. Coregistration of quantitative proton magnetic resonance spectroscopic imaging with neuropathological and neurophysiological analyses defines the extent of neuronal impairments in murine human immunodeficiency virus type-1 encephalitis. J Neurosci Res. 2005 May 15;80(4):562-75. PubMed.


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  1. The seeming paradox that human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) occurs in the absence of virus infection of neuronal cells has long been known. The presumed cause of neuronal impairment is a bystander-type effect due to infected perivascular macrophages and microglia which, even if relatively few in number, can cause widespread neuronal dysfunction. Another paradox is that the extent of neuronal death seems markedly insufficient to account for the degree of cognitive impairment that can occur. To examine these phenomena, Nelson et al. studied SCID mice (wild-type mice are not susceptible to HIV infection), which they injected intracranially with virus-infected monocyte-derived macrophages (MDM), thus causing HIV encephalitis (HIVE) which, they state, is the hallmark of HAD. HIV cannot spread from the injected cells to mouse brain cells, so any injuries or malfunction occurring in neurons remote from the needle track must be due to “action-at-a-distance” effects of the virus. This work follows previous studies in the same laboratory (Persidsky et al., 1997) showing that in these mice, HIV-1-associated pathological features and inflammatory markers in the brain closely resembled those in human HIVE, and that anti-inflammatory drugs combined to reduce inflammation and also neuronal damage (axonal injury) in the animals, independently of viral replication (Persidsky et al., 2001).

    The present study investigated histopathology and neuronal function in the mouse brains by immunohistochemistry and measurements of hippocampal long-term potentiation (LTP), and used proton magnetic resonance spectroscopic imaging (1H MRSI) to monitor several brain metabolites, in particular, N-acetyl aspartate (NAA), as a marker of neuronal viability. The aim was to seek biomarkers for HAD to supersede the present slow method of diagnosis—exclusion of other diseases—so that treatment of patients with highly active antiretroviral therapy (HAART), which can ameliorate HAD symptoms, could be started early in the disease. [As Mattson et al. (2005) have commented, combination antiretroviral therapy has led to a decreased incidence of HIV dementia and to less severe clinical effects, but also to a continued increase in prevalence rates of HIV dementia; in the milder cases of dementia, cognitive dysfunction is more common.]

    Nelson et al. found that 7 days after injection, the mice suffered a focal giant cell encephalitis, with reactive astrocytes, microgliosis, and neuronal dropout. NAA and LTP levels decreased in both injected and contralateral hemispheres, and also in regions such as the hippocampus, where there was only limited or no pathology. However, they deduced that the decrease in neuronal health was not caused solely by glial inflammatory responses, and that the observed NAA decrease on the contralateral side was not a direct consequence of neuronal apoptosis or synaptic injury, but instead indicated “functional” neuronal health. The authors concluded that 1HMRSI is an important tool for assessing neuronal function, and that remote effects on neuronal function and metabolism can indeed occur after highly focal encephalitis, even from low numbers of injected HIV-infected cells.

    Is this study—or indeed, others on HIV-infected brain—relevant to AD? Well, the main connections are, of course, that HIV causes inflammation, that it leads to the deposition of amyloid (Esiri et al., 1998; Rempel et al., 2005; Green et al, 2005), and that eventually, cognitive impairment occurs, ranging from mild to severe dementia. Our studies on AD have implicated the common virus HSV1 as a strong risk factor in a high proportion of cases, when it is present in brain of ApoE4 carriers (Itzhaki et al., 1997; Dobson et al., 2003). We have found that on infection of human neural cells in culture, HSV1 has major effects on APP degradation (Shipley, SJ, Parkin, ET, Itzhaki, RF, Dobson, CB, submitted). Overt herpes simplex encephalitis, an acute infection of human brain caused by HSV1 (fortunately a very rare event) occurs in both neurons and glial cells; it causes severe focal inflammation, and in those who survive, cognitive, emotional, and behavioral impairments are common. A question relevant to the study by Nelson et al. is: Do bystander-type effects of HSV1 occur in AD, too? We suggested in 1997 that the combined action of brain HSV1 and ApoE4 in causing AD could be due either to ε4 permitting greater viral spread and damage, or possibly to a less efficient repair, in ε4 carriers, of damage to cells that are not infected by HSV1 but suffer indirectly (presumably, the cells actually containing the replicating virus would be killed). We do not yet know the answer, but are now investigating this using cell culture.

    Yet another link is that in at least some studies, ApoE4 has been shown to be a risk factor for HAD. Underlying this may be the finding that syndecans, a class of heparin sulfate proteoglycans (HSPG), are implicated in brain invasion by HIV, both directly (Bobardt et al., 2004) and indirectly, because HSPGs are required for HIV entry into macrophages, the cells responsible for carriage of virus into brain. ApoE is plentiful in extracellular fluids and CSF, and it attaches to cells by binding to HSPGs; therefore, competition with HIV for HSPG binding (Itzhaki et al., 1998) may account for the effect of ApoE genotype on risk of HAD. Indeed, we proposed a similar mechanism for ApoE-HSV1 involvement in AD, as HSV1, too, uses HSPGs to enter cells (this is the basis of the alternative mechanism to the "repair" outlined above). Thus, despite pathological, histological, and physiological differences, HAD and AD may yet be linked via the action of ApoE in modulating viral spread.


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