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HIV cure strategies [interruptions/viral rebound brain/immune affects]: response to ignore the central nervous system at your patients' peril
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"a further adverse outcome, which could be a catastrophic event, is immune reconstitution inflammatory syndromes occurring in the CNS compartment. This could occur due to cytokine storms caused by immunotherapeutic agents modifying neuroinflammatory responses, or immune activation following viral rebound and blips caused by HDAC inhibitors (and similar agents) or viral rebounds associated with antiretroviral treatment interruptions"
Winston, Alan; Julie, Fox; Fidler, Sarah
AIDS: April 24th, 2017
We read with interest the recent article published in AIDS by Gama et al. [1], highlighting evidence for a significant central nervous system (CNS) reservoir in simian immunodeficiency virus macaque models despite effective long-term peripheral viral suppression by antiretroviral therapy. This was followed by an informative editorial by Spector and Rappaport [2], cautioning those involved in HIV cure research not to overlook this important viral reservoir. Future cure strategies, which test the impact of interventions on measures of viral reservoir in peripheral body compartments, may not assume that they have the same efficacy in the CNS and thereby mitigate the effectiveness of HIV cure interventions.
Although we acknowledge and fully agree with this potential lack of efficacy for HIV cure strategies if sanctuary sites are overlooked, we would like to highlight additional potential perils facing HIV cure strategists with respect to the CNS; namely adverse CNS outcomes that may include toxicities of HIV cure therapies, direct immune-mediated CNS pathogenesis or the impact of viral reactivation on the brain [3].
Mechanisms of negative outcomes on the CNS and neuronal tissue due to cure strategies could include, first, adverse effects on brain function secondary to the removal or elimination of latently infected neuronal cells with crucial function for brain health, such as microglial cells and astrocytes [4]. Second, neuronal damage from either drug utilized during cure research strategies or neuronal damage from viral proteins, the expression of which may be upregulated during cure treatments. An example being the gene upregulation resulting from histone deacetylase (HDAC) inhibitor use. Finally, a further adverse outcome, which could be a catastrophic event, is immune reconstitution inflammatory syndromes occurring in the CNS compartment. This could occur due to cytokine storms caused by immunotherapeutic agents modifying neuroinflammatory responses, or immune activation following viral rebound and blips caused by HDAC inhibitors (and similar agents) or viral rebounds associated with antiretroviral treatment interruptions. Cases of HIV encephalopathy associated with viral rebound and cerebrospinal fluid viral escape are well described in the literature [5]. In addition, cure approaches that include the use of therapeutic HIV vaccines that induce HIV-specific CD8+ cytotoxic cells have the potential to trigger CD8+-mediated encephalitis [6].
To date and to our knowledge, no significant adverse effects on CNS function have been observed in HIV cure trials, but limited data are available. One small study has reported on the effects of HIV-latency-reversing agents on CNS parameters in HIV-positive participants with no adverse impact on cerebrospinal-fluid neuroinflammatory or degenerative soluble biomarkers observed [7]. Such results are reassuring. However, one should be weary of the results from other fields such as cancer studies, from which some of the agents used in HIV cure strategies originate. The syndrome of chemotherapy-related cognitive dysfunction or 'chemobrain' is being increasingly recognized with the use of modern oncological treatments, although the pathophysiology of this condition remains elusive [8].
For HIV cure strategists and researchers, consideration of and monitoring for CNS adverse events within HIV cure studies will be crucial. Monitoring for CNS adverse events is challenging given the closed anatomical sanctuary site of the brain and the complexity of monitoring nervous system function. Brain biopsies are clearly not possible, and repeated cerebrospinal fluid examinations are costly and not practical for every study. However, monitoring clinical parameters such as cognitive function and patient-related outcome measures of cognitive health, coupled with the monitoring of sensitive peripheral markers of neuronal integrity, such as highly sensitive plasma neurofilament light protein [9], and noninvasive neuroimaging could be practical approaches to consider.
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