McElrath: Mucosal Immunology Group
Since HIV-1 is transmitted primarily via mucosal routes, interventions that prevent or limit mucosal infection are major priorities to halt the HIV-1 epidemic. While anti-viral innate and adaptive immunity contribute protective host responses against HIV infection at mucosal surfaces, gaps remain in understanding which mucosal immune functions are critical targets to develop efficacious HIV-1 vaccines and prevention modalities. Analyses of mucosal cellular immunity in HIV vaccine and microbicide clinical trials are particularly challenging in part due to operational constraints on the collection of mucosal samples in at-risk populations as well as to limited cell yields obtained from non-invasive or minimally invasive mucosal specimen collections. To address these issues, the HIV Mucosal Immunology Group (MIG) was founded in 2009 through NIAID DAIDS (Clinical Vaccine Branch) funding to the HVTN Laboratory Center. Leading mucosal investigators formed three MIG working groups—gastrointestinal, genitourinary and systems biology—tasked with identifying and standardizing best practices for the collection, storage, and analysis of mucosal specimens in HIV prevention trials. The MIG has since yielded fruitful, cross-network collaborations, and dissemination of best practices is proceeding in the clinical research setting. The MIG Project builds on this momentum to further optimize and augment methods for the evaluation of mucosal endpoints in clinical trials, in order to advance knowledge of how HIV vaccine and prevention measures can alter mucosal immune responses that potentially impact efficacy outcomes.
1. Improve ex vivo Mucosal Tissue Explant Assay Models
2. Evaluate Potential Mucosal Quality Indicators
3. Advance Systems Biology-based Assays for Clinical Trials
4. Define Best Practices for Conduct of Mucosal PK/PD Analyses
- Rena Astronomo and Maria Lemos (FHCRC) have highly optimized and harmonized standard protocols for ex vivo HIV infection challenge models using human mucosal tissue explants and demonstrated the utility of these explant models to evaluate the potentially protective function of in vivo-infused VRC01 mAb in rectal and vaginal biopsies collected from HVTN 104 volunteers.
- Importantly, in this small cohort of mucosal tissues collected within 3-14 days of VRC01 infusion, 14 of 14 vaginal explants and 17 of 21 rectal explants were protected from ex vivo infection by a highly VRC01-sensitive reporter virus expressing BaL26 Env, whereas 21 of 21 rectal explants were infected by ex vivo challenge with a highly VRC01-insensitive reporter virus expressing Du422.1 Env. Moreover, VRC01 was detected in matched tissue extracts by high sensitivity Singulex Erenna immunoassays done by Adrian McDermott’s laboratory (VRC).
- These pilot findings set the stage for an intensive study of the mucosal PK/PD characteristics of passively-infused VRC01 (and VRC01LS) in the upcoming HVTN 116 trial (opening Q1 2017) in low-risk volunteers in the US and RSA. Among other goals, HVTN 116 will seek to understand potential mechanisms of efficacy that may be observed in ongoing, large-scale, Phase 2b Antibody Mediated Prevention (AMP) trials in the Americas and Southern Africa.
- Standard protocols were fully transferred to the Cape Town HVTN Immunology Laboratory (CHIL), a research facility co-funded by the Bill & Melinda Gates Foundation, to establish on-site lab capability for ex vivo HIV infectivity assays of human mucosal tissue explants. Clinical studies are ongoing via collaborations with Lynn Morris (NICD) for foreskin tissue models and with Linda-Gail Bekker (U Cape Town) for cervicovaginal and rectal biopsy models.
- Georgia Tomaras (Duke U) extensively characterized the HIV-specific antibody binding and anti-viral properties of genital tract secretions collected from a cohort of HIV-positive men and women so that these samples can serve as archival reference standards to qualify/validate new mucosal endpoint assays being developed for clinical trials.
- Chris Love (MIT) established a core facility in conjunction with the Koch Institute (Boston) to enable access to his single-cell, multiplex imaging platform for phenotypic and functional analyses of sparse mucosal immune cell populations obtained in clinical studies. Major platform advances in on-chip, single-cell RNA sequencing and computational analysis have spurred further efforts to create a commercially-manufactured imaging cytometer instrument with higher-throughput capabilities based on manufactured, SBS-standard microplates and a fully-supported, cloud-based data analysis and informatics suite, which are key features to move these systems-based technologies into clinical trials.