IAS 2007 - Models for Mucosal Immunity and Transmission

Models for Mucosal Immunity and Transmission

MOPDA

Type:

Poster discussion

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Venue:

Bayside 204 B

Time:

13:00 - 14:00, Monday, 23.07.2007

Code:

MOPDA

Co-Chairs:

J. Victor Garcia-Martinez, United States
Naoki Yamamoto, Japan

Presentations in this session:
13:00
MOPDA01 Introduction and overview
J. Victor Garcia-Martinez, United States

13:10
MOPDA02
Abstract
Powerpoint (6.7 MB) Triggering innate resistance to HIV-1 infection in cervicovaginal tissue
Presented by Madeleine Hayes, United Kingdom
Hayes M.¹, Alder G.², Shianna K.³, Laing K.⁴, Hu Q.¹, Coulton G.², Harman S.¹, Kasali O.², Shattock R.¹
¹St George's, University of London, Centre for Infection, London, United Kingdom, ²St George's, University of London, Medical Biomics Centre, London, United Kingdom, ³Duke IGSP, Genotyping Facility, Durham, United States, ⁴St George's, University of London, Medical Microbiology, London, United Kingdom

13:20
MOPDA03
Abstract
Powerpoint (26 KB) In vitro production of novel HIV-1 specific IgA antibody variable heavy and light chains from HIV-1 resistant sex workers from Nairobi, Kenya
Presented by Caitlin Sarna, Canada
Sarna C.¹, Ball T.B.¹, Gubbins M.J.², Berry J.D.², Plummer F.A.²
¹University of Manitoba, Department of Medical Microbiology, Winnipeg, Canada, ²National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada

13:30
MOPDA04
Abstract
Powerpoint (472 KB) Development of dendrimer-based microbicides
Presented by Steve Wesselingh, Australia
Tachedjian G.¹, Tyssen D.¹, Henderson S.², Lowe M.², Zanin M.¹, Paull J.², Krippner G.², McCarthy T.², Wesselingh S.¹
¹Macfarlane Burnet Institute, Melbourne, Australia, ²Starpharma Pty Ltd, Melbourne, Australia

13:40
MOPDA05
Abstract
Powerpoint (2.71 MB) Fluorescent detection of individual HIV virions within genital tissues
Presented by Scott G. McCoombe, United States
McCoombe S.G.¹, Hope T.J.¹
¹Northwestern University, Cell and Molecular Biology, Chicago, United States

13:50
MOPDA06
Powerpoint (256 KB) Conclusion
Naoki Yamamoto, Japan

Rapporteur reports

Track A: HIV Basic Science report by Anthony Jaworowski

Surprisingly little is known about the natural protective mechanisms against HIV infection in mucosal tissues. Presentations in this session addressed antibody based and innate immune protection, the role of the physical mucosal surface and a potential new microbicide.

Toll-like receptors are major innate immunity mediators. Madeleine Hayes and coworkers exposed cervicovaginal tissue (CV) to a wide variety of TLR ligands and found suprisingly that only some oligonucleotide ligands caused inhibition of infection by R5 viruses (the type that cause de novo infection) in this model. By studying a variety of CpG and GpC oligonucleotides, it was concluded that the inhibition was TLR independent but was mediated by a secreted protein with a MW>100kDa. Identification of this factor is underway using a combination of proteomic and genomic approaches and may indicate important protective mechanisms within the vagina.

It has been a long standing question why some female sex workers in Kenya remain uninfected despite persistent exposure to HIV. The paper by Sarna et al examine whether CV B cells produce effective neutralising secretory IgA. IgA H and L chains were cloned from these B cells then expressed to produce human monoclonal monomeric antibodies. In preiminary experiments, binding to gp120 and neutralising activity was found but it remains to be compared quantitatively with that of known neutralising antibodies such as the IgG monoclonal, b12. Whether such antibodies are found in protective levels in vaginal secretions is an open question, but the expression of IgA monoclonals from these women is a first step to evaluating their protective role in the genital tract.

The goal of the research presented by Scott McCoombe is to define how HIV virions penetrate the CV barrier epithelium. In technically demanding experiments using HIV labelled with photoactivateable Vpr, Scott showed that virions can be found both within and between squamous epithelia of the ectocervix and the columnar epithelia of the endocervix. While penetration is more evident in regions of the explant model which have less mucous, the virus is able to penetrate intact barriers and access the underlying CD4+ T cells and dendritic cells suggesting that disruption of the barrier is not essential to establish infection. While the mechanism of locomotion through the barrier remains to be established Tom Hope says that it appears to be aided by Env.

Steve Wesselingh of the Burnet Institute presented data from their collaboration with StarPharma on the development of a novel dendrimer based microbicide candidate. This compound inhibits infection via a wide variety of HIV strains and has proved safe in short-term phase 1 trials in both penile irritation and vaginal models. It protected against vaginal infection in primate models but unfortunately these studies were not performed with R5 HIV. Nevertheless, SPL7013 is equally active against R5 and X4 utilizing laboratory and clincial isolates in cell culture assays. It was not possible to show generation of high levels of resistance by HIV to the dendrimer after 44 passages in cells suggesting that multiple mutations may be required. Professor Wesselingh indicated that a second generation of dendrimer compounds is being developed to test structure function relationships.

Track C: Biomedical Prevention report by Nick Walsh

Also covered in Track A – here the focus is on prevention.

This session on Models for Mucosal Immunity and Transmission sought to highlight research relating to HIV transmission and immunity within the human genital tract, particularly of the vaginal and foreskin mucosa. There are a number of outstanding questions: What host factors are responsible? What environmental factors? Are there local immune responses present? The session covered some of these questions.

McCoombe et al. illustrated a technique that allows fluorescent detection of individual HIV virions within genital tissues prior to uptake into cells. This gives the opportunity to visually track the translocation of virus across the mucosa. The model presented were explants of human foreskin and vaginal mucosa. An important step in this field of research.

Why are some people protected to a greater degree from HIV sexual transmission than others? One theory is innate IgA cervicovaginal mucosal immunity among HIV resistant sex workers from Kenya. Sarna et al. cloned IgA of B-cells of HIV-1-resistant women and produced human monoclonal HIV-1-specific IgA in vitro. Their efforts will allow the ability to generate the large amounts of IgA needed for examination of the mechanisms leading to protective immunity. Is there potential to incorporate these antibodies in vaginal microbicides? Although a fascinating question, we are still not there yet.

Topical microbicide research has taken off in earnest over the last few years. Microbicides attempt to enhance protection from sexual HIV transmission. Wesselingh et al. reported on the microbicide dendrimer SPL7013 which they have found is effective demonstrated through serial in vitro passage against CCR5- and CXCR4-utilising HIV-1. Only limited in vitro resistance was found. An area of early but important research. Watch this space.

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