Abstract: A simple concept of directly operative viral neurotropism appears inadequate to explain a full spectrum of phenomena associated with the creation of a viral reservoir as occurs with central nervous system HIV-1 infection. Indeed, a full series of directly and indirectly operative steps would involve peripheral blood monocytes, CNS perivascular cells, vascular endothelia, and resident microglia. In an overall context of a highly integrated CNS and immune system responsiveness, viral encephalitis might actually constitute shifting levels of involvement ranging from dysregulation of cytokine production to autoimmune reactivity to potentially evolving pathways of secondary neuronal injury as by reactive oxygen radicals and phagocytic activity. HIV-1 infection of the CNS, in addition, would appear to add attributes of viral genomic integration and of possible emergence of resistance to anti-retroviral drug therapy to various other mechanisms arising from a central role played by CNS macrophages and microglia beyond a strict concept of viral neurotropism. It appears significant that long-term nonprogressors are selectively predetermined at an early stage in the development of the HIV-1 infected state.