PMC:2678986 / 1778-6457 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2678986","sourcedb":"PMC","sourceid":"2678986","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2678986","text":"1 Introduction\nInitially recognised in a handful of cases during the early 1980s, human immunodeficiency virus (HIV) has infected an estimated 33 million people worldwide (UNAIDS Epidemic Update, 2008), causing the acquired immunodeficiency syndrome (AIDS). In 2007 the HIV/AIDS epidemic killed approximately 2 million individuals. The central nervous system (CNS) is a major target of HIV, becoming infected in the primary stage of infection and this continues in the majority of untreated seropositive individuals throughout the course of infection.\nHIV infection in the CNS is associated with the development of asymptomatic neurocognitive impairment, HIV-associated mild neurocognitive disorder (MND), and eventually HIV-associated dementia (HAD) or AIDS dementia complex that manifests as a clinical syndrome of cognitive, motor and behavioural dysfunction (Antinori et al., 2007). These neurological complications arise most likely due to the early penetration of HIV-1 into the CNS via infected immune cells such as CD4+ T lymphocytes, dendritic cells, monocytes and macrophages, which are all cellular reservoirs of HIV-1 (Valcour and Paul, 2006; McArthur, 2004; Blankson et al., 2002). A key feature of HIV populations in the CSF is that initially they may be identical to that in the plasma, but as the infection progresses the viral populations diverge, with the greatest divergence being observed in patients with HAD (Wong et al., 1997; Strain et al., 2005).\nIn the late stages of AIDS, the CNS is also vulnerable to several severe opportunistic diseases including cryptococcal meningitis and primary CNS lymphoma. All these neurological conditions were initially associated with high morbidity and mortality, and this continues to be the situation in resource-poor countries where highly active antiretroviral therapy (HAART) is not readily available (Table 1). However, where there is wide-spread use of HAART there has been a profound reduction in the incidence/severity of HAD (d’Arminio et al., 2004) and the major CNS opportunistic infections, although the prevalence of minor HIV-1 associated cognitive impairment appears to be rising. Various factors including toxicity, insurgence of drug resistance, poor medication adherence and sometimes limited access to HAART, contribute to this phenomenon. It has also been speculated that the constant presence of HIV and the associated immunoactivation and inflammation in CSF is linked to this more subtle form of brain injury. As elevated viral loads in the CSF, predict subsequent neuro-cognitive impairments (Ellis et al., 2002). Overall it would suggest that treatment of CNS disease associated with HIV-infection may be sub-optimal and clinical data has suggested that the CNS effectiveness of anti-HIV drug regimens can be significantly improved by treating with CSF-penetrating antiretroviral drugs in patients with cognitive impairments (Letendre et al., 2004, 2008a,b).\nThe classification of the antiretroviral drugs into either low-CNS penetration (rank 0), intermediate CNS penetration (rank 0.5) or high-CNS penetration (rank 1) was based on extensive literature reviews and considered the physico-chemical characteristics of the drug, measured CSF concentrations and effectiveness in the CNS (Table 2) (Letendre et al., 2008a). Drug combinations are ranked by combining the individual drug rankings. However, this simple ranking for drug combinations does not allow for other drug properties, such as drug interactions at the blood–CNS interfaces to be considered, and these factors may actually contribute to lack of, or in fact enhanced, CNS efficacy of specific drug combinations. Recent progress strongly suggests that certain transporters in the BBB impede the access of anti-HIVs to the CNS and that pharmacological modulation of these transporters could be used to our advantage (Eilers et al., 2008).\nIn order to examine drug interactions at the transporter level of the blood–CNS interfaces in more detail, a clear picture of drug movement into the CNS is clearly warranted. This may prove useful in fine-tuning this ranking scheme and is the focus of this review. We will start with a summary of current anti-HIV drugs and how molecules are restricted from crossing the blood–CNS interfaces. This will then be followed by a brief overview of those membrane transporters considered to be relevant to the disposition and effectiveness of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) and protease inhibitors (PIs). Possible future research directions will then be 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