PMC:2678986 / 32821-37168
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2678986","sourcedb":"PMC","sourceid":"2678986","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2678986","text":"5 Other aspects\nBBB disruption during HIV infection is thought to provide a primary portal for infected cells to enter the brain and to contribute significantly to neuropathology such as HIVE and HAD (Toborek et al., 2005; Wang et al., 2008). Several processes have been attributed to the disruption of the BBB in HIV infection, in addition to those discussed earlier. Morphological changes such as an increase in the diameter of cortical vessels as well as alterations such as the thinning of basal lamina and loss of glycoproteins present in endothelial cells are all features of the disrupted BBB observed in HIV-infected patients. Furthermore, apoptosis of endothelial cells and tight junction disruption are thought to be other mechanisms by which the integrity of the BBB is impaired in HIV (Toborek et al., 2005).\nHIV infection is also associated with a wide range of vasculitides including that affecting small, medium and large vessels and one common feature amongst all vasculitides seen in HIV infection is the underlying inflammation of the vessel wall (Guillevin, 2008). A recent study has also indicated that HIV-1 increases the sensitivity of the BBB to disruption by systemic lipopolysaccharide, which is elevated in HIV-1-infected individuals (Wang et al., 2008). Furthermore, monocytes that were infected with HIV-1 provirus were more able to cross the BBB particularly after lipopolysaccharide administration. Interestingly, HAART has been shown to reduce the elevated systemic levels of lipopolysaccharide present in HIV-1-infected individuals (Brenchley et al., 2006). It has thus been suggested that HAART may reduce the incidence of HAD by not only reducing HIV-1 replication but also by reducing circulating lipopolysaccharide and thereby reducing compromise of the BBB and migration of HIV-1-infected monocytes from the systemic circulation into the brain (Wang et al., 2008). However, it may also be that disruption of the brain barriers facilitates the entry of drugs into the CNS and consequently alleviates the symptoms of HAD. The potential toxic effects this may have due to excessive drug concentrations accessing the brain (see below) or other unknown effects precipitated by higher concentrations of anti-HIV drugs in the CNS are important factors that remain to be explored (Toborek et al., 2005; Gimenez et al., 2004).\nBoth in vitro and in vivo studies, as well as clinical observations, have shown that conventional anti-HIV drugs can have significant toxic effects. HAART has been directly associated with the development of endothelial dysfunction and consequently with cardiovascular diseases. Clinical toxicities of NRTIs include peripheral neuropathy, skeletal myopathy, lactic acidosis and hyperlactatemia (Kline and Sutliff, 2008). There are two types of CNS adverse reactions associated with HAART (1) direct drug toxicity and (2) immunopathology related to immune restoration and toxicity (Price and Spudich, 2008). Although there is little evidence to suggest that NRTIs and PIs have direct adverse effects on the CNS, the NNRTI efavirenz clearly affects CNS function, and its use is complicated by neuropsychiatric symptoms such as dysphoric dreams. Additionally, one report suggested an interactive effect of efavirenz and tenofovir on neuropsychiatric symptoms, which were however, fully reversible following the cessation of treatment (Price and Spudich, 2008). Furthermore, a recent study has revealed that prolonged HAART usage and aging may play a role in the overall increase in amyloid deposition in HIV dementia mediated by either inhibition of insulin degradation enzyme or disrupted amyloid precursor protein transport (Nath and Sacktor, 2006).\nRecently the term “Immune reconstitution inflammatory syndrome” (IRIS) has been created to recognise the improvement of the immune system generally seen a few weeks after the initiation of HAART. Paradoxically, IRIS also results in a decline in clinical status and is predominantly associated with a huge rise in the CD4 T-lymphocyte count as well as a reduction in the peripheral HIV RNA viral load. If IRIS is untreated and affects the CNS, then it is associated with significant morbidity and mortality. Recently, IRIS fatally affected two patients with HIV dementia, despite control of the virus in the periphery (Nath and Sacktor, 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