Background

Human Immunodefirus Virus (HIV) infection has transitioned into a manageable chronic disease following the introduction of potent Antiretroviral Therapy (ART). However, the fundamental reason why a cure is not achieved, even when viral loads are reduced below the limit of detection, lies in the latent viral reservoirs within the body and continuous chronic immune dysfunction. This is why proviruses hidden in resting memory CD4+ T cells begin to proliferate again upon discontinuation of medication.

Even when viral replication is suppressed, systemic inflammation and immune system disruption persist. The academic community has focused on extracellular vesicles (EVs), which act as intercellular signaling mediators, as the underlying cause of these pathological phenomena. As lipid bilayer nano-particles secreted by cells, EVs serve as key mediators for transferring proteins, lipids, and nucleic acids from parent cells to surrounding cells. Existing virological research has focused primarily on direct contact between free virus particles and target cells, but the complex functions of EVs exchanged between infected and uninfected cells have not been sufficiently elucidated. There is a growing call to comprehensively elucidate the molecular mechanisms of EVs at the interface between viral and host cell pathways, which is essential for achieving breakthroughs in reservoir clearance and alleviating chronic inflammation.

Key Findings

This study systematically identifies the molecular mechanisms through which EVs intervene in host-virus interaction, immune regulation, chronic inflammation, and the maintenance of viral latency during the HIV infection process. EVs released from infected cells exhibit opposing or complex actions depending on their cell of origin and loaded cargo. EVs carrying viral proteins such as Nef or Tat, and non-coding RNA fragments like TAR, move to uninfected immune cells, showing patterns of inducing cell death or promoting immune activation. Conversely, evidence was also found that they help the infectious agent evade immune surveillance by suppressing antiviral immune responses.

EVs also act as a key link in maintaining the viral latency reservoir. The EV cargo in the microenvironment surrounding latently infected cells performs functions such as delivering transcriptional repression signals to solidify latency or interfering with latency reversal signals to neutralize immune cell detection. The study explains that even in patients on ART with suppressed viral replication, EVs carrying pathogenic cargo are continuously secreted, inducing chronic inflammation and immune exhaustion.

Furthermore, therapeutic strategies that exploit EV biology were extensively discussed. The starting point is a method to delay disease progression by blocking the biogenesis and secretion of pathogenic EVs using sphingomyelinase inhibitors, etc. Using highly biocompatible engineered EVs as drug delivery vehicles is also a promising approach. Customized EVs loaded with CRISPR gene scissors, latency reversal agents, or antivirals are considered next-generation platforms for targeted correction of the reservoir genome or deep delivery of drugs within the body. However, the incomplete separation of damaged virus particles and EVs, and the high heterogeneity between vesicles, were pointed out as limitations to be wary of during data interpretation.

Significance and Outlook

This review provides an opportunity to expand the scope of HIV treatment research from simple viral suppression to the control of intercellular communication networks. Targeted delivery technology using engineered EVs is considered a viable alternative to overcome the immunogenicity and Blood-Brain Barrier (BBB) permeability limitations faced by synthetic nanoparticles. It has opened up a biocompatible means to deliver precise therapeutic substances to deep-seated reservoirs, such as the central nervous system.

Barriers remain to be resolved before actual clinical implementation. The establishment of standardized protocols for selectively isolating and quantifying HIV-specific pathogenic EVs among the countless vesicles in body fluids must come first. Establishing mass production processes for therapeutic EVs and suppressing side effects caused by uptake by non-target cells are also challenges to be addressed. If these foundational technologies mature, EV control technology is expected to serve as a decisive foothold toward a cure when combined with strategies to awaken and eliminate latent viruses.