#INHSU19: what are you looking forward to? https://t.co/VM8fLoFAPw
Serena Spudich presented information about HIV infection causing ongoing active injury to the central nervous system (CNS) - comprising the brain, meninges and cerebrospinal fluid (CSF) - despite antiretroviral therapy (ART). Abstract #66
CNS injury can be measured by:
- Neurocognitive testing: persistent milder forms of HIV associated neurocognitive disorder (HAND) can be demonstrated in 18-50% of individuals on ART.
- Inflammatory biomarkers: examination of CSF shows elevated levels of neurofilament light chain (NFL) which is a marker for axonal injury marker
- Neuroimaging: structural or functional imaging shows persistent abnormalities of HIV positive individuals on treatment.
The mechanism of CNS injury is unknown, but is likely multifactorial:
- CNS injury prior to treatment. HIV is brought into the brain by infected lymphocytes (and perhaps infected monocytes) in the setting of immune activation. The viral load of CNS HIV is reflective of the plasma HIV levels in primary infection. Infection of brain cells occurs, with immune activation of microglia and macrophages, leading to breakdown of the blood brain barrier and release of cytokines. This results in axonal death and further HIV infection and mutation in the CNS of susceptible cells.
- Persistent compartmentalised infection. Despite suppressed plasma viral load, researchers can still demonstrate detectable virus in the CSF ("CSF escape"). Active CNS replication of HIV occurs despite apparent peripheral control. HIV in the CNS undergoes distinct evolution, with analysis of CSF showing that CSF HIV is distinct from plasma HIV during suppressive ART.
- Ongoing immune activation. Elevation of inflammatory biomarkers such as neopterin (a derived product of activated monocytes and macrophages in the brain) demonstrate ongoing immune activation.
- Contribution of vascular disease. Vascular immune activation and/or co-morbid risk factors contribute to vascular disease in HIV positive individuals on ART. Higher stroke rates are seen in HIV positive women and younger patients, compared to their HIV negative counterparts.
- Acceleration of normal brain ageing. Normal brain ageing may be accelerated in the setting of HIV and ART, with increased macrophage activation and increased permeability of the blood brain barrier.
- Effect of co-morbidities. Higher rate of cognitive impairment are seen in HIV positive individuals with concurrent depression and substance abuse.
- CNS penetration of antiretrovirals. Antiretroviral medications with higher CNS penetration show lower CSF viral loads, but this may not reduce the risk of CNS disease.
Additionally, the use of mono/dual therapy may increase risk of CSF escape. Potential neurotoxicity is only seen with particular antiretrovirals such as efavirenz.
Apart from the persistent smouldering immune activation in the CNS compartment, viral latency and integration may be important. HIV-1 DNA can be found in microglial cells, macrophages and astrocytes. Animal models show that by day 4 of primary infection with treatment, SIV RNA is no longer found in CSF, but SIV DNA can be demonstrated.
In the future there may be the ability to block HIV entry into CNS during primary infection. While the exact reasons for CNS perturbations is unknown, and likely multifactorial, there is plenty of opportunity for further research.