Neurologic conditionsassociated with HIV remain major contributors to morbidity and mortality, and are increasingly recognizedin the aging population of individuals living with HIV who are receiving long-standingcombination 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 HIVare on continuing ART, which is widely recognized to offer a much extended lifeexpectancy to approximately the lifespan of people without HIV; however, asmany as one-half of patients also have neurocognitive dysfunction.1,3Prior 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 theHopkins Global Neurology Program at Johns Hopkins University School of Medicine inBaltimore, Maryland. In the ART era, the overallprevalence of HAND is unchanged, but we have seen a dramatic shift from themost severe forms to milder forms of HAND such as asymptomatic neurocognitiveimpairment and mild neurocognitive disorder. HAND is no longer a relentlesslyprogressive 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.

DrMcArthur coauthored a 2019 study by Dastgheyb et al4 thatdistinguished 4 phenotypes of neurocognitive dysfunction, including verbalfluency, executive function, learning and recall, and motor function. Thissmall study of 38 women helps to illuminate that HAND is not stereotypic fromone individual to another, he observed, and contains variations which may beexplainable by where the virus is in the brain or by other inherentcharacteristics of the patient, such as traumatic brain injury of acceleratedvascular disease.

HIV Reservoir in the Brain

Oneof the ongoing challenges to effective treatment of HAND is the discovery thatthe brain may serve as a reservoir for HIV replication, even when systemicviral suppression has been achieved.2,5 We know that HIV DNA can beisolated from the spinal fluid, even in individuals who are on antiretroviralsand it suggests that there is still perhaps a small but still quite importantreservoir of HIV within the central nervous system, Dr McArthur pointed out,which explains how a recurrent reseeding of infection from the brain can keepthe virus alive despite effective therapy.

Monocyte Activation

Itnow appears that a core driver for the development of HAND is cellularactivation of monocytes, macrophages, and microglia in the brain. High levelsof monocyte activation have been reported in patients with long-standing HIVmanaged by cART. The COBRA study of 134 PLHIV on cART and 79 non-HIV-infectedcontrols reported plasma markers showing high levels of monocyte activation,inflammation, and intestinal damage in the HIV cohort that were all predictiveof mortality and morbidity in treated HIV patients. At the same time, systemicT-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 dont 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

Newavenues of research that aim to explore potential eradication of the virus byfirst eliminating the CNS reservoir are needed, Dr Saylor noted, as well as thedevelopment of treatments that fully normalize systemic and CNSinflammation.Current ART regimens reduce but do not normalize systemicand CNS inflammation, and we believe many of the non-infectious complicationsof 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 existingHIV-associated cognitive impairment.

DrMcArthur also highlighted that the dynamics of how the virus is produced andeliminated in specific cell types such as macrophages and microglia is quitedifferent than in the major cellular target in the body, the T-lymphocyte. Weneed to understand much more about the viral dynamics in the central nervoussystem, he said.

References

1. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorderpathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12(4):234-48.

2. D Saylor. Neurologic Complications of Human Immunodeficiency Virus Infection.

Continuum (Minneap Minn)2018;24:1397-1421.

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;82:6170.

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.

Excerpt from:
Neurocognitive Conditions Among People Living With HIV - Infectious Disease Advisor