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The impact of HIV central nervous system persistence on pathogenesis

Brew, Bruce J.a,b,c; Barnes, Stephanie L.a

doi: 10.1097/QAD.0000000000002251
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The persistence of HIV in the central nervous system is somewhat controversial particularly in the context of HIV viral suppression from combined antiretroviral therapy. Further, its significance in relation to HIV pathogenesis in the context of HIV-associated neurocognitive disorders, systemic HIV pathogenesis, and eradication in general, but especially from the brain, are even more contentious. This review will discuss each of these aspects in detail, highlighting new data, particularly from recent conference presentations.

aDepartments of Neurology and HIV Medicine, St. Vincent's Hospital, Darlinghurst, Sydney

bApplied Neurosciences Program, Peter Duncan Neuroscience Research Unit, St. Vincent's Centre for Applied Medical Research, Darlinghurst

cFaculties of Medicine, UNSW Australia, and University of Notre Dame Sydney, New South Wales, Australia.

Correspondence to Bruce J. Brew, Professor, Department of Neurology, Level 4 Xavier Building, St Vincent's Hospital, Victoria, St Darlinghurst, Sydney, NSW 2010, Australia. Tel: +61 2 8382 4100; fax: +61 2 8382 4101; e-mail: B.Brew@unsw.edu.au

Received 17 June, 2018

Revised 9 March, 2019

Accepted 9 April, 2019

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Introduction: definitions

The interpretation of HIV persistence in this review will be deliberately broad. It will be taken to mean detection of HIV in the central nervous system (CNS), regardless of whether it is whole viral particles, viral components, cell-associated or not, replication-competent or not. It will include HIV infection that is productive (i.e. associated with production of whole infectious virions), restrictive (i.e. production of parts of virus but not whole intact virions), and latent infection (i.e. where there is proviral DNA but no HIV transcription). CNS will also be liberally interpreted to include the brain as well as the meningeal compartment. This approach has been taken to be as inclusive as possible of all relevant published or presented data to minimize selection bias founded in preconceived notions of pathogenesis. Further, emphasis will be placed upon data relating to combination antiretroviral therapy (cART)-induced viral suppression to reflect current management practice.

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Evidence for central nervous system persistence

There is extensive evidence for persistent HIV infection in the CNS that derives from clinical, cerebrospinal fluid (CSF), neuroimaging and neuropathological data.

The clinical data relate to the development of HIV-associated neurocognitive disorders (HAND) in the context of prolonged viral suppression in both blood and CSF. This is best shown in Cysique et al.[1] where 18.1% develop HAND, principally the milder forms – asymptomatic neurocognitive impairment (ANI) or mild neurocognitive disorder (MND) – in the absence of confounding conditions, such as substance use, mood disorder and so on. Other studies have shown similar results but have been open to the criticism that progression to HAND was the result of confounding conditions or poor adherence to cART [2,3]. Some researchers have suggested that the continued prevalence of HAND in the context of successful cART simply represents a ‘legacy’ effect in individuals who had HAND with only a partial response to cART. This may be true for some individuals and in some instances but it is difficult to see how it would explain the development de novo of HAND in the context of effective cART. Other researchers have questioned the validity of the criteria for ANI and MND raising concerns over unacceptably high false positive rates. As discussed in detail by Saloner and Cysique [4], it is a balance between sensitivity and specificity. Importantly though, the current definition of ANI/MND is in accord with that for mild cognitive impairment in Alzheimer's disease where similar false positive rates occur [5].

Still others have suggested that HAND development with cART is the result of Wallerian degeneration from earlier HIV-related brain damage. This is also a difficult argument to sustain as Wallerian degeneration should not spread to involve other areas that were not affected by the original damage. There is, however, a caveat. Patients with chronic traumatic encephalopathy develop progressive neurological decline years after the repeated traumatic brain insults [6]. The mechanism for this prolonged delay with progression but without further trauma is unclear. It is conceivable that a similar mechanism exists in some patients who develop HAND, perhaps as a consequence of HIV-related brain injury years before.

