In recent research, the scientific community has been increasingly focused on deciphering how amyloidogenic processing disrupts HIV-1 replication and the potential for utilizing this knowledge as a therapeutic avenue for HAND treatment.
This article delves into the profound findings that not only provide mechanistic insights into the inhibitory effects of amyloidogenic processing on HIV-1 replication but also illuminate the enigmatic host factors and processes influencing the intracellular vesicle-based replication of HIV-1 in immune cell types, particularly microglia and macrophages.
Vesicle Dynamics in HIV-1 Replication
An intriguing revelation is that HIV-1 forms expansive intracellular multivesicular bodies (MVBs) that play pivotal roles in the replication and transmission of the virus in these immune cell types.
Research indicates that during initial stages, Gag – a key structural protein of HIV-1 – is localized at the plasma membrane and buds akin to T-cells, notwithstanding substantial Gag internalization via endocytosis. Disruption of actin-dependent phagocytosis, while redistributing Gag and virions to the plasma membrane, does not significantly affect virus release. This nuanced dynamic indicates that while plasma membrane budding is an early route, it may become saturated rapidly in macrophages.
Distinct MVB subpopulations supporting virus replication are distinguished by their marker expression profiles, with low levels of LAMP1 and tetraspanins like CD53, but elevated CD63. These modified MVBs are organized spatially by microtubules, positioning at the periphery to facilitate virus dissemination through cell-cell contacts. Beyond serving as sites for exocytic release and cell-cell spread, these vesicular hubs also potentially serve as infection reservoirs within macrophages.
Interplay of Host Factors in MVB Formation
Nonetheless, the complex interplay of host factors that influence HIV-1’s capacity to form and exploit MVBs as replication sites, or “Virus-Containing Compartments” (VCCs), remains inadequately understood. Intriguingly, membrane-associated factors, Tetherin/BST-2 and Siglec-1/CD169, implicated in capturing and internalizing HIV-1 particles, contribute to VCC formation. However, these factors might exhibit opposing roles in the transmission of HIV-1 from macrophages to T-cells. These intricate host-virus interactions lay the foundation for the exploration into the role of Amyloid Precursor Protein (APP) in HIV-1 infection and its modulation.
Amyloidogenic Processing’s Dual Role
The study delves into APP’s multifaceted role beyond amyloid generation. The researchers discovered that APP’s non-amyloidogenic product, C83, not only fails to inhibit HIV-1 infection but surprisingly enhances it. This enhancement is connected to heightened Gag expression in C83-expressing cells, potentially owing to C83’s higher plasma membrane localization compared to the amyloidogenic product, C99.
This phenomenon might augment both entry into MVBs and internalization of Gag into these intracellular replication sites. Remarkably, while C83 is localized to MVBs, it does not hinder infection, suggesting that C83’s presence at these sites doesn’t inherently suppress Gag localization or virus replication.
The article also uncovers how APP’s impact on HIV-1 infection pivots on its amyloidogenic processing. Specifically, it highlights that HIV-1 triggers the ubiquitination and degradation of C99. Notably, C99 boasts an extended N-terminal region that inserts into membranes, featuring a lysine residue crucial for the inhibitory activity of the C99-7KA mutant. Partial mutants with intermediate effects on C99 stability align with existing amyloidogenic APP processing studies, revealing the pivotal role of ubiquitination in regulating vesicle sorting for either lysosomal clearance or exocytic release of toxic amyloids.
Convergence of APP and Gag in Vesicular Sorting
A pivotal discovery is the intersection of both APP and Gag at CD63-positive MVB subsets. Despite overlapping and unique vesicular protein sorting (VPS) subunits for APP and Gag, they ultimately converge at MVBs with contrasting objectives – lysosomal clearance for APP and exocytic release for HIV-1. The interplay between the two proteins potentially extends into a battleground where control over vesicle sorting dictates the outcome. HIV-1 manipulates exocytic release pathways to prevent APP from obstructing its access to MVBs crucial for replication.
APP as a Sentient Guardian Against Pathogens
Interestingly, this research uncovers parallels between APP and pathogen defense. Increased APP or C99 expression impairs endocytic sorting and axonal trafficking, leading to neurodegeneration. These findings resonate with the notion that the bifurcation of the amyloidogenic pathway into lysosomal and exocytic vesicles might serve as a sentinel system against pathogens such as HIV-1, redirecting them away from productive MVBs. If C99 prevails, it might block MVB access or redirect pathogens towards non-productive lysosomes. Conversely, if exocytic pathways triumph, they may release amyloids, signaling the overcoming of APP’s antiviral defenses and provoking an inflammatory response.
Therapeutic Prospects
Intriguingly, this research points to the dual manipulation of amyloid production and APP’s antiviral properties through clinically-approved γ-secretase inhibitors. This raises exciting prospects for the treatment of HAND, hinting that these inhibitors might hold greater promise in this context than they have shown in non-HIV-related neurodegenerative conditions like Alzheimer’s Disease.
Conclusion
The intricacies of amyloidogenic processing’s impact on HIV-1 replication open a captivating frontier in understanding both viral pathogenesis and host defense mechanisms. The convergence of viral replication and host responses within vesicular compartments offers new insights into the delicate balance that shapes disease progression. As we navigate this complex landscape, the potential for therapeutic interventions that leverage our growing understanding of these intricate interactions holds the promise of transforming the landscape of HIV-associated neurocognitive disorders.
referrence link : https://www.nature.com/articles/s41467-023-40000-x#Sec8
