Summary: Human immunodeficiency virus-1 (HIV-1) neuroinvasion occurs early (during period of initial viremia), leading to infection of a limited amount of susceptible cells with low CD4 expression. Protective cellular and humoral immunity eliminate and suppress viral replication relatively quickly due to peripheral immune responses and the low level of initial central nervous system (CNS) infection. Upregulation of the brain protective mechanisms against lymphocyte entry and survival (related to immune privilege) helps reduce viral load in the brain. The local immune compartment dictates local viral evolution as well as selection of cytotoxic lymphocytes and immunoglobulin G specificity. Such status can be sustained until peripheral immune anti-viral responses fail. Activation of microglia and astrocytes, due to local or peripheral triggers, increases chemokine production, enhances traffic of infected cells into the CNS, upregulates viral replication in resident brain macrophages, and significantly augments the spread of viral species. The combination of these factors leads to the development of HIV-1 encephalitis-associated neurocognitive decline and patient death. Understanding the immune-privileged state created by virus, the brain microenvironment, and the ability to enhance anti-viral immunity offer new therapeutic strategies for treatment of HIV-1 CNS infection.