CSF studies also support persistent CNS infection. There may be what has been termed ‘CSF viral escape’ wherein patients have detectable HIV viral load in CSF in the presence of undetectable HIV RNA in blood [7]. Whilst it is uncommon, it nonetheless occurs [8]. Immune activation may occur in CSF and not blood in both HAND and non-HAND patients [9,10]. Although this evidence is indirect, this likely reflects ongoing viral replication, albeit at below currently detectable limits, given that this occurs in some patients in the systemic circulation [11] and there is some evidence that such immune activation correlates with CSF HIV RNA even at low levels [12]. There is also evidence suggesting infection of microglia or at least macrophages in the CNS [13–15]. This is further supported by pathological studies demonstrating persistence of HIV in multiple body tissues, including brain, despite undetectable serum levels [16,17]. HIV isolated from CSF in some patients can show phylogenetic evolution independent of the blood leading to compartmentalization [18–23]. This is true even when cART is started early in HIV disease [24]. Furthermore, CSF can show different cART resistance patterns to those found in the systemic circulation, again supporting independent HIV persistence in the CNS at least in some patients [25–27]. Such different resistance patterns may be related to particular classes of antiretrovirals (ARVs), namely those with limited brain penetration [28–30]. Further, several studies have demonstrated increased CSF concentrations of S100β, suggesting at least astrocyte reaction [31,32], and raised concentrations of various forms of tau (total and phosphorylated) as well as neuronal filament light chain, suggesting neuronal damage [33–38].

Neuroimaging data also demonstrate brain changes reflecting persistent HIV infection in the CNS. Studies are consistent with progressive brain atrophy, neurochemical abnormalities suggesting neuronal injury and inflammation, reduced blood flow, disruption of white matter tracts, and disturbance of activation and connectivity. Computed tomography (CT), and more particularly MRI, show generalized cerebral atrophy along with regional, especially subcortical, atrophy in areas, such as caudate, putamen, amygdala, hippocampus, and thalamus [39], and deep subcortical white matter, especially corpus callosum [40]. These changes seem to be minimized but not negated by early effective cART [41,42]. Lower intracellular levels of glutamate and glutamine in frontal white matter and inflammatory changes, as reflected by myoinositol and choline elevations, have been observed [43]. These correlate with neuropsychological impairment, though only dementia was associated with significant reduction in the neuronal marker N-acetyl aspartate. However, the extent to which these changes occur in patients who have been on suppressive cART for years is less clear. PET studies have similarly shown evidence consistent with inflammation by virtue of microglial activation even in early HIV disease and in those on suppressive cART [44]. Reduced cerebral blood flow, reflecting neuronal injury, has been found in frontal and parietal brain regions [45] and the lenticular nuclei [46]. White matter hyperintensities and tract disruption are also common in HIV [47]. These white matter tract abnormalities, however, seem to be less prominent in patients who have been virally suppressed in the long-term [48]. fMRI studies reveal less activation in attention, working memory and executive function networks with increased activation in other networks, perhaps as a compensatory mechanism, though there are concerns over the long-term implications of calling on the brain's reserve capacity [49]. Similar disturbances in network connectivity, particularly in the default mode, executive and salience networks, have been found even in patients who have been virally suppressed for years [50].

