The pace of therapeutic developments in HIV presents unique challenges to the neurologist caring for patients. Combination antiretroviral therapy (cART) is remarkably effective in suppressing viral replication, preventing, and often even reversing disease progression. Still, not every patient benefits from cART for a variety of reasons, ranging from the cost of therapy and the burden of lifelong daily treatment to side effects and inadequate access to medical care. Treatment failure inevitably leads to disease progression and opportunistic complications. Many of these complications, even those that are treatable, produce permanent neurological disability. With ART, immune recovery itself may paradoxically lead to severe neurological disease; strategies for managing so-called immune reconstitution inflammatory syndrome are beginning to show benefits. Effective cART may nevertheless leave in its wake persistent neurocognitive impairment. Treatments for persistent impairment despite virologic suppression and good immune recovery are being tested but are not yet proven. As we shall see, these treatments target several proposed mechanisms including cerebral small vessel disease, which is highly prevalent in HIV. Most recently, an ambitious initiative has been undertaken to develop interventions to eradicate HIV. This will require elimination of all infectious forms of viral nucleic acid throughout the body. The influence of these interventions on the brain remains to be characterized. Meanwhile, clinical investigators continue to develop antiretroviral treatments that optimize effectiveness, convenience, and tolerability, while minimizing long-term toxicities.

Investigators reported many new neuroHIV research findings at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI). These findings included confirmation that HIV-associated neurocognitive disorder (HAND) remains common with an increasingly recognized role for comorbidities (eg, obesity) and neurodegenerative conditions (eg, Alzheimer's disease), especially as persons living with HIV (PLWH) advance into their seventh decade of life and beyond. HAND is increasingly recognized as a heterogeneous disorder that differs between individuals (eg, by sex) in the trajectory of specific neurocognitive abilities (eg, executive functioning). A more recent focus at this year's conference was toxicity of combination antiretroviral therapy: neurocognitive performance and neuroimaging data from several studies were presented but did not consistently support that integrase strand transfer inhibitors are associated with worse neurologic outcomes. Neuroimaging studies found that white matter changes reflect a combination of the effects of HIV and comorbidities (including cerebrovascular small vessel disease) and best correlate with blood markers of inflammation. The pathogenesis of HIV in the central nervous system (CNS) was the focus of a plenary lecture and numerous presentations on HIV compartmentalization in the CNS and cerebrospinal fluid viral escape. Novel findings were also presented on associations between HIV-associated neurologic complications and glycomics, neuron-derived exosomes, and DNA methylation in monocytes. This summary will review findings from CROI and identify new research and clinical opportunities.

The 2022 Conference on Retroviruses and Opportunistic Infections featured new and important findings about the neurologic complications of HIV-1, COVID-19, and other infections. Long-term analyses identified that cognitive decline over time, phenotypic aging, and stroke are associated with various comorbidities in people with HIV. Neuroimaging studies showed greater neuroinflammation, white matter damage, demyelination, and overall brain aging in people with chronic HIV infection. Childhood trauma and exposure to environmental pollutants contribute to these neuroimaging findings. Studies of blood and cerebrospinal fluid biomarkers showed that systemic inflammation, neurodegeneration, endothelial activation, oxidative stress, and iron dysregulation are associated with worse cognition in people with HIV. Some animal studies focused on myeloid cells of the central nervous system, but other animal and human studies showed that lymphoid cells also contribute to HIV neuropathogenesis. The deleterious central nervous system effects of polypharmacy and anticholinergic drugs in people with HIV were demonstrated. In contrast, a large randomized controlled trial showed that integrase strand transfer inhibitor therapy was not associated with neurotoxicity. Studies of cryptococcal meningitis demonstrated he cost-effectiveness of single high-dose liposomal amphotericin and the prognostic value of the cryptococcal antigen lateral flow assay. People hospitalized with COVID-19 had more anxiety over time after discharge. The SARS-CoV-2 nucleocapsid antigen is present in cerebrospinal fluid in the absence of viral RNA. Systemic inflammation, astrocyte activation, and tryptophan metabolism pathways are associated with post-COVID-19 neurologic syndromes. Whether these processes are independent or intertwined during HIV-1 and COVID-19 infections requires further study.

