PATHOGENIC INSIGHTS FROM STUDIES OF LYMPHOID-TISSUE FROM HIV-INFECTEDINDIVIDUALS

Studies of lymphoid tissue from HIV-infected individuals have provided critical insights into the pathogenesis of HIV disease. Systemic diss emination of virus via the lymphatic system occurs at a very early sta ge after infection. Explosive viral replication within lymphoid tissue ensues, before the development of cell-mediated and humoral immune re sponses. By the time potent immune responses downregulate viral expres sion, an immense viral reservoir within lymphoid tissue has already be en established. During the stage of dichotomy in viral load between ly mph node and peripheral blood, the viral reservoir is maintained by th e ability of the follicular dendritic cells (FDC) network to efficient ly trap extracellular virions, as well as by immunologic and microenvi ronmental factors favoring infection of susceptible cells and sequestr ation of cells already infected. Degeneration of the FDC network and w holesale disruption of lymphoid architecture herald late-stage disease . The dysfunctional lymphoid tissue contributes directly to immunodefi ciency and to sharp increases in viral burden and replication as mecha nical and immune controls are lost. Studies in HIV-infected long-term nonprogressors indicate that these individuals are able to maintain ex cellent cell-mediated and humoral immune responses against HIV. These immune responses are responsible, at least in part, for the maintenanc e of intact lymphoid tissue architecture and the low levels of viral b urden and replication detected in these individuals. Studies of the ef fect of antiretroviral therapy on HIV infection in lymphoid tissue sho w that decreases in plasma viremia are associated with and most likely are caused by decreases in viral replication within lymphoid tissue. Further understanding of the pathogenic mechanisms within lymphoid tis sue will have important implications for early intervention aimed at i nducing a long-term nonprogressor state (i.e., preventing disruption o f lymphoid tissue integrity), and later intervention aimed at arrestin g or even reversing damage to the lymphoid system.