Early in the epidemic, one of the most terrifying consequences of late-stage, AIDS-related illness was the various neurocognitive disorders, the worst of which was dementia. At that time, with no effective antiretroviral therapies, the virus quickly penetrated the blood-brain barrier. AIDS dementia complex, along with early opportunistic infections (OI) such as Kaposi sarcoma and Mycobacterium avium complex (MAC), typically occurred when a person's CD4 count fell below 200, but it was the result of the virus itself, not an OI. Individuals who experienced this severe dementia declined rapidly and tragically.
Fortunately, the advent of combination antiretroviral therapies (ART) has greatly reduced the severity of HIV-associated dementia, but other HIV-associated neurocognitive disorders (HAND) remain pervasive. Among these, symptoms are typically much less severe than earlier, but they remain highly concerning because they impact cognitive processing, memory, and motor skills.
HAND-related symptoms are often indistinguishable from cognitive impairment due to other causes. They include short attention span, memory loss, mood disorders, irritability, poor judgment, confusion, and impairment of fine motor skills. There are three classifications of HAND: 1) asymptomatic cognitive impairment (some decline, but it doesn't impair functioning); 2) mild neurocognitive disorder (a noticeable change in performance of everyday tasks); and 3) HIV-associated dementia, the more severe form described above that was common early in the epidemic. Significantly, it is estimated that half of people living with HIV, despite viral suppression, fall into either of the first two classifications: asymptomatic or mild.
Despite significant advances in the biomedical treatment of HIV-related conditions, the pathogenesis, diagnosis, and treatment of HAND remains poorly understood. As the number of aging people living with HIV expands, it is more important than ever to better understand HAND and develop clinical interventions. Here is a summary of some of this research:
When Does Pathological Involvement With the Central Nervous System First Occur?
The central nervous system (CNS) has long been recognized as a target of HIV. The most severe forms of neurocognitive disorders, such as AIDS-associated dementia, are related to severe immunosuppression. It was hoped that ART would reduce the severity of neurocognitive impairment, but people with undetectable viral loads remain at significant risk for more mild forms. A 2015 study by Zaina Zayyad, M.D., Ph.D., suggests that HIV neuropathogenesis may begin with the initial viral entry into the CNS, followed by processes including neuroinflammation and neurotoxicity, and the establishment of local and compartmentalized HIV replication in brain tissue. A better understanding of when and how HIV establishes local infection in the CNS, which CNS cells are the primary target of HIV, and the process by which neurons are damaged by HIV will significantly improve both the diagnosis and treatment of HAND.
What Are the Biomarkers for HAND?
Because the diagnosis of HIV-associated neurocognitive disorders relies on imprecise neuropsychometric assessments, a diagnostic biomarker would be extremely useful. A 2017 study published in Viruses proposed that the pathogenesis of HAND begins outside the brain, particularly in the peripheral blood. The researchers found that the total HIV DNA in the peripheral blood mononuclear cells (PBMCs) correlates with disease progression and could be a promising biomarker to predict HAND. These analyses are done by PCR assays (a laboratory method that can create large amounts of genetic material from a small sample). But assessments of HIV DNA in cell compartments are complex, because of a lack of standardization, which limits their utilization in predicting HAND. In this review, the clinical relevance of total HIV DNA in circulating mononuclear cells is evaluated using different PCR protocols in order to identify those that can accurately predict severity of neurocognitive impairment. Examining the role of monocytes as the carrier of HIV into the CNS makes it a valuable indicator for determining a HAND-associated reservoir. Cost-effective PCR assays may prove to be important in identifying biomarkers for HAND.
Can Various Risk Profiles Be Discerned?
A 2018 study used latent profile analysis (LPA) of neuropsychological tests and machine learning to define neurocognitive performance profiles and identify their associated risk factors in people with HIV receiving ART. Three profiles emerged: Profile 1 exhibited the highest cognitive performance; profile 2 displayed reduced executive function (the cognitive control of behavior) and verbal memory (words and other language-based abstractions); and profile 3 had global impairment. Not having been born in North America was the dominant predictor of profile 3, followed by female sex and toxoplasma seropositivity. Additional predictors included unemployment, current depressive symptoms, a lower CD4 nadir, and longstanding HIV. Specifically in North Americans, higher levels of HIV in cerebrospinal fluid (CSF) and older age predicted profile 3. HAND diagnoses occurred most commonly in profile 3 (89.8%), followed by the group with reduced higher-order neurocognitive performance (profile 2 = 16.6%).
What Role Is Played by Host Genetics?
The pathogenesis and risk factors of HAND are still not completely understood, partly due to the complexity of HAND phenotypes, which present with high variability and change over time. The role of host (human) genetics determines, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. A review called "Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics" looked at studies that investigated the role of human host genetics in the pathogenesis and risk factors of HAND. While variations in host genes that regulated immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, the review finds that a few specific gene variants affect the risk for developing HAND. Identifying these will improve our understanding of HAND pathogenesis and potential treatments.
How Has Pathogenesis of HAND Changed With Antiretroviral Therapy?
As noted earlier, despite widespread use of ART and higher rates of undetectable viral loads, HAND remains a common complication of HIV. It now typically occurs in earlier stages of HIV infection, and the clinical course differs from before. An article published in the Journal of Neurology reviewed these distinctions and possible variations in pathogenesis. Today, the predominant clinical feature remains a subcortical dementia with deficits in the domains of concentration, attention, and memory, but motor signs such as gait disturbance and impaired manual dexterity have become less prominent. The authors note that, prior to ART, cerebral dysfunction could at least partially be explained by viral load and virus-associated complications. In subjects with undetectable or at least very low viral load, the pathogenic virus-brain interaction appears to be less direct, implicating an array of poorly understood immunological and (probably) toxic phenomena.
What Is the Relationship Between Vascular Cognitive Impairment (VCI) and HAND?
It has been proposed that VCI is clinically linked to the persistence of mild forms of HAND in aging people living with HIV. A new study in the Journal of Neurovirology proposes more fundamental links between VCI and HAND, noting that the neuropsychological and neuroimaging phenotypes of VCI and HAND largely overlap, suggesting that further research is needed to accurately distinguish them. The researchers also linked VCI and HAND at the biomechanical level by proposing that the neuro-vascular unit (NVU, the structural cellular composition of neurons, astrocytes, and endothelium) may be the primary target of HIV-related brain injury in treated HIV infection. They propose that the potential contribution of vascular damage to overall brain damage in aging people living with HIV is probably much higher than currently estimated, because of methodological limitations and because this research is only emerging. They also note that VCI risk factors are more prevalent, occur earlier, and are sometimes accelerated in the HIV-positive population at large, significantly increasing the risk for neurocognitive disorders over the age of 60.
As neurocognitive disorders continue to afflict people living with HIV, including those with undetectable viral loads, new research is illuminating more details about the pathogenesis, diagnosis, and treatment of these conditions.