Neurologic conditions associated with HIV remain major contributors to morbidity and mortality, and are increasingly recognized in the aging population of individuals living with HIV who are receiving long-standing combination antiretroviral therapy (cART).
Neurologic complications are common among individuals who are not receiving treatment for HIV as a result of immunosuppression caused by the infection, but are also widely reported after establishing a treatment regimen. Although the advent of ART, and particularly cART, have successfully reduced the risk for progression of HIV-associated neurocognitive disorders (HAND), these therapies are not effective in all patients, and thus allow for the development of neurocognitive dysfunction.2 In addition, during the early stages of infection, HIV can readily enter the central nervous system (CNS), where a persistent reservoir of HIV infection and inflammation serves to re-infect healthy cells to produce symptoms of HAND, despite therapy.1,2 And finally, drug toxicity from cART may also contribute to the development of HAND.1,2
The Evolution of HAND
The majority of patients diagnosed with HIV are on continuing ART, which is widely recognized to offer a much extended life expectancy to approximately the lifespan of people without HIV; however, as many as one-half of patients also have neurocognitive dysfunction.1,3 “Prior to the ART era, HIV-associated dementia, the most severe form of HAND, was common in patients with AIDS and was generally irreversible,” noted Deanna Saylor, MD, MHS, director of the Hopkins Global Neurology Program at Johns Hopkins University School of Medicine in Baltimore, Maryland. “In the ART era, the overall prevalence of HAND is unchanged, but we have seen a dramatic shift from the most severe forms to milder forms of HAND such as asymptomatic neurocognitive impairment and mild neurocognitive disorder. HAND is no longer a relentlessly progressive disease,” she said.
Further, Justin C McArthur, MBBS, MPH, director of the department of neurology at Johns Hopkins Hospital and founding director the of the Johns Hopkins/National Institute of Mental Health Research Center for Novel Therapeutics of HIV-associated Cognitive Disorders in Baltimore, Maryland, has observed that as many as 50% of the current population living with HIV is now aged >50 years, and living with the infection as a long-term condition, putting them at risk for a potentially milder form of a combination of HIV- and age-related cognitive impairment. “Because of the potency of antiretrovirals and the strategies to treat everyone as early as possible, the spectrum of HIV-associated neurocognitive dysfunction has really shifted from what could be a severe disease with frank dementia and neurologic depth to a much milder type of disorder that is really analogous to [mild cognitive impairment] outside the disease spectrum,”he said.
Dr McArthur coauthored a 2019 study by Dastgheyb et al4 that distinguished 4 phenotypes of neurocognitive dysfunction, including verbal fluency, executive function, learning and recall, and motor function. This small study of 38 women helps to illuminate that HAND is not stereotypic from one individual to another, he observed, and contains variations which may be explainable by where the virus is in the brain or by other inherent characteristics of the patient, such as traumatic brain injury of accelerated vascular disease.
HIV Reservoir in the Brain
One of the ongoing challenges to effective treatment of HAND is the discovery that the brain may serve as a reservoir for HIV replication, even when systemic viral suppression has been achieved.2,5 “We know that HIV DNA can be isolated from the spinal fluid, even in individuals who are on antiretrovirals and it suggests that there is still perhaps a small but still quite important reservoir of HIV within the central nervous system,” Dr McArthur pointed out, which explains how a recurrent reseeding of infection from the brain can keep the virus alive despite effective therapy.
It now appears that a core driver for the development of HAND is cellular activation of monocytes, macrophages, and microglia in the brain. High levels of monocyte activation have been reported in patients with long-standing HIV managed by cART. The COBRA study of 134 PLHIV on cART and 79 non-HIV-infected controls reported plasma markers showing high levels of monocyte activation, inflammation, and intestinal damage in the HIV cohort that were all predictive of mortality and morbidity in treated HIV patients. At the same time, systemic T-cell activation in HIV did not have predictive value.6,7
“Monocytes are cells that circulate in the blood and occasionally are found in the , but we think most of the reservoir in the brain and in the meninges are actually in tissue macrophages and in the microglia,” Dr McArthur explained. “These are cells that tend not to migrate. They don’t move around like monocytes, they just sit there, but they can potentially induce or spread infection to other cells that are moving past them.” As the “mobile cells continue to travel, the infection is reintroduced into the spinal fluid, lymphatic circulation, and back into the blood,” he added.
Areas for Future Research
New avenues of research that aim to explore potential eradication of the virus by first eliminating the CNS reservoir are needed, Dr Saylor noted, as well as the development of treatments that fully normalize systemic and CNS inflammation. “Current ART regimens reduce but do not normalize systemic and CNS inflammation, and we believe many of the non-infectious complications of chronic HIV infection are related to persistent low levels of inflammation, including stroke, dementia and other systemic complications,” she said. Moreover, she pointed to the need for new more effective treatments to improve existing HIV-associated cognitive impairment.
Dr McArthur also highlighted that the dynamics of how the virus is produced and eliminated in specific cell types such as macrophages and microglia is quite different than in the major cellular target in the body, the T-lymphocyte. “We need to understand much more about the viral dynamics in the central nervous system,” he said.
1. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder–pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12(4):234-48.
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3. Nightengale S, Winston A, Letendre S, et al. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol. 2014;13:1139-1151.
4. Dastgheyb RM, Sacktor N, Franklin D, et al. Cognitive Trajectory Phenotypes in Human Immunodeficiency Virus-Infected Patients. J Acquir Immune Defic Syndr. 2019;82:61–70.
5. Wong ME, Jaworowski A, Hearps AC. The HIV Reservoir in Monocytes and Macrophages Front Immunol. 2019;10:1435. doi:10.3389/fimmu.2019.01435
6. Booiman T, Wit FW, Maurer I, et al. High Cellular Monocyte Activation in People Living With Human Immunodeficiency Virus on Combination Antiretroviral Therapy and Lifestyle-Matched Controls Is Associated With Greater Inflammation in Cerebrospinal Fluid. Open Forum Infect Dis. 2017;4:ofx108.
7. Wright EJ, Thakur KT, Bearden D, Birbeck GL. Global developments in HIV neurology. Handb Clin Neurol. 2018;152:265-287.