildly. Furthermore, we determined that the ability to use additional coreceptors other than CCR5 and CXCR4 did not contribute significantly to increased HIV-1 pathogenicity in lymphoid tissue cultured <italic>ex vivo</italic>. Therefore, CCR5 and CXCR4 appear to be the dominant coreceptors influencing HIV-1-specific killing of T-cells in these tissues. A secondary goal of this study was to determine how host factors such as cellular activation, maturation, and proliferation impact HIV-1 replication and depletion of CD4<super>+</super> lymphocytes within human lymphoid tissues. Despite considerable <italic>in vitro</italic> evidence that these cellular attributes regulate HIV-1 replication, the endogenous microenvironment within lymphoid histocultures permitted <italic>de novo</italic> HIV-1 replication and depletion in essentially all CD4<super>+</super> T-cells regardless of phenotypic classification or proliferative status. Therefore, lymphoid histocultures support the infection and depletion of virtually all recognized T-cell subsets, including resting, naïve CD4<super>+</super> T-cells. Collectively, these studies exploited a human lymphoid histoculture model to identify and characterize major HIV-1- and host-specific factors that likely contribute significantly to the widespread collapse of the CD4<super> +</super> T-cell repertoire that characterizes the acquired immunodeficiency syndrome.