Editorial

HIV-1 infection's diverse effects on the nervous system represent major obstacles facing the management of the HIV/AIDS epidemic today. Given the rapid evolution in conceptual advances and clinical care in the field of HIV/AIDS, this issue of Current Opinion in HIV and AIDS devoted to the neurological aspects of HIV infection is timely and valuable to investigators and clinicians alike. In the past 30 years, the neurological complications of HIV/AIDS have changed in terms of range of clinical phenotypes and their diagnoses together with new treatments, especially the extraordinary success of combination antiretroviral (cART). To attain viral eradication in the long term, it is likely that strategies for clearing the viral reservoir in the nervous system will need to be included in future clinical protocols. Although neurological opportunistic infections and primary HIV-induced disorders, such as HIV-associated neurocognitive disorders (HANDs) and distal symmetric polyneuropathy (DSP), continue to dominate present day clinical aspects, their phenotypes and associated complications have altered diagnostic and therapeutic approaches. Sacktor and Robertson (pp. 517–520) provide an overview of the current understanding of HAND, emphasizing its spectrum that encompasses an asymptomatic stage, which is the most prevalent phenotype to the most severe disorder, HIV-associated dementia, now a relatively rare entity among persons receiving cART. Nonetheless, progression in HAND severity seems to be limited in the setting of available cART. The contemporary features of DSP are reviewed by Kaku and Simpson (pp. 521–526) during which they point out that symptomatic and curative treatment options for DSP are lacking despite its high prevalence including in children. Likewise, the PNS manifestations of HIV/AIDS are protean and should be kept in mind during clinical assessment because of their significant morbidities. Valcour and colleagues (pp. 527–532) address the impact of aging in their review because of the burgeoning population of individuals with HIV/AIDS who are over 50 years. There are limited data to suggest that the effects of HIV-1 infection and aging directly interact regarding neuropsychological performance but cerebrovascular disease may play an important role in neurocognitive signs and symptoms among older patients with HIV/AIDS. HIV-1's neuropathogenic effects in children remain a major problem in settings with limited access to cART, as described by Wilmshurst et al. (pp. 533–538) Indeed, identification and treatment of neurocognitive impairment and/or neurodevelopmental delay as well as epilepsy and cerebrovascular disease in children are ongoing issues facing pediatric caregivers in developing countries. Wright (pp. 539–544) highlights the ongoing importance of neurological opportunistic infections in high, middle and low-income settings emphasizing the impact of cryptococcal meningitis, tuberculous meningitis and progressive multifocal leukoencephalopathy in circumstances in which cART is not available. An area of unparalleled growth in clinical neurosciences is neuroimaging, and similarly, its impact on diagnosis and management neurological disorders in HIV/AIDS has been immense with newer technologies providing insights into pathogenesis and guides to interventions. Ances and Hammoud (pp. 545–551) provide an informative update on cutting-edge neuroimaging tools and the applications of magnetic resonance spectroscopy and positron emission tomography to neuroAIDS; the use of functional MRI in HIV/AIDS signals major breakthroughs in the knowledge of factors contributing to specific neurological disease phenotypes. Despite advancements on all fronts in neuroAIDS, the cellular and molecular events underlying the development of clinical features remain unclear, although consensus has been achieved in some areas. Churchill and colleagues (pp. 552–558) highlight the need for a fuller understanding of the extent of viral infection of the nervous system in terms of neuroanatomical site, viral integration and latency status as well as the target cell types; the impact of current cART regimens on these variables remains to be clarified in order for viral eradication from different cellular reservoirs to be considered a realistic goal. The effects of recurrent detection of viral RNA in plasma or cerebrospinal fluid during cART may herald uncontrolled viral replication within central nervous system (CNS) parenchyma and as such deserves review of treatment decisions, as reviewed by Kolson and colleagues (pp. 559–564); in fact, there is a link between intermittent virus replication in the CNS and adverse neurological consequences, perhaps mediated by induction of neuroinflammation. The components and influence of chronic innate immune activation in the nervous system continue to be elucidated, as described by Croteau and colleagues (pp. 565–571). The effects of type 1 interferons as well as inflammasomes represent new avenues of research together with their effects on autophagy in the brain that potentially offer novel therapeutic possibilities for neuroAIDS. Thus, numerous fundamental questions remain to be addressed regarding HIV-1's actions in the nervous system. The conceptualization and implementation of cART is one of the greatest achievements in healthcare over the past 20 years or longer. Nonetheless, the newer cART regimens have led to the emergence of new neurological disorders such as the neurological immune reconstitution inflammatory syndrome (IRIS) as well as controversy around the neurotoxic actions of different antiretroviral drugs. Johnson and Nath (pp. 572–578) provide a highly instructive review of the current issues surrounding IRIS as it affects the CNS; their review underlines the broadening appreciation for IRIS’ clinical features and management depending on the primary antigenic stimulus, which can include specific opportunistic infections as well as uncontrolled HIV-1 infection in the nervous system. The pathogenic mechanisms triggering and driving IRIS remain obscure at present but infiltration of the CNS by activated T cells that target specific molecular targets with ensuing and unfavorable actions are important determinants. The interactions between cART and the brain are complex and driven multiple determinants including antiretroviral therapies’ concentrations at the sites of virus replication, the efficacy of individual therapies with respect to inhibition of viral replication in different cell types, potential cytotoxic effects, drug resistance and interactions with other drugs; these issues are addressed by Meeker et al. (pp. 579–584) cART's impact on neurocognitive performance remains uncertain with older studies reporting improvement, but more recent reports are less definitive. The neurotoxic effects of cART in the brain have received increased consideration of late, possibly due to the achievement of high antiretroviral therapy concentrations within the CNS. However, actual drug concentrations in brain parenchyma, particularly in combination, remain uncertain today. The contribution from Gendelman and Gelbard (pp. 585–590) takes us into the realm of future therapies and perhaps provide a roadmap by which we in the research community can achieve these novel and exciting new treatments. The present collection of reviews provides readers with contemporary assessments of the concerns encountered by investigators and clinicians involved in HIV/AIDS neurological research and care. Nonetheless, other relevant topics are not included herein for logistical reasons and should not be discounted. The impact of substance abuse, other comorbidities such as hepatitis C virus infection, polypharmacy and the evolution in neuropathological phenotypes with cART are important topics that bear close scrutiny. On reviewing the field of HIV-1 and the nervous system, there has been substantial knowledge creation over the past 30 years from which valuable interventions have been derived that have improved the survival and quality of life for those affected by HIV/AIDS. At same time, the continual high prevalence rates of neurological disorders and their associated disease burden among HIV-infected persons underscore the ongoing need to advance this field. Acknowledgements None. Conflicts of interest Disclosures: None of the authors have conflicts of interest regarding the contents of this manuscript.

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