Nearly 38 million people around the world are living with HIV, which, with access to treatment, has become a lifelong chronic condition. Understanding how infection changes the brain, especially in the context of aging, is increasingly important for improving both treatment and quality of life.
In January, researchers at 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 researchers pooled magnetic resonance imaging (MRI) data from 1,203 HIV-positive individuals across Africa, Asia, Australia, Europe and North America. Their findings were published in JAMA Network Open.
“Brain injury caused by HIV can lead to cognitive challenges, even in those receiving treatment,” says Talia Nir, Ph.D., a postdoctoral scholar at the USC Stevens INI’s Laboratory of Brain eScience (LoBeS) and first author of the study.
“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 researchers 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, they 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.
These 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. They highlight deficits in brain areas that are also vulnerable to age-related neurodegenerative diseases.
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.
“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,” says Neda Jahanshad, Ph.D., associate professor of neurology at the INI and one of the senior authors of the study. “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.”
The analysis was a product of the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium’s HIV Working Group, established by Jahanshad and colleagues in 2013 to pool harmonized data across neuroimaging studies.
The ENIGMA network at large, led by the institute’s associate director, Paul M. Thompson, Ph.D., unites neuroimaging researchers in 45 countries to study psychiatric disorders, neurodegenerative diseases and other aspects of brain function.
In addition to 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.
Investigators from 13 existing HIV studies in the United States, France, Serbia, Australia, Thailand and South Africa collaborated on the JAMA Network Open paper.
Next, the team will 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.
“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,” Nir says.
Natural progression of HIV disease is associated with a gradual exhaustion of the immune system and a rise in complications such as opportunistic infections or other comorbidities.
HIV can also cross the blood brain barrier and infect the central nervous system (CNS), which results in a wide array of complications, ranging from HIV associated dementia (HAD) to asymptomatic neurocognitive impairment (ANI) [1].
The introduction of highly active anti-retroviral therapy (HAART) has drastically reduced the severity of neurological diseases, but has not reduced their prevalence [2]. This indicates a need for a comprehensive treatment approach to ameliorate current therapies to target HIV replication in the CNS.
The blood brain barrier (BBB) is a highly selective barrier that restricts the passage of elements from the circulatory system to the CNS. This restriction prevents toxic molecules, viruses, bacteria and inflammatory cells from reaching the CNS, which could damage the brain.
While BBB is important in preventing CNS infection, it also hinder the treatment of brain pathology. Crossing the BBB has proved to be a major obstacle in treatment of a variety of brain diseases, from viral and bacterial infections to cancer or brain metastasis [3, 4].
The successful delivery of drugs to the CNS is highly dependent on the structure of the molecule. In the treatment of HIV, several anti-retroviral drugs have been analyzed to identify their ability to cross the BBB. While some demonstrate a relatively high CNS penetration-effectiveness (CPE), a high proportion of therapeutics show low to poor CPE (see table 1). This hinders the efficiency of treatment and increases the probability of drug resistance due to CNS HIV replication at sub-optimal drug levels [5].
Table 1: CNS penetrating efficiency (CPE) of anti-retroviral drugs used in HIV treatment.
| CNS penetrating efficiency (CPE) | |||||
|---|---|---|---|---|---|
| Drug Class | 4 | 3 | 2 | 1 | Non-classified |
| Nucleoside Reverse Transcriptase Inhibitors | Zidovudine | Abacavir | Didanosine | Tenofovir | |
| Emtricitabine | Stavudine | Zalcitabine | |||
| Lamivudine | |||||
| Nonnucleoside Reverse Transcriptase Inhibitors | Nevirapine | Delavirdine | Etravirine | Rilpivirine: CSF/Plasma ratio 1.2–1.6% but above IC50 | |
| Efavirenz | |||||
| Protease | Indinavir/r | Darunavir/r | Atazanavir | Nelfinavir | |
| Inhibitors | Fosamprenavir/r | Atazanavir/r | Ritonavir | ||
| Indinavir | Fosamprenavir/r | Saquinavir | |||
| Lopinavir/r | Saquinavir/r | ||||
| Tipranavir/r | |||||
| Entry/Fusion | Vicriviroc | Maraviroc | Enfuvirtide | ||
| Inhibitors | |||||
| Integrase | Raltegravir | Dolutrgravir: CSF/Plasma ratio 0.467–0.546% but above IC50 Elvitegravir: | |||
| Inhibitors | |||||
BBB and HIV infection
There are over 35 million people in the world living with AIDS, and of those around 1.5 million per year succumb to AIDS related illnesses [27]. Disease burden was highly alleviated by the introduction of HAART in 1990s, shifting HIV from a deadly disease to a chronic infection.
While some complications related to HIV infections, such as immunodepletion, can be prevented, HIV-infected patients still demonstrate a high incidence of various comorbidities, including neurological disorders [1, 28–30].
HIV is a neuroinvasive virus that can cross into the CNS causing inflammation and neurotoxicity. The crossing of the virus across the BBB is still not fully elucidated; however, most evidence points to a “Trojan horse” model, in which infected immune cells migrate to the CNS, releasing virus into the brain tissue allowing the subsequent infection of microglial cells and astrocytes [31–33].
