The brain, a sanctuary for HIV, poses one of the final frontiers in the quest for a cure.
Imagine a virus so cunning that it not only attacks the immune system but also finds sanctuary in the one organ most shielded from the body's defenses. For the millions living with HIV, this is not a hypothetical scenario. Despite modern antiretroviral therapy (ART) successfully controlling the virus in the bloodstream, 2 HIV establishes a hidden reservoir in the brain, where it can persist for decades. This hidden presence can lead to chronic inflammation and HIV-associated neurocognitive disorders (HAND), affecting nearly half of all individuals with HIV even during treatment 2 .
The intricate relationship between HIV and the brain became a central focus when the 4th International Symposium on NeuroVirology was held conjointly with the 10th International Conference on Neuroscience of HIV Infection in Düsseldorf, Germany, in June 2002 1 4 . This landmark gathering highlighted emerging issues in the field, from the clinical aspects of HIV-associated dementia to the viral and non-viral factors driving neuropathogenesis 4 . Over two decades later, the questions raised then continue to fuel groundbreaking research into how HIV invades, persists within, and impacts the central nervous system (CNS).
The CNS is a highly protected environment, shielded from the bloodstream by the blood-brain barrier (BBB). This barrier tightly regulates what can enter the brain, making it a formidable defense. However, HIV has developed clever strategies to cross it.
HIV infects immune cells in bloodstream
Infected cells migrate to BBB
Viral proteins disrupt tight junctions
Infected cells enter neural tissue
The most widely accepted mechanism is known as the "Trojan horse" method. During the initial peak of viremia, infected CD4+ T cells and monocytes—immune cells themselves—circulate throughout the body. When these infected cells reach the BBB, HIV's envelope protein and its Tat protein can disrupt the tight junctions between endothelial cells, making the barrier more permeable 2 .
Proinflammatory cytokines and chemokines secreted during infection further increase this permeability 2 . The infected immune cells then migrate across the compromised barrier, carrying the virus directly into the neural tissue. Research using SIV-infected primate models detected infected CD4+ T cells in the brain within just 12 days of infection, highlighting the startling speed of this invasion 2 9 .
HIV can cross the blood-brain barrier within just two weeks of initial infection, establishing footholds in the brain long before symptoms appear.
Studies show infected immune cells can be detected in the brain in as little as 12 days post-infection in primate models.
Once inside the CNS, HIV predominantly infects myeloid cells: microglia (the brain's resident immune cells) and perivascular macrophages 2 . Because of the BBB and the brain's unique microenvironment, the virus evolves in isolation, leading to genetically distinct, compartmentalized viral populations 2 .
This compartmentalization, combined with the poor penetration of some antiretroviral drugs across the BBB, allows HIV to establish a persistent reservoir in the brain. This reservoir is not effectively targeted by standard ART and is capable of causing a rebound of viremia if treatment is stopped, making it a major obstacle to an HIV cure 2 .
The blood-brain barrier prevents many antiretroviral drugs from reaching therapeutic concentrations in the brain, allowing HIV to persist in sanctuary sites even during effective systemic treatment.
The presence of HIV in the brain has significant consequences, primarily due to two mechanisms: neuroinflammation and direct neurotoxicity.
Infected brain cells and those exposed to viral proteins become chronically activated, releasing a storm of proinflammatory cytokines and chemokines. This ongoing inflammation is toxic to neurons and contributes to neuronal damage and death 2 .
HIV proteins, such as gp120 and Tat, are directly toxic to neurons. They can disrupt neuronal function and promote neurodegeneration, even in the absence of full viral replication 2 .
| Viral Protein | Primary Function | Effect on the Brain |
|---|---|---|
| gp120 | Envelope protein | Neurotoxic, promotes neurodegeneration |
| Tat | Transactivator protein | Disrupts BBB, directly toxic to neurons |
Before the widespread use of ART, severe HIV-associated dementia (HAD) was common. Today, the most prevalent form of HAND is a milder, but still impactful, asymptomatic neurocognitive impairment 2 . This condition underscores the persistent, low-level toll that the viral reservoir takes on the brain.
A 2025 Northwestern Medicine study published in the Proceedings of the National Academy of Sciences revealed a surprising molecular link between HIV replication and a protein fragment associated with Alzheimer's disease, offering new insights into the viral mechanisms within brain cells 5 .
The research team, led by Professor Mojgan Naghavi, investigated how HIV-1 assembles and releases new virus particles in macrophages and microglia—the primary viral reservoirs in the brain. Unlike in T-cells, where the virus buds from the plasma membrane, in these brain cells, HIV-1 uses intracellular compartments called multivesicular bodies (MVBs) for assembly 5 .
The study focused on the interaction between the HIV-1 Gag polyprotein and a fragment of the amyloid precursor protein (APP) known as C99. Using biochemical and cell-biological techniques, the researchers depleted key host sorting proteins, TSG101 and VPS4A, to observe the effects on both viral replication and APP processing 5 .
The experiment revealed a direct competition between the HIV-1 Gag protein and the host C99 fragment for the same cellular machinery, namely the ESCRT protein TSG101, which is essential for viral budding from MVBs 5 .
| Experimental Manipulation | Effect on HIV Replication | Effect on APP/C99 Processing |
|---|---|---|
| TSG101 depletion | Impaired replication | Reduced processing to toxic amyloids |
| TSG101 depletion + APP reduction | Replication restored | Not applicable |
| Presence of C99 fragment | Blocked HIV-1 access to MVBs | Increased amyloidogenic processing |
The data showed that the C99 fragment blocks HIV's access to the MVBs, hindering its replication. In response, the virus promotes the breakdown of C99. However, this defensive maneuver inadvertently increases the production of toxic amyloids, which are harmful to brain cells and linked to Alzheimer's disease progression 5 .
This study provides a fascinating new understanding of how viral replication and neurodegenerative processes intersect. It suggests that the cellular machinery needed for HIV to replicate in the brain is also involved in creating proteins toxic to neurons, creating a "lose-lose" situation that drives both viral pathogenesis and neural damage 5 .
The journey to eradicate HIV from the brain is advancing on multiple fronts, building on the foundations laid by decades of symposiums and conferences.
Controls systemic viral load but poorly penetrates the blood-brain barrier, allowing persistence of brain reservoirs.
Attempts to reactivate latent virus in reservoirs so it can be eliminated by the immune system, though effectiveness in the brain remains uncertain 2 .
CRISPR-Cas9 technology can target and excise integrated HIV proviral DNA from the host genome, offering potential for a permanent cure .
CRISPR-based approaches to excise HIV DNA from infected cells.
Developing ART with better BBB penetration and novel delivery systems.
Using humanized mouse models and organoids to study neuro-HIV.
Advanced Models and Global Collaboration: Research centers like the Center for Neurovirology and Gene Editing (CNVGE) at Temple University are at the forefront, using interdisciplinary approaches to combat virus-induced CNS disorders 7 . Furthermore, non-human primate models continue to be instrumental, as shown by a 2023 study from the California National Primate Research Center that mapped the immune response to HIV in the brain and clarified the role of CD4 T cells in viral entry 9 .
The fight against Neuro-HIV is ongoing, but each discovery brings us closer to understanding and ultimately defeating this stealthy invader of the brain. As research continues to unravel the complex interplay between virus and host, the goal of a true cure becomes increasingly tangible.
This article was inspired by the scientific discussions that began at the 4th International Symposium on NeuroVirology and the 10th International Conference on Neuroscience of HIV Infection, and it reflects the progress built upon that foundational knowledge.