Brain Myeloid Cells are Sources of HIV-associated Damage and Viral Dispersal

SUMMARY
HIV infects the brain soon after transmission, but it is unknown how infected brain cells contribute to HIV
persistence and whether these cells release viable virus that can seed cells outside the brain. It is also unclear
how HIV persistence leads to local cellular damage, although inflammatory and external factors (like antiretroviral
[ARV] penetration and opioids) likely impact such damage. Such new knowledge could be important for HIV cure
strategies and ways to improve brain health in persons with HIV (PWH).
This project will address stated objectives of RFA-MH-20-701, Role of Myeloid Cells in Persistence and
Eradication of HIV-1 Reservoirs from the Brain, by: (i) mapping HIV reservoir size, composition, and activity in
brain myeloid cells (BMC) in relation to cellular density and levels of ARV and opioids, (ii) determining the role
of BMC in HIV dispersal within the central nervous system (CNS) and across the body in the setting of ARV
treatment (ART) and after treatment interruption, and (iii) defining how HIV reservoir size and activity in BMC is
associated with local inflammation and cell damage.
Our goal is to examine the role of BMC in HIV persistence, local inflammatory-induced damage and as a source
of viruses that can egress from the CNS to re-seed peripheral organs.
The rationale for this project is supported by literature demonstrating that brain macrophages and microglia can
harbor HIV that persists during modern ART. The low turnover of these macrophages and microglial cells (from
months to years) make them unique reservoirs for HIV. While HIV in resting T cells has been extensively
characterized, the role of BMC as a source of rebound upon cessation of ART is yet to be determined. Further,
HIV in BMC likely triggers immune responses, even during ART, causing local damage.
Our overall hypothesis is that BMC (primarily microglial cells) contribute to HIV persistence in the CNS with
regional heterogeneity. HIV harbored in these BMC likely also causes inflammation-associated brain damage
and contributes to viral dispersal when ART is stopped. We also hypothesize that HIV persistence, local damage
and viral dispersal are influenced by local ARV and opioid levels.
To address these open questions, our study will collect and analyze tissues throughout the CNS (white and grey
matters of frontal cortex, thalamus, hippocampus, basal ganglia, cerebellum, spinal cord), ileum, spleen, blood
and cerebrospinal fluid (CSF) of altruistic PWH enrolled in the Last Gift cohort, an ongoing rapid autopsy study.
Some participants (n=15) will remain virally suppressed until the time of death, while others (n=5) will want to
stop their ART before death. Half of the population will use prescription opioids.
These studies will be important for PWH because they will provide new insights for the development of strategies
to clear HIV infection and lessen inflammatory-dependent microglial-induced neurological damage.

Grant Number: 5R01DA055491-05
NIH Institute/Center: NIH
Principal Investigator: Antoine Chaillon