Our recent studies indicate that BBB pericytes are also permissible to HIV infection [34, 35]. While HIV-associated dementia (HAD) is rare in patients under HAART, milder neurodegenerative diseases, such as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), are still present in 40 to 60% of patients [36, 37].
Typical symptoms of MND are confusion, forgetfulness, and problems with cognition and movement, effecting daily life and work duties. The main cause of HIV associated neurocognitive disorders (HAND) is mainly associated with HIV-encephalitis; however, other factors, such as neurotoxic viral proteins or BBB disruption can play a significant role in cognitive decline and HAND progression.
HIV-induced disruption of the BBB is an important part neuropathogenesis induced by the virus. While HIV does not infect endothelial cells, it can directly infect astrocytes and pericytes, i.e., cells important in maintaining BBB integrity [35, 38, 39].
This process affects a variety of cellular functions important for the maintenance of the barrier integrity, such as the secretion of growth factors and tight junction regulation. The presence of cell-cell communication channels, formed by connexin43 and gap junctions, extends the reach of HIV infection, affecting a wider area and bystander cells.
In addition, the ensuing immune responses exacerbate BBB disruption by the secretion of matrix metalloproteinases (MMPs) [40] and decreased expression of tight junction proteins due to pro-inflammatory molecules, such as TNF-α, IL-1β or IFNγ [41–43].
Several HIV proteins exhibit high level of toxicity, which may also induce vascular and neuronal pathology. Exposure of neurons to gp120, even at picomolar levels, is highly toxic and has been linked to HIV-associated sensory neuropathy [44, 45].
Furthermore, gp120 can bind the viral co-receptors, CCR5 and CXCR4, present on BMEC and lead to an increase in monolayer permeability due to downregulation of tight junction proteins and an increase in the levels of MMPs [46]. HIV Tat is another viral protein that has potent toxicity.
It can affect BBB integrity and TJ assembly in BMEC, via a process that has been linked to signaling via small GTPases [47]. In addition, Tat exposure can lead to elevated intracellular ROS levels and cause apoptosis [48]. Finally, viral proteins Nef and Vpr have also been shown to be associated with BBB permeability and neurotoxicity [49, 50].
TARGETING THE CNS RESERVOIRS
The confined nature of the CNS is highly effective at protecting it from pathogens. However, in the event of failure of this system and established brain infection, the BBB becomes an obstacle that can severely obstruct treatment efficacy. While therapeutic levels of drugs can be achieved in the plasma, several factors can lead to a low degree of penetration into the CNS leading to hindered viral inhibition.
As a result, the CNS can act as a viral reservoir where HIV can replicate and increasing the number of latently infected cells [51]. In the event of HAART interruption, virus may cross back into circulation and restore high levels of viremia. Furthermore, the sub-optimal concentrations of antiretroviral drugs (ARVd) in the brain can result in the selection of resistant mutations that lead to loss of treatment efficacy [52].
Finally, HIV replication in the brain stimulates neurodegeneration and cognitive disorders. These facts highlight the need for drugs that can efficiently cross the BBB to achieve therapeutic concentrations in the CNS to prevent HIV replication.
The efficiency of ARVd in crossing the BBB varies greatly. Efavirenz and atazanavir demonstrate low CSF concentrations, averaging 0.5% and 1% of plasma levels, respectively [53, 54]. In comparison, nevirapine can reach CSF concentration that represent 29–63 % of plasma levels [55, 56]. To further enhance this problem, the ratio of CSF to plasma drug concentration can vary greatly between individuals and over time, in part in association with BBB permeability [57].
It has been demonstrated that treatment of patients with drugs demonstrating low BBB penetration is associated with higher prevalence of neurocognitive disorders. A CHARTER study of 300 individuals demonstrated that 26% of patients with undetectable HIV RNA levels (below 2 copies per ml) had detectable CSF viremia [58].
This study also indicated that patients treated with drug regimen with low BBB penetration levels demonstrate poorer performance on neuropsychological tests. These findings indicate that uncontrolled low levels of CNS HIV replication could lead to nervous system injury leading to HAND.
This report is supported by other studies that evaluated patients who developed neurocognitive disorders despite stable antiretroviral treatment and undetectable blood HIV RNA levels [59, 60].
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219022/
List abbreviation
| ANI | Asymptomatic neurocognitive impairment |
| ARVd | Anti-retroviral drug |
| BBB | Blood brain barrier |
| BMEC | Brain microvascular endothelial cells |
| CNS | Central nervous system |
| CPE | CNS penetrating efficiency |
| CPP | Cell penetrating peptide |
| FUS | Focused ultra-sound |
| HAART | Highly active anti-retroviral therapy |
| HAD | HIV associated dementia |
| HAND | HIV associated neurocognitive disorder |
| IC | Inhibitory concentration |
| JAMs | Junctional adhesion molecules |
| LRP-1 | Lipoprotein receptor-related protein-1 |
| MENC | novel electro-magnetic carrier |
| MMPs | Matrix metalloproteases |
| MNC | Magnetic nanocarrier |
| MND | Mild neurocognitive disorder |
| NNRTI | non-nucleoside reserve transcriptase inhibitor |
| NRTI | nucleoside reverse transcriptase inhibitor |
| PI | Protease inhibitor |
More information: JAMA Network Open (2021). jamanetwork.com/journals/jaman … tworkopen.2020.31190
