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.

HIV-associated neurocognitive disorders (HAND) persist in the era of effective combined antiretroviral therapy (cART). A large body of literature suggests that mitochondrial dysfunction is a prospective etiology of HAND in the cART era. While viral load is often suppressed and the immune system remains intact in HIV+ patients on cART, evidence suggests that the central nervous system (CNS) acts as a reservoir for virus and low-level expression of viral proteins, which interact with mitochondria. In particular, the HIV proteins glycoprotein 120, transactivator of transcription, viral protein R, and negative factor have each been linked to mitochondrial dysfunction in the brain. Moreover, cART drugs have also been shown to have detrimental effects on mitochondrial function. Here, we review the evidence generated from human studies, animal models, and in vitro models that support a role for HIV proteins and/or cART drugs in altered production of adenosine triphosphate, mitochondrial dynamics, mitophagy, calcium signaling and apoptosis, oxidative stress, mitochondrial biogenesis, and immunometabolism in the CNS. When insightful, evidence of HIV or cART-induced mitochondrial dysfunction in the peripheral nervous system or other cell types is discussed. Lastly, therapeutic approaches to targeting mitochondrial dysfunction have been summarized with the aim of guiding new investigations and providing hope that mitochondrial-based drugs may provide relief for those suffering with HAND.

Persistent inflammation occurs in people with HIV (PWH) and has many downstream adverse effects including myocardial infarction, neurocognitive impairment and death. Because the proportion of people with HIV who use cannabis is high and cannabis may be anti-inflammatory, it is important to characterize the impact of cannabis use on inflammation specifically in PWH. We performed a selective, non-exhaustive review of the literature on the effects of cannabis on inflammation in PWH. Research in this area suggests that cannabinoids are anti-inflammatory in the setting of HIV. Anti-inflammatory actions are mediated in many cases through effects on the endocannabinoid system (ECS) in the gut, and through stabilization of gut-blood barrier integrity. Cannabidiol may be particularly important as an anti-inflammatory cannabinoid. Cannabis may provide a beneficial intervention to reduce morbidity related to inflammation in PWH.

A 22-year-old man presented to the emergency department with 10 days of malaise, generalized rash, sore throat, oral ulcers, headache, nausea, and vomiting. On examination he had fever (101.5°F), hepatosplenomegaly, generalized maculopapular rash, and lymphadenopathy. He rapidly became obtunded, requiring intubation. Initial laboratory studies showed mild transaminitis, increased lactate dehydrogenase, and 4,600 leukocytes per μL with 61% bands and 18% lymphocytes. Bacterial and fungal blood cultures were negative as well as a rapid HIV test, additional serologies (including rapid plasma reagin and Treponema pallidum particle agglutination), quantitative PCRs (for viruses other than HIV), and urine and blood toxicology. CSF, on hospital day 4, showed a lymphocytic pleocytosis (total leukocytes: 100), high protein, borderline hypoglycorrhachia, and negative Gram stain and culture. Brain MRI revealed no meningeal enhancement or masses. EEG revealed no epileptiform activity. Flow cytometry on bone marrow biopsy and CSF found no evidence of malignancy; neither did an excisional lymph node biopsy (figure 1). An immunofluorescent assay test for HIV returned inconclusive and a Western blot detected HIV gp120/gp160 bands. Quantitative HIV RNA PCR was 1.4 × 10⁶ copies/mL in plasma and in CSF exceeded the upper limit of quantitation (10⁷ copies/mL) (figure 2).

Background

Immunocompromised patients are at increased risk for developing meningitis or, rarely, brain abscess with opportunistic organisms like Listeria monocytogenes.

Case report

A 52 year-old Saudi Arabian woman who was diagnosed with pemphigus vulgaris and diabetes and had been on prednisolone and azathioprine for about 4 years. She presented with headache, low-grade fever, and left-sided weakness 2 weeks after receiving the second dose of rituximab infusion. Magnetic resonance imaging revealed an enhanced space-occupying lesion with multiple small cyst-like structures and vasogenic edema in the right temporoparietal area. Her blood culture was positive for Listeria monocytogenes, and a brain biopsy showed necrotic tissues with pus and inflammatory cells. She recovered after a 6-week course of antibiotics with ampicillin and gentamycin.

