Dr. Kallianpur’s team found that higher levels of the iron-delivery proteins heavy-chain ferritin and transferrin predict better cognitive outcomes in people with HIV, independent of factors like inflammation, over an extended period of follow-up.
Cognitive performance in people with HIV (PWH) may be predicted by levels of two proteins involved in iron delivery and myelin maintenance, according to a new Cleveland Clinic-led study published in Molecular Neurobiology.
PWH remain at high risk for developing problems with cognitive and/or motor function, known collectively as HIV-Associated Neurocognitive Disorder (HAND), for which there is currently no effective treatment. HAND develops and often progresses despite effective antiretroviral therapy and suppressed HIV replication, highlighting the need to better understand the underlying mechanisms in order to identify novel preventive and treatment strategies.
HAND has been linked to significant degradation and/or loss of myelin, the fatty substance that surrounds nerve fibers and facilitates rapid transmission of nerve impulses in the central nervous system. Iron is essential for the production of myelin and for the survival of the cells that synthesize it (oligodendrocytes), but the role of iron transport in HAND is largely unexplored.
In this study, the researchers investigated two major iron-delivery proteins, which are also involved in the synthesis and preservation of myelin—heavy-chain ferritin (Fth1) and transferrin—as potential predictors of cognitive function over time in PWH, including virally suppressed persons.
“To our knowledge, this represents the first prospective study to evaluate the role of these proteins in cognitive impairment among PWH,” said Asha Kallianpur, MD, MPH, associate staff in the Genomic Medicine Institute and the study’s corresponding author. “It also happens to be the first study, of which we are aware, to identify a neuroprotective role for the distinct, heavy-chain form of ferritin in humans. Our findings provide a rationale for further investigation into how Fth1 and transferrin might be targeted to prevent or treat the cognitive decline often seen in PWH.”
In collaboration with investigators at Penn State/Hershey Medical Center, the researchers measured levels of Fth1, transferrin and biomarkers of inflammation in the cerebrospinal fluid (CSF) of more than 400 PWH enrolled in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study, based at the University of California-San Diego. All study participants had undergone neuromedical and psychiatric evaluations, as well as comprehensive testing to assess cognitive performance. Follow-up assessments, with or without CSF sampling, occurred every six months for up to three and a half years.
They found that PWH who had the highest levels of CSF Fth1 and transferrin at baseline had consistently better cognitive function at up to 30, 36 and/or 42 months compared to PWH who had the lowest levels of these proteins, adjusting for key factors, such as CSF inflammation. Fth1 was particularly protective in PWH who had no detectable plasma virus, were under the age of 50 or had minimal comorbidity. Transferrin was most neuroprotective in individuals with detectable HIV in plasma and heightened inflammation.
“We speculate that higher CSF levels of these critical proteins protect both developing and myelinating oligodendrocytes from inflammation-induced iron deficiency in PWH, thereby preserving cognitive function,” said Dr. Kallianpur. “With new NIH funding, we hope to confirm our results in a much larger study with many more women and older PWH, and to further evaluate interactions between these iron-related proteins, age, genetic factors and comorbid conditions. However, this study indicates that Fth1 and transferrin might have a role to play in interventions to prevent HAND or halt its progression.”
Harpreet Kaur, PhD, a postdoctoral fellow in Dr. Kallianpur’s lab, is first author on the study, which was also a collaboration with team members at Case Western Reserve University (William Bush, PhD), UC-San Diego and Vanderbilt. The work was supported by the National Institutes of Mental Health, part of the National Institutes of Health.
Dr. Kallianpur will investigate if kidney disease and cognitive impairment in people with HIV share an underlying mechanism and potentially highlight non-invasive biomarkers for these disorders.
Dr. Kallianpur’s team will investigate the role of iron in depression and cognitive impairment in people with HIV.