Neuropathological and neurovirological data also support persistent HIV infection of the CNS. From the 1980s, it has been appreciated that in some patients, HIV causes encephalitis with productive infection of macrophages and probably microglia resulting in multinucleated giant cells [51]. With suppressive cART, there is little CNS inflammation and little-to-no appreciable viral replication. However, significant amounts of postintegration HIV DNA may be present in some, but certainly not all [52–55]. Some in the field question the true neuropathological/neurovirological substrate for HAND in the context of sustained viral suppression [56,57]. Indeed, some investigators have argued that HAND in the cART era is multifactorial, reflecting the effects of substance use, mood disorders, comorbid viral infections, smoking, vascular disease and so on but is unrelated to HIV. A number of potential explanations for the presence and development of milder forms of HAND with cART have been published [58]. It is a curious situation: despite the potent activity of cART where one would expect milder forms to respond and more severe forms to be refractory, the exact opposite is found, a ‘therapeutic paradox’. If cART-related HAND is just ‘dampened’ precART HAND then some CNS inflammation and productive infection should still be seen but that is not the case. Similarly, severe forms of HAND should still be prevalent and mild forms not but the opposite is true. These observations strongly suggest an alternate neuropathogenesis for cART-related HAND. Two explanations are likely and are not mutually exclusive. The first is that cART-related HAND is unrelated to HIV in the brain but rather reflects neurotoxicity of cART, for which there is some evidence [59–62]. However, studies have provided conflicting results as to which drugs consistently lead to neurotoxicity, likely as a result of different modelling systems and conditions. The second explanation is that cART-related HAND is related to HIV but not productive infection – rather it is a result of restricted or even latent infection of the brain. There is a good evidence base for this. First, it is well known that current ARVs do not target early transcription of HIV so that there can be intermittent production of nonstructural proteins, such as tat, nef and vpr. These viral proteins have neurotoxic, pro-atherosclerotic, pro-inflammatory and amyloidogenic effects [63–66]. CSF analysis for tat has shown that it can be present despite HIV RNA levels being below 20 copies/ml in both plasma and CSF (Nath et al., unpublished observation, Brew et al., unpublished observation). Further, tat has been detected in the brains of patients without evidence of productive infection [67].

Lastly, such production is very likely to be a long-term issue as the brain cells that HIV infects are long lived: the turnover rate of astrocytes is not known in humans but in mice, it is 0.4% per day [68]. Most researchers consider the evidence for astrocyte infection by HIV convincing [69] as there are data from both in-vitro [70–72] and in-vivo studies [73–75]. Recently, one group has put forward evidence that astrocytes engulf infected material from other cells, such as macrophages rather than truly being infected [76]. Another group has advanced evidence against astrocyte infection being able to be reactivated [77]. This goes against the majority of the data in the field as discussed at the recent NIH sponsored meeting ‘Astrocytes as an HIV CNS Reservoir’, 10 April 2018, Chicago [78]. Indeed, there is good evidence for epigenetic regulation of HIV latency in astrocytes suggesting that different factors and culture techniques may explain some findings of lack of ability to reactivate [79]. There is some controversy over the extent of astrocyte infection as the infection rate may be only a few percent in patients without HAND. However, given that astrocytes are the most populous cell in the brain, even a small percentage of infected cells does amount to a potentially significant burden. Another source of some controversy is whether such infection is more often transcriptionally silent. Recent data from the Astrocyte symposium (see above) point against this. It is unknown when astrocytes become infected though it is likely early in HIV disease as the CNS is infected early and astrocytes are an integral part of the neurovascular unit with close proximity to the blood vessel lumen. Lastly, it is not known whether there are astrocytotropic strains of HIV – if there are then these would potentially contribute a significantly greater HIV reservoir.

Microglia are also long lived cells that are infected by HIV. Recently, there was controversy as to whether perivascular macrophages, which are closely related to microglia, were truly infected by HIV. One group provided data that supported macrophages engulfing infected cells as part of their phagocytic function but without actually leading to productive infection [80]. Although this likely occurs, it does not invalidate the concept of macrophage infection by HIV as was definitively shown by Honeycutt in the humanized mouse model treated with cART [81]. Some investigators have questioned whether parenchymal microglia are definitely infected by HIV as opposed to perivascular macrophages. The distinction is critical as microglia are very long lived cells with life spans of years. Data by Cosenza et al.[82] convincingly show that parenchymal microglia are productively infected at least in the case of HIV encephalitis. The same is probably not true though for milder forms of cART-related HAND where there is little-to-no evidence of productive infection [57]. Whether microglia can support latent HIV infection and have replication competent virus that can be rescued remains to be definitively shown.

