The neuropathology of adult HIV infection

Since the onset of the acquired immune deficiency syndrome (AIDS) epidemic fifteen years ago, much has been learned about the effects of the human imm unodeficiency virus (HIV) in the nervous system. This review summarizes the pathology findings in the central nervous system (CNS). There is now abund ant evidence that HIV can infect the CNS directly, leading to a characteris tic HIV encephalitis (HIVE) which occurs in 10-50 p. 100 of AIDS autopsy se ries. Multinucleated giant cells are the pathognomonic feature of HIVE and are found predominantly in the central white matter and deep grey matter, E vidence of productive HIV infection in the CNS is confined to cells of the microglial/macrophage lineage, from which the giant cells are almost certai nly derived. These cells are known to express both CD4 and beta-chemokine r eceptors, which act in conjunction to permit HIV entry. Restricted infectio n of astrocytes has also been identified by a variety of methods. HIVE is f requently associated with white matter damage ranging from inflammatory (mi croglia, macrophages and sparse lymphocytes) to degenerative (myelin loss a nd axonal damage) pathology Although giant cells are seen less frequently i n neocortical grey matter, significant neuronal loss has been established i n a number of studies. Recent investigations using markers of apoptosis, (i ncluding TUNEL, Bcl-2 and BAX), have established the presence of DNA damage in some neurons and in other cell types. Axonal damage has also been confi rmed by evidence of amyloid precursor protein expression. The CNS is also vulnerable to opportunistic infections and high grade B-cel l lymphomas as a result of the immune suppression of advanced HIV infection . Cytomegalovirus (CMV) infection is reported in 10-30 p. 100 of AIDS cases at autopsy, toxoplasma in 10-25 p. 100 progressive multifocal leucoencepha lopathy in about 5 p. 100 and lymphomas, usually primary, in up to 10 p. 10 0 A wide variety of other infections has also been reported. These may coex ist with HIVE and may be difficult to diagnose in life. CMV gives rise to m icroglial nodular encephalitis, ventriculitis, necrotising encephalitis and myelo-radiculitis. Presymptomatic HIV positive patients do not show HIVE or opportunistic infe ctions or lymphomas in the CNS. They frequently display a low-grade T-cell infiltrate in the leptomeninges and parenchyma, particularly around vessels . This lymphocytic infiltrate has been attributed to presumed early invasio n of the CNS by HIV although the exact timing of entry is uncertain. It is possible that reported abnormalities in presymptomatic cases such as gliosi s, microglial activation and rising proviral load may anticipate the onset of HIVE but most studies show that significant CNS damage and HIV-related p athology is confined to patients with AIDS. HIV-related pathology in the spinal cord includes not only HIV myelitis, op portunistic infections and lymphomas, but also vacuolar myelopathy (VM) whi ch affects predominantly the dorsolateral white matter tracts. The cause of VM is not understood and has not been unequivocally linked with HIV infect ion. It is noted that none of these neuropathological features (including HIVE) correlates exactly with the clinical expression of AIDS-related dementia (A RD). The exact contribution of macrophage activation and cytokine release a strocytic infection, neuronal loss and axonal damage to the neuropsychiatri c syndromes of advanced HIV infection remain to be determined. While the cu rrent understanding of the pathogenesis of HIVE and ARD is beyond the scope of this review if is axiomatic that accurate documentation of neuropatholo gy findings will help to resolve the outstanding dilemmas relating to HIV i nfection of the CNS. There is considerable optimism that progress in therapeutic regimes for HIV -infected patients will succeed in eliminating the virus from the blood and from lymphoid tissue. However concern has been expressed that the CNS may act as a sanctuary for HIV and that CNS complications will continue to caus e morbidity in treated patients. Since the majority of infected individuals around the world do not have access to effective therapy, the CNS complica tions of AIDS will continue to be a major problem.