infection. It is thought that HIV uses a "Trojan horse" mechanism to enter the brain. Normally, the blood–brain barrier (BBB) serves as a protective mechanism by preventing entry of foreign substances; disruption of the BBB by HIV contributes to the progression of infection. The virus is able to enter the brain through infected cells that pass through the BBB to replace the immune cells surrounding the blood supply in the brain. When infected, immune cells are able to better migrate into tissues compared to uninfected cells. Infected microglia add to the production of the virus. This activation of the microglia may contribute to the process of neuropathogenesis that spreads the infection to nearby cells. Other cells that can get infected include the astrocytes, which can trigger bystander cellular dysfunction and apoptosis, further compromising the blood–brain barrier. The toxicity spreads through a gap junction-dependent mechanism. Brain regions affected HIV is associated with pathological changes in mainly subcortical and fronto-striatal areas of the brain, including the basal ganglia, deep white matter, and hippocampal regions. Neuroimaging studies of HIV patients indicate that significant volume reductions are apparent in the frontal white matter, whereas subcortically, hypertrophy is apparent in the basal ganglia, especially the putamen. Moreover, the results of some studies suggest loss of brain volume in cortical and subcortical regions even in asymptomatic HIV patients and patients who were on stable treatment. A recent longitudinal study of a small representative cohort of HIV-positive patients on stable medication regiments suggests that this cortical atrophy is progressive, and is in part related to nadir CD4. Cerebral brain volume is associated with factors related to duration of the disease and CD4 nadir; patients with a longer history of chronic HIV and higher CD4 nadir loss present with greater cerebral atrophy. CD4 lymphocyte counts have also been related to greater rates of brain tissue loss. Current factors, such as plasma HIV RNA, have been found to be associated with brain volumes as well, especially with regards to basal ganglia volume and total white matter. Loss of cortical grey matter oligodendrocytes might also contribute to the symptomatology. Changes in the brain may be ongoing but asymptomatic, that is with minimal interference in functioning, making it difficult to diagnose HIV-associated neurocognitive disorders in the early stages. Diagnostic criteria Marked acquired impairment of at least two ability domains of cognitive function (e.g. memory, attention): typically, the impairment is in multiple