Animal models similarly provide robust evidence of HIV persistence in the brain. In the accelerated simian immunodeficiency virus (SIV), macaque model SIV DNA was detectable in the brain despite undetectable levels in the blood [83–85]. Isolated microglia from SIV-infected animals produce infectious virus upon in-vitro culture, thereby emphasizing the importance of microglia as a source of HIV [86]. Importantly, latent SIV has been found in some SIV-infected macaque brains leading to reactivation and replication in the context of treatment with latency reversing agents (LRAs) [87,88].

Thus, there is good-quality evidence from multiple sources that HIV persists in the brain in some patients and that it affects and infects the brain at an early stage of HIV infection. The intrinsic brain cells that are most likely infected are perivascular macrophages, microglial cells and astrocytes. The nature of the infection ranges from productive to latent with an emphasis on restricted and latent infection of these cells in the context of effective cART.

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Impact on pathogenesis

Persistence of HIV infection in the brain, even in the presence of effective cART, is the likely significant cause of HAND as explained above. However, there are other consequences that impact on pathogenesis. These relate to accelerated ageing and neurodegenerative disease especially vascular cognitive impairment, Alzheimer's disease and Parkinson's disease. Lastly, persistence of HIV in the CNS may contribute to re-seeding of the systemic circulation by HIV.

In relation to HAND, it seems likely that the continued production of viral components such as tat, nef and vpr contributes to cognitive impairment, possibly with additional neurotoxicity from cART. This would explain the focal brain atrophy observed in the frontal lobes of patients with asymptomatic neurocognitive impairment (ANI) who have effective viral suppression as the deep frontal white matter is a known site of predilection for HIV infection of the brain [89]. Some researchers have questioned the validity of the entity of ANI and others have suggested that it is a reflection of lifestyle factors such as substance use (Nightingale et al.[90]) but the finding of such focal atrophy underlines its validity and its relationship to HIV, albeit that the data are cross-sectional and longitudinal studies would be more definitive. Furthermore, brain energy metabolism, as reflected by creatine levels on magnetic resonance spectroscopy (MRS), is reduced with suppressive cART without markers of inflammation [91]. This finding suggests that latent brain infection is not inert but rather associated with compromised cellular metabolism. The long-term consequences of this are currently unknown. The mechanism of reduced metabolism is unclear though data from Desplats et al.[92] suggest that latent infection leads to inflammation in the microenvironment – presumably not significant enough to be seen by MRS.

Whether HIV brain disease can lead to accelerated ageing and neurodegenerative diseases is also controversial. Once again lifestyle factors, especially substance use and smoking, have been implicated as the cause of accelerated brain ageing and vascular cognitive impairment. Some studies have failed to show a difference in the frequency of neuroimaging abnormalities in lifestyle-matched HIV-positive and HIV-negative cohorts; changes seen have correlated with other factors, such as age and hypertension [93,94]. Although these factors undoubtedly play a role in some patients, more recent rigorous data addressing such confounds point to a direct relationship with HIV [43,95–101]. Analyzing the effect of age on cognition in HIV disease has been difficult as essential data have sometimes been unavailable. For example, it is important to know the duration of HIV disease (the age-duration effect [102]) as the influence of HIV in say a 55-year-old patient is likely different if the patient has only had infection for 5 years as opposed to 25 years. Establishing the duration of HIV disease relies on knowing the approximate date of seroconversion, which can be difficult, if not impossible, to ascertain. Nonetheless, an approximation should be attempted. The data showing a relationship between HIV and vascular cognitive impairment and cerebrovascular disease in general are also controversial, though it is generally accepted that HIV accelerates cardiovascular and peripheral vascular disease [103–106] and can be associated with a vasculopathy [107]. Su et al.[108], Brew et al.[109] and Janjua et al.[110] have shown a definite relationship. There are early data suggesting that HIV-associated cerebrovascular disease may disproportionately affect motor function as opposed to cognition [111]. However, some have considered the relationship to either not exist or to be related to confounds, such as smoking, or the use of cART known to cause vascular disease, such as abacavir and protease inhibitors [112,113]. More recent studies, however, have either excluded such confounds or corrected for them. Another important consideration in any study is to ensure that the study population is sufficiently at-risk for a signal to be observed, especially in longitudinal study designs. Given that some studies have not included such an at-risk population, the negative finding is unsurprising.

