Unraveling the Links Between HIV-1 and neurodegenerative diseases

Published in Biomedical Research
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Fluorescence microscopy images showing Aβ40, α-synuclein, and EF-C fibrils that were stained with Amytracker 540 dye (red) and CFP labeled HIV (yellow) in the presence of cells stained with the cytoskeleton dye (CellTrace) (blue) and actin dye (ATTO-phalloidin) (white).
Caption

Lia-Raluca Olari, Sichen Liu and Frank Kirchhoff

With the progressing aging of people living with HIV (PLWH), there is growing concern about the long-term effects of viral persistence despite the availability of effective antiretroviral therapy. While HIV-1 primarily targets CD4+ T cells in lymphoid tissues, it is also a neurotropic virus that invades the brain in up to 50% of infected individuals. There, HIV-1 mainly infects and replicates in microglia cells, establishing latent reservoirs that ensure a good hideout for long-term persistence. Although antiretroviral therapy suppresses viral replication, it cannot eradicate the latent viral reservoirs and entirely prevent viral protein expression. This triggers a low-grade chronic immune activation resulting in neurological symptoms collectively known as HIV-1-associated neurological disorders (HAND). The most severe form of HAND is dementia, a progressive neurodegenerative condition similar to Alzheimer’s and Parkinson’s diseases, both characterized by the accumulation of neurotoxic amyloid aggregates in the brain.

Almost two decades ago, our group made the surprising discovery that semen from healthy individuals contains an abundance of amyloid fibrils. Later studies identified multiple types of amyloid fibrils and suggest that they may promote rapid and effective removal of damaged or apoptotic sperm. In addition, these seminal fibrils boost HIV-1 attachment and infection. Thus, amyloid fibrils in semen may promote sexual transmission of HIV-1.

Mechanistic studies revealed that the overall positive charge of semen-derived fibrils allows the virus to overcome repulsion by the negatively charged viral and cellular membranes.

What about the brain? In the present study, we examined the effect of amyloids associated with neurological disease on HIV-1 infection. We found that amyloids formed by the two main proteins misfolded in Parkinson’s and Alzheimer’s, α-synuclein and Aβ, bind HIV-1 particles and promote their attachment and fusion with target cells. This was not necessarily expected because these brain-derived fibrils have an overall negative surface charge. Previous data showed that semen-derived fibrils enhance HIV-1 infection by serving as a polycationic bridge that neutralizes the negative charge repulsion between the viral and cellular membranes. Notably, α-synuclein fibrils were substantially more efficient in promoting virus fusion compared to Aβ fibrils. This difference is likely due to the number and strength of fibril-virus electrostatic and hydrophobic interactions determined by the structural characteristics of the fibrils. Fibril-mediated enhancement of viral attachment and fusion was associated with strongly increased virus replication in primary CD4+ T cells, as well as blood-derived macrophages and microglia. In contrast, infection by other neurotropic viruses, such as Herpes Simplex, or Zika virus, was hardly affected by the presence of fibrils. Thus, the enhancing mechanism seems specific for HIV-1 particles, likely because they have a relatively low number of envelope glycoproteins in their membranes, making attachment a limiting factor.

Does HIV-1 generate its own infection enhancers? Several previous studies have shown that a variety of peptides derived from the HIV-1 external envelope protein gp120 can form amyloid fibrils that increase HIV-1 infectivity. Some of these gp120-derived peptides form fibrils instantaneously and are so efficient that they have been commercialized as enhancers of retroviral gene transfer. Their physiological role remains to be determined. However, they have recently been detected in the cerebrospinal fluid and intercellular spaces of the brain in infected individuals and may thus interact with endogenous amyloidogenic peptides and proteins. Indeed, we found that an amyloidogenic HIV-1 gp120-derived peptide (EF-C) accelerates amyloid formation by α-synuclein protein in in vitro experiments.  The end result of these kinetic interactions is the formation of mixed cross-seeded fibrils, where the two precursor species are homogeneously distributed in the amyloid structure. Interestingly, these fibrils retain their ability to enhance HIV infection, raising the possibility that the virus may promote the formation of its own infection enhancers. However, it remains to be clarified whether the levels of gp120-derived amyloidogenic peptides reached in vivo are sufficient to cause such effects. Notably, amyloid plaques derived from patients with neurodegenerative diseases were reported to contain hundreds of components. Thus, studies on potential cross-seeding activities of different types of amyloids are highly warranted.

What is the potential relevance of these findings? Our results reveal a pathological interplay between the harmful effects of HIV-1 and amyloids in the brain. Amyloids formed in the brain may promote HIV entry and spread by promoting attachment of viral particles to their target cells. Consequently, enhanced numbers of infected cells may result in enhanced production and shedding of gp120-derived amyloidogenic peptides that could potentially further increase virus infection and promote amyloid formation of native proteins. Notably, amyloid fibrils can also promote in trans infection of HIV-1 by cells that are not susceptible to infection. For example, many microglia lack CD4 but can bind virion/fibril complexes and are highly migratory and interacting with other cells. HIV-1 infection, production of viral proteins (like gp120) and amyloids impact not only each other but also act together to trigger inflammation driving disease progression.

Significance and perspectives.  Our results suggest that a detrimental interplay between HIV-1 and amyloids drives neurological complications in people living with the virus. Thus, combining antiretroviral therapy with amyloid inhibitory agents may be highly beneficial. We are continuing our journey by analyzing HIV-1 infection, amyloid formation, and inflammaging in iPSC-derived cerebral organoids. We are confident that this powerful tool that revolutionized the field of neurobiology will results in more unexpected discoveries.

 

 

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