Conclusions

Brain abscess due to Listeria monocytogenes is a risk that should be considered when adding rituximab to the regimen of a patient who is already Immunocompromised.

The purpose of this brief review is to prepare readers who may be unfamiliar with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) and the rapidly accumulating changes in the epidemic by providing an introduction to HIV disease and its treatment. The general concepts presented here will facilitate understanding of the papers in this issue on HIV-associated neurocognitive disorders (HAND). Toward that end, we briefly review the biology of HIV and how it causes disease in its human host, its epidemiology, and how antiretroviral treatments are targeted to interfere with the molecular biology that allows the virus to reproduce. Finally, we describe what is known about how HIV injures the nervous system, leading to HAND, and discuss potential strategies for preventing or treating the effects of HIV on the nervous system.

Background

Age-related comorbidities accumulate faster in people with HIV (PWH) than in those without HIV. We evaluated whether a validated multimorbidity scale, the Charlson index, predicted neurocognitive trajectories in PWH.

Methods

Scaled scores of a comprehensive neuropsychological battery were averaged across all visits. Multilevel modeling examined between- and within-person predictors of global neurocognition. At the between-person level, averaged Charlson scores were examined as a predictor of neurocognitive change rate, covarying for HIV disease characteristics. Within-persons, visit-specific Charlson index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for disease measures.

Results

Participants were 1195 PWH (mean baseline age: 43.0; SD: 9.7 years) followed for a mean of 7.1 years (range: 0.5-20.5). At the between-person level, more rapid neurocognitive worsening correlated with higher (worse) average Charlson scores (standardized β: -0.062; SE: 0.015; P = .001) and lower CD4 nadir (standardized β: 0.055; SE: 0.021; P = .011), but not viral suppression or average CD4+ lymphocytes (P > .05). At the within-person level, poorer visit-specific neurocognition was related to worse concurrent, but not preceding, Charlson scores (standardized β: -0.046; SE: 0.015; P = .003), detectable HIV viral load (standardized β: 0.018; SE: 0.006; P = .001), and higher CD4+ (standardized β: 0.043; SE: 0.009; P < .001).

Conclusions

The impact of comorbidities on neurocognitive decline exceeded that of HIV disease factors. Although correlative, the temporal relationships suggested that treatment of comorbidities might improve neurocognitive prognosis for PWH.

People living with HIV infection (PWH) disclose that cannabis is an effective strategy for alleviating symptoms associated with HIV disease. However, some medical providers feel ill-informed to engage in evidence-based conversations. HIV leads to alterations in the gut microbiome, gut-brain axis signaling, and chronic inflammation. The endocannabinoid system regulates homeostasis of multiple organ systems. When deficient, dysregulation of the gut-brain axis can result in chronic inflammation and neuroinflammation. Cannabis along with the naturally occurring endocannabinoids has antioxidant and anti-inflammatory properties that can support healing and restoration as an adjunctive therapy. The purpose of this literature review is to report the physiologic mechanisms that occur in the pathology of HIV and discuss potential benefits of cannabinoids in supporting health and reducing the negative effects of comorbidities in PWH.

The development of novel antiretroviral treatments has led to a significant turning point in the fight against HIV. Although therapy leads to virologic suppression and prolonged life expectancies, HIV-associated neurocognitive disorder (HAND) remains prevalent. While various hypotheses have been proposed to explain this phenomenon, a growing body of literature explores the neurotoxic effects of antiretroviral therapy. Research to date brings into question the potential role of such medications in neurocognitive and neuropsychiatric impairment seen in HIV-positive patients. This review highlights recent findings and controversies in cellular, molecular, and clinical neurotoxicity of antiretrovirals. It explores the pathogenesis of such toxicity and relates it to clinical manifestations in each medication class. The concept of accelerated aging in persons living with HIV (PLWH) as well as potential treatments for HAND are also discussed. Ultimately, this article hopes to educate clinicians and basic scientists about the neurotoxic effects of antiretrovirals and spur future scientific investigation into this important topic. Graphical Abstract.

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.