In many studies, the control groups used are often not similar to the HIV-infected cohort, which is a significant weakness. To combat this, the COBRA study group identified a lifestyle-matched HIV-negative control group, in which evidence of accelerated biological aging and inflammation were seen in both HIV-positive and –negative groups compared with healthy age-matched blood donors [114,115]. Other independent drivers of this process include chronic hepatitis B, high-titre cytomegalovirus antibody and CD8+ T-cell count [114]; however, accelerated aging was even more pronounced in the HIV-positive group, suggesting an additional effect of HIV brain disease [114]. Furthermore, in this same group, structural brain changes, namely reduced grey matter volume and increased white matter microstructural abnormalities, have been identified that were variably attributed to ongoing HIV-independent inflammation, other comorbidities, such as hypertension as well as the effects of previous AIDS despite current disease control with cART [94]

The issue of neurodegenerative diseases and HIV is even more divided in the research community. Observational evidence is emerging and largely linked to an older age population with genetic risk factors, such as ApoE-ε4 homozygosity in Alzheimer's disease. Neuritic amyloid plaques, as seen in Alzheimer's disease, have been identified in postmortem brain tissue in HAND and moderately correlated with neurocognitive criteria. However, the overall burden of β-amyloid plaque deposition in HIV patients was not increased compared with age-matched controls in two studies [116,117]. Discordant findings may be attributable to ApoE-ε4 status: in a study cohort of 160 individuals the probability of HAND was increased in the presence of β-amyloid plaques among ApoE-ε4 carriers, but not in nonε4 carriers [118]. Three of five CSF studies have found an Alzheimer's disease-like profile; however, this variability may be related to differences in patient selection, particularly relating to ApoE status [119]. Other potentially relevant abnormalities including disruption of ubiquitin-proteosome apparatus function and excess deposition of hyperphosphorylated tau in the hippocampus have also been noted [116,117].

An increased rate of Parkinson's disease has also been recorded [120] though it is controversial, probably because of inclusion of patients who were not old enough to see a signal and the retrospective design of the study [121]. As noted above, it is important to include patients with HAND in such studies as they will likely be at greater risk of neurodegenerative disease through diminished cerebral reserve from HAND. This will increase the likelihood of a signal in cross-sectional studies and will facilitate longitudinal studies over a shorter, more realistic time frame. The problem, however, is that there is significant overlap with the neuropsychological profile of HAND and that of vascular cognitive impairment [99,102]. Thus studies need to utilize alternate biomarkers that are specific for cerebrovascular disease and vascular cognitive impairment in particular. Neuroimaging with MRI/magnetic resonance (MR) angiography can be useful in this regard but the early identification of cerebral small vessel disease by imaging can be difficult as investigations at this stage are nascent and it is unclear, for example, what the sensitivity and specificity are for newer MRI techniques alone or in combination: arterial spin labelling, microbleeds, siderosis and so on [122].

More definitive data linking HIV, cerebrovascular diseases and neurodegenerative diseases in a causal way rest on basic science data. One of the key enzymes in Alzheimer's disease pathogenesis (beta-site amyloid precursor protein cleaving enzyme or BACE) is upregulated by supernatants from HIV-infected macrophages and is mediated by N-methyl-D-aspartate activation [123]. Further there are convergent and overlapping pathogenetic pathways between HIV and Alzheimer's disease [124,125]. In relation to Parkinson's disease, there is reason to expect an association with HIV disease, especially HAND. Both disorders are characterized by basal ganglia inflammation [126] and in patients with HAND, there is likely a degree of compromise of cerebral reserve, particularly in the basal ganglia. Furthermore, there are neuropathological data showing that HIV-infected brains have increased deposition of alpha-synuclein, a key protein in Parkinson's disease pathogenesis [127].

