HIV News: International Study led By University Of Southern California Shows Degree Of Brain Damage Inflicted By Immunosuppression and HIV Viral Load

HIV News: A new international study led by the University of Southern California, involving various other research entities including University of Cape Town-South Africa,Thai Red Cross AIDS Research Centre-Thailand, University of Amsterdam-Netherlands, Washington University School of Medicine-USA, Missouri University of Novi Sad-Serbia ,University of New South Wales-Australia, University of California Los Angeles-USA and Cote d’Azur University-France have found that the HIV affects brain volumes and other cognitive issues in infected patients over time.


 
In this research the study team wanted to investigate HIV plasma markers that are universally used to monitor immune function and treatment response associated with subcortical brain volumes in clinically and demographically heterogeneous HIV-infected individuals.
 
Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date.
 
The study was aimed to examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4⁺ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide.
 
This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019.
Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4⁺ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status.
 
The study findings showed that after quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4⁺ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm³ per 100 cells/mm³; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm³ per 100 cells/mm³; P < .001) volumes and larger ventricles (mean [SE] β = −391.50 [122.58] mm³& ;nbsp;per 100 cells/mm³; P = .001); in participants not taking cART, however, lower current CD4⁺ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm³ per 100 cells/mm³; P = .003). A dVL was associated with smaller hippocampal volumes (d = −0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = −0.23; P = .004).
 
The study findings concluded that in a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. The findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
 
The study findings were published in the peer reviewed journal: JAMA Network Open, an open-access journal from the American Medical Association. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2775217
 
Currently almost 40 million people around the world are living with HIV, which, with access to treatment, has become a lifelong chronic condition.
 
Detailed understanding how infection changes the brain, especially in the context of aging, is increasingly important for improving both treatment and quality of life.
 
Researchers from the Mark and Mary Stevens Neuroimaging and Informatics Institute (USC Stevens INI), part of the Keck School of Medicine of USC, and other international NeuroHIV researchers, published one of the largest-ever neuroimaging studies of HIV.
 
The study team pooled magnetic resonance imaging (MRI) data from 1,203 HIV-positive individuals across the world.
 
Dr Talia Nir, PhD, postdoctoral scholar at the Univerity of Southern California (USC) Stevens INI's Laboratory of Brain eScience (LoBeS) and first author of the study told Thailand medical News, “Brain injury caused by HIV can lead to cognitive challenges, even in those receiving treatment. Establishing a common pattern of effects on the brain across different populations is a key step toward addressing those issues. The strength of this large dataset is that it is more representative of an era where treatment for HIV infection is widely available."
 
The study team looked at the link between blood plasma, which is routinely collected to monitor immune function and treatment response, and the volume of various structures in the brain. Lower white blood cell counts generally indicate that the immune system is being suppressed.
 
Here, the team found, for example, that participants with lower white blood cell counts also had less brain volume in the hippocampus and thalamus, parts of the brain's limbic system involved in regulating memory, emotion and behavior.
 
The study findings are important because they were largely derived from brain scans of individuals undergoing antiretroviral therapy--and they indicate that people receiving such treatment may exhibit a different brain injury signature compared to untreated individuals, which earlier studies tended to focus on.
 
The findings highlight deficits in brain areas that are also vulnerable to age-related neurodegenerative diseases.
 
Importantly accelerated atrophy of the hippocampus, the region that showed the most consistent effects in the study, is a hallmark of neurodegenerative diseases such as Alzheimer's disease. Common age and HIV-related pathological processes, such as inflammation and blood brain barrier impairment, may accelerate age-related neurodegenerative processes.
 
The hippocampus had consistent associations with both CD4+ cell count and VL measures. In postmortem studies, hippocampal tissue has some of the highest viral concentrations. Hippocampal neurons also have increased gliosis and HIV chemokine coreceptors and expression and may be particularly susceptible to Tat-induced apoptosis. https://pubmed.ncbi.nlm.nih.gov/9546286/
https://pubmed.ncbi.nlm.nih.gov/11305873/
https://pubmed.ncbi.nlm.nih.gov/9878167/
 
A previous cART-era pathologic study suggests a potential shift in HIV-related inflammation to the hippocampus and surrounding entorhinal cortex. https://pubmed.ncbi.nlm.nih.gov/15977645/
 
Hippocampal atrophy is consistently reported across aging populations, and accelerated atrophy is a hallmark of neurodegenerative diseases, such as Alzheimer disease. Neuropathologic hallmarks of healthy aging and Alzheimer disease, including elevated levels of phosphorylated tau and β-amyloid deposits, have been detected in the hippocampus of HIV-positive individuals taking cART. https://pubmed.ncbi.nlm.nih.gov/16718349/
https://pubmed.ncbi.nlm.nih.gov/15750394/
 
Common age- and HIV-related pathologic processes, such as inflammation and blood-brain barrier impairment, may accelerate age-related neurodegenerative processes. https://pubmed.ncbi.nlm.nih.gov/24871088/
 
Study participants ranged in age from 20 to 81 years, and although age was associated with smaller brain volumes, the study did not detect any interactions between age and CD4+ cell count or dVL in the full group, perhaps because the subgroup taking cART was older than the group not taking cART. A better understanding of chronic infection in the context of aging remains an important topic of research.
 
Dr Neda Jahanshad, PhD, associate professor of neurology at the INI and one of the senior authors of the study  added, "There are many factors that contribute to brain tissue loss and subsequent cognitive impairments as we age, and a person's immune function is no exception. Through these large-scale efforts, we're beginning to understand the link between immune function and brain alterations in individuals living, and aging, with HIV."
 
This detailed analysis was a product of the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium's HIV Working Group, established by Dr Jahanshad and colleagues in 2013 to pool harmonized data across neuroimaging studies.
 
The ENIGMA network at large, led by the institute's associate director, Dr Paul M. Thompson, PhD, unites neuroimaging researchers in 45 countries to study psychiatric disorders, neurodegenerative diseases and other aspects of brain function.
 
Besides housing ENIGMA, the USC Stevens INI is a powerhouse of neuroimaging and related science, known for large cohort analyses of imaging, genetics, behavioral, clinical and other data.
 
Researchers from 13 existing HIV studies in the United States, France, Serbia, Australia, Thailand and South Africa collaborated on this study.
 
The study team next plans to analyze imaging data over time, including diffusion imaging data, another type of MRI data that maps the brain's white matter pathways, to further understand how clinical markers of HIV infection affect the brain and the rate of neurodegeneration. As part of that ongoing work, they are inviting researchers around the world to join the ENIGMA-HIV Working Group.
 
Dr Nir added, "With a greater collaborative effort, we hope to be able to assess how genetic, environmental, lifestyle and treatment-related factors may further impact neurological outcomes."
 
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