Early Colorectal Responses to HIV-1 and Modulation by Antiretroviral Drugs

Abstract

Innate responses during acute HIV infection correlate with disease progression and pathogenesis. However, limited information is available about the events occurring during the first hours of infection in the mucosal sites of transmission. With an ex vivo HIV-1 challenge model of human colorectal tissue we assessed the mucosal responses induced by R5- and X4-tropic HIV-1 isolates in the first 24 h of exposure. Microscopy studies demonstrated virus penetration of up to 39 μm into the lamina propia within 6 h of inoculation. A rapid, 6 h post-challenge, increase in the level of secretion of inflammatory cytokines, chemokines, interferon- γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) was observed following exposure to R5- or X4-tropic isolates. This profile persisted at the later time point measured of 24 h. However, exposure to the X4-tropic isolate tested induced greater changes at the proteomic and transcriptomic levels than the R5-tropic. The X4-isolate induced greater levels of CCR5 ligands (RANTES, MIP-1α and MIP-1β) secretion than R5-HIV-1. Potential drugs candidates for colorectal microbicides, including entry, fusion or reverse transcriptase inhibitors demonstrated differential capacity to modulate these responses. Our findings indicate that in colorectal tissue, inflammatory responses and a Th1 cytokine profile are induced in the first 24 h following viral exposure.

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue

“…It has been shown that consistent results can be obtained among different laboratories through protocol standardization [56] and that the model can be used to refine animal models and increase their predictive power [57]. Furthermore, in vivo viral replication fitness can be mimicked in mucosal tissue explants [21,57,58] and, following ex vivo challenge, virus has been shown in different mucosal tissue explant models to penetrate the lamina propia with similar kinetics to those observed in vivo [34,59,60].…”

“…The mucosal tissue explant model [29][30][31][32] has limitations, including (i) progressive loss of architecture despite the maintenance of CD4:CD8 T cell ratios and sufficient viability to sustain viral replication for more than 10 days [33]; (ii) a paucity of data regarding the preservation of immune competence [30]; (iii) limitation in demonstrating sterilizing protection; and (iv) an inability to metabolize certain prodrugs, such as TFV disoproxil fumarate, which is the formulated version of TFV for oral administration. Despite these limitations, tissue explants are an important tool for basic research [34][35][36][37][38][39] and pre-clinical screening of PrEP regimens [40] and are increasingly being used in clinical trials for PK-PD assessment [4,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. It has been shown that consistent results can be obtained among different laboratories through protocol standardization [56] and that the model can be used to refine animal models and increase their predictive power [57].…”

Ex Vivo Evaluation of Mucosal Responses to Vaccination with ALVAC and AIDSVAX of Non-Human Primates

“…The colorectal mucosa has a single-cell columnar epithelium, in contrast to the pluri-stratified squamous epithelium of the lower female genital tract. The intestinal lamina propia contains an abundance of highly activated target cells for HIV infection [78][79][80][81]. Furthermore, the colon and rectum produced higher levels of IgA compared to the lower female genital tract, where IgG is prevalent (Figure S3a-d) [82].…”

Pre-clinical evaluation of antiproteases as potential candidates for HIV-1 pre-exposure prophylaxis

“…Furthermore, a multi-site study has shown that protocol standardization provides measurement consistency among different laboratories ( 54 ). This model recapitulates the histological and immunological characteristics of the genital mucosae and early responses to stimuli can be measured ( 55 , 56 ). However, limitations include (i) progressive loss of architecture despite the maintenance of CD4:CD8 T cell ratios and sufficient viability to sustain viral replication for more than 10 days ( 57 ); (ii) paucity of data regarding preservation of immune competence ( 58 ); (iii) limitation to demonstrate sterilizing protection.…”