The 2021 Conference on Retroviruses and Opportunistic Infections (CROI) featured a timely review of the neurologic complications of COVID-19 as well as new research findings on mechanisms by which SARS-CoV-2 may affect the brain. CROI included new and important findings about the neurologic complications of HIV-1, human polyomavirus 2 (also known as JC Virus), and cryptococcus. New long-term analyses of cognition in people with HIV-1 identified that cognitive decline over time is associated with multimorbidity, particularly diabetes, chronic lung disease, and vascular disease risk conditions. These conditions are associated with aging, and the question of whether people with HIV are at risk for premature aging was addressed by several reports. New findings from large analyses of resting state networks also provided valuable information on the structural and functional networks that are affected by HIV-1 infection and cognitive impairment. Several reports addressed changes after initiating or switching antiretroviral therapy (ART). Findings that will improve understanding of the biologic mechanisms of brain injury in people with HIV were also presented and included evidence that host (eg, myeloid activation, inflammation, and endothelial activation) and viral (eg, transcriptional activity and compartmentalization) factors adversely affect brain health. Other research focused on adjunctive therapies to treat HIV-1 and its complications in the central nervous system. This summary will review these and other findings in greater detail and identify key gaps and opportunities for researchers and clinicians.

The etiology and pathogenesis of human immunodeficiency virus type-I (HIV)-associated neurocognitive disorders (HAND) remain undetermined and are likely the produce of multiple mechanisms. This can mainly include neuronal injury from HIV, inflammatory processes, and mental health issues. As a result, a variety of treatment options have been tested including NeuroHIV-targeted regimens based on the central nervous system (CNS) penetration effectiveness (CPE) of antiretroviral therapy (ART) and adjuvant therapies for HAND. NeuroHIV-targeted ART regimens have produced consistent and statistically significant HIV suppression in the CNS, but this is not the case for cognitive and functional domains. Most adjuvant therapies such as minocycline, memantine, and selegiline have negligible benefit in the improvement of cognitive function of people living with HIV (PLWH) with mild to moderate neurocognitive impairment. Newer experimental treatments have been proposed to target cognitive and functional symptoms of HAND as well as potential underlying pathogenesis. This review aims to provide an analytical overview of the clinical treatment options and clinical trials for HAND by focusing on NeuroHIV-targeted ART regimen development, CPE, and adjuvant therapies.

Purpose of review

Cognitive impairment and depression continue to be common among people with HIV (PWH) in the combination antiretroviral therapy (ART) era. A better understanding of the biological mechanisms that may underpin these disorders is needed. The purpose of this review is to describe published findings on soluble biomarkers from blood and cerebrospinal fluid (CSF) that have been associated with either cognition or depression among PWH in the setting of ART.

Recent findings

Several biomarkers, including those that reflect viral persistence, monocyte/macrophage activation, and other processes, are associated with cognition and depressive symptoms. Some but not all results have been consistent across multiple studies. More research has been published on biomarkers of cognition relative to biomarkers of depression (particularly from CSF). More studies are needed that investigate multiple biomarkers to understand the role of distinct but additive pathways in these disorders and to guide the development of new therapies.

The accumulation of soluble proteins and metabolites during wakefulness and their clearance during sleep via the glymphatic system occurs in healthy adults and is disturbed in some neurological conditions. Such diurnal variations in the cerebrospinal fluid (CSF) proteins produced outside the central nervous system and entering via the blood-brain barrier (BBB) have not been evaluated in people with HIV (PWH). CSF and blood were collected in 165 PWH at six US centers between 2003 and 2007. The time of collection was compared to CSF albumin, globulin, and total protein concentrations using bivariate and multivariate regression. Participants all took antiretroviral therapy (ART) and were mostly middle-aged (median age 44.0 years) men (78.8%), with AIDS (77.0%), plasma HIV RNA ≤ 200 copies/mL (75.8%), and immune recovery (median CD4+ T-cell count 414/µL). CSF was collected at median 1:10 p.m. (range 9:00 a.m. to 5:20 p.m.) and within a median of 15 min of blood collection. A later time of CSF collection was associated with higher total protein (p = 0.0077) and albumin (p = 0.057) in CSF but not in serum, and was additionally associated with higher CSF globulin (p = 0.013). The glymphatic clearance of albumin, globulin, and total protein is preserved in PWH. The analyses of soluble biomarkers in CSF should account for the time of collection.