However, there is another potential consequence of persistent HIV brain infection: re-seeding of systemic circulation from the CNS. This has often been discussed as a concept despite the absence of published human data to support it. There is no theoretical reason why it should not occur and there is one study in an animal model that supports the possibility (L. Al-Harthi, personal communication; 26 April 2018). There are two problems to address before human research can answer this adequately. First, there is the need to study patients longitudinally with serial lumbar punctures. Second, there must be sufficiently sensitive techniques available to detect the presence of CNS-derived virus amidst the much greater swarm of viruses in the systemic circulation. Deep sequencing techniques may provide such technology.

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The broader consequences of persistent HIV brain infection

Persistent HIV brain infection has consequences beyond HAND. Given the above evidence, strategies to eradicate HIV should include the brain. Several approaches are at various stages of development and can be encompassed by a ‘shock and kill’ or ‘block and lock’ strategy. ‘Shock and kill’ involves reawakening HIV from its latent state and then killing HIV. There are several problems from a CNS perspective with this approach. First, LRAs must cross the blood–brain barrier and be effective in microglia, macrophages and astrocytes. This is an issue with at least some of the current LRAs [128]. Second, reawakening HIV in the brain risks inducing HAND [129]. Current cART has variable ability to cross the blood–brain barrier and work in such cells [128,130–132]. Third, HIV infection of microglia, macrophages and astrocytes is generally noncytolytic. Reawakened HIV in the presence of limited cART efficacy would lead to infection of other neighbouring cells. Ironically, this eradication approach has significant potential to increase the pool of infected cells in the brain. Unfortunately, the ‘block and lock’ strategy, where HIV is kept in a latent state, is also associated with potential problems. Aside from the problems of blocking/locking agents gaining CNS access and being efficacious in relevant cells, there is the concern that latent HIV, at least in the brain, is not innocuous. There are two pieces of evidence that validate this concern. First, Desplats et al.[92] provided in-vitro evidence that latent HIV in microglia and astrocytes was pro-inflammatory. As discussed previously, such inflammation in the brain is likely detrimental. Second, our own observations have shown diminished cellular energy in latent infection [91]. However, these are not definitive – there is always the possibility that what appears to be constant latent infection is actually punctuated by intermittent low-level transcription.

What can be done to address these concerns? We consider that the fundamental problem is the lack of current ARVs that affect HIV transcription. If such agents were available, then the production of neurotoxic and pro-inflammatory viral components would be blocked. Work is underway to develop these antiviral agents [133], including RNA interference, antisense oligonucleotides and monoclonal antibodies against viral proteins. Additionally, definitive data are needed on the issue of neurotoxicity from latent infection.

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Conclusion

Persistent HIV brain infection does occur, though not in all patients. It is potentially significant with impacts on cognition directly and indirectly, on the systemic circulation through re-seeding (possibly), and on eradication strategies. Nonetheless, it is addressable with the development of better cART that targets HIV transcription. A mechanistic understanding of how latent infection could be neurotoxic (if in fact it is) would allow the development of adjuvant therapies to block such neurotoxicity.

All in all, the CNS is a challenge but, as long as it is recognised, it is not an insurmountable one.

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Acknowledgements

Conflicts of interest

B.J.B. served on the scientific advisory board of Biogen Idec, ViiV, and Merck Serono; received travel funding from Abbott and ViiV; serves on the editorial board of the International Journal of Tryptophan Research, Faculty of 1000, Journal of Neurovirology, and Neurobehavioral HIV Medicine; received publishing royalties from Oxford University Press and Cambridge University Press; consulted for GlaxoSmithKline, ViiV Healthcare, Boehringer Ingelheim, Abbott, Biogen Idec, and Novartis; and received research support from Eli Lilly, GlaxoSmithKline, Merck Serono, ViiV Healthcare, Biogen Idec, NIH, NHMRC, NINDS, NIMH, University of New South Wales, University of Notre Dame – Sydney, and St. Vincent's Clinic Research Foundation. S.L.B. has no relevant disclosures.

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Keywords:

brain; central nervous system; eradication; HIV; HIV-associated neurocognitive disorders

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