Neuropathology of Early HIV‐1 Infection

Abstract

Early HIV-1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV-1 carriers remain neurologically unimpaired during the so called "asymptomatic" period lasting from seroconversion to symptomatic AIDS. Therefore, neuropathological studies in the early pre-AIDS stages are very few, and the natural history of central nervous system changes in HIV-1 infection remains poorly understood. Examination of brains of asymptomatic HIV-1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV-1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T-cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also interfere. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV-1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV-1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV-1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV-1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T-lymphocytes, continuously inhibits viral replication at that stage.

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

“…33,34 Similarities and differences between the neuropathological findings seen in HIV-1-infected humanized mice, human HIV-1 infection, and SIV-infected nonhuman primate models are listed in Table 4. 28,31,[61][62][63][64][65][66][67][68][69] It is not surprising that all HIV-1-infected animals did not develop acute inflammatory responses in the brain because such aseptic meningitis was seen only in 20% of HIV-1 infected humans. 28,61,70 -72 The encephalitis observed after CD8 cell depletion in these mice were distinct from that reported in HIV-1 and SIV encephalitis.…”

“…Immune activation of brain parenchyma with increased number of microglial cells, up-regulation of major histocompatibility complex class II antigens, and local production of cytokines was described. 28,29 In both acute and chronic infection phases, CD8 ϩ cytotoxic T lymphocytes (CTL) play a dual role:…”

Neuropsychiatric applications of DTI – a review

“…15 Psychiatric symptoms such as anxiety and depression are common in HIV-1-infected individuals. Impairments in attention, learning and speed of information processing are also common and can range in severity from a mild cognitive motor disorder to dementia in later disease stages.…”

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

“…Although the mechanism(s) for HIV introduction to the CNS is unclear, it appears that the CNS is invaded early after contracting HIV [39], perhaps due at least in part to an influx of infected mononuclear phagocytes and possibly T cells (i.e., the Trojan Horse theory). HIV then spreads to other cells, such as microglia and astrocytes, thus increasing the population of cells producing virions and viral proteins.…”