Background

Integrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection. During HIV infection, macrophages can extravasate from the blood to the brain, while producing chemotaxic proteins and cytokines, which have detrimental effects on central nervous system cells. The main goal of this study was to understand the effects of raltegravir (RAL) on human brain macrophage production of immune-mediators when infected with HIV, but did not compare with other antiretroviral agents.

Methods

Pro-inflammatory cytokines, IFN-γ, IL-10, IL-12-p70, IL-1, IL-8, TNF-α, and IL-6 were measured simultaneously in tissue culture supernatants from primary brain derived macrophages, microglia. We tested the effects of RAL on markers of astrocytosis and neurite integrity in primary human neuroglial cultures.

Results

RAL administered at 20 nM effectively suppressed HIV infection in microglia over 9 days. Only IL-8, IL-10, and TNF-α were above the detection limit in the majority of samples and RAL significantly suppressed the rate of cytokine production in HIV-infected microglia. During RAL-alone, the rate of IL-8 secretion was higher.

Conclusions

RAL did not affect neurite area but inhibited astrocyte growth in the neuroglial cultures. Exploring the effects of RAL on pro-inflammatory molecule production in brain macrophages may contribute to designing ARV neuroprotective strategies in chronic HIV infection.

Objective

HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition.

Methods

Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores.

Results

HIV significantly interacted with METH (P < 0.001) such that compared with HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d = 0.96; HIV-/METH+: d = 0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d = 0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r = -0.19), learning (r = -0.23), and delayed recall (r = -0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH- groups (ie, HIV-/METH- and HIV+/METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (ie, HIV-/METH+, HIV+/METH+).

Discussion

HIV and METH independently, but not additively, relate to noradrenergic excess in the central nervous system, and perturbations to noradrenergic function may represent a pathophysiological mechanism of HIV-related neurocognitive dysfunction. Consistent with prior reports that noradrenergic excess compromises hippocampal and prefrontal function, higher NE related to worse neurocognition, even among successfully treated persons with HIV. Pharmacological and psychosocial interventions that stabilize NE function may improve neurocognition in persons with HIV.

Human immunodeficiency virus (HIV)-associated cognitive disorders (HAND) is characterized by impaired motor and intellectual functions, as well as mood disorders. Brain-derived neurotrophic factor and its receptor TrkB (or NTRK2) mediate the efficacy of antidepressant drugs. Genomic studies of BDNF/TrkB have implicated common single-nucleotide polymorphisms in the pathology of depression. In the current study, we investigated whether single-nucleotide polymorphisms (SNPs) (rs1212171, rs1439050, rs1187352, rs1778933, rs1443445, rs3780645, rs2378672, and rs11140800) in the NTRK2 has a functional impact on depression in HIV-positive subjects. We have utilized the Central Nervous System (CNS) HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. Our methods explored the univariate associations of these SNPs with clinical (current and lifetime) diagnosis of depression via chi-square. The distribution of alleles was significantly different for African-Americans and Caucasians (non-Hispanic) for several SNPs, so our regression analyses included both "statistical controls" for race group and models for each group separately. Finally, we applied a method of simultaneous analysis of associations, estimating the mutually shared information across a system of variables, separately by race group. Our results indicate that there is no significant association between clinical diagnosis of major depression and these SNPs for either race group in any analysis. However, we identified that the SNP associations varied by race group and sex.