HIV-1 transmission: modelling and direct visualization in the third dimension

Abstract

Identifying initial events of mucosal entry of HIV-1 in laboratory-based, physiologically-relevant and high-throughput contexts may aid in designing effective strategies to block local transmission and spread of HIV-1. Several paradigms have been posited for how HIV-1 crosses mucosal barriers to establish infection based on 2D culture or animal-based models. Nevertheless, despite these models stemming from 2D culture and animal studies, monolayers of cells poorly replicate the complex niche that influences viral entry at mucosal surfaces, whereas animal models often inadequately reproduce human disease pathophysiology and are prohibitively expensive. Organoids, having never been directly utilised in HIV-1 transmission investigations, may offer a compromise between 2D culture and animal models as they provide a platform which mimics the biophysical and biochemical niche of mucosal tissues. Importantly, observation of events downstream of viral inoculation is potentially accessible to researchers via an array of microscopy techniques. Because of the potential insights organoids may provide in this context, we offer this review to highlight key physiological factors of HIV-1 transmission at common mucosal sites and a discussion highlighting how many of these factors can be recapitulated in organoids, their current limitations and what questions can initially be addressed, particularly by a selective inclusion of quantitative light microscopy techniques. Harnessing organoids for direct observation of HIV-1 entry at mucosal sites may uncover potential therapeutic targets which prevent the establishment of HIV-1 infection.