The mechanisms by which HIV-1 infection promotes neuropathogenesis is based on viral entry into the central nervous system (CNS) early during the course of infection by breaching of the blood-brain barrier (BBB) followed by a series of events that center around the neurotoxic activity of a number of HIV-1 proteins including gp120, Tat, Vpr, and likely others, along with alterations in CNS homeostasis that involve the metabolic integrity of the blood-brain barrier and metabolism of astrocytes, perivascular macrophages, and resident microglial cells. Here, ITIH4 is linked to infection.