4th International AIDS Society Conference on HIV Pathogenesis and Treatment Sydney, Australia - July 22 - 25, 2007

TRIGGERING INNATE RESISTANCE TO HIV-1 INFECTION IN CERVICOVAGINAL TISSUE

IAS Conf HIV Pathog Treat 2007 Jul 22-25;4th: Abstract No. MOPDA02

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}

OBJECTIVES: Triggering of the innate immune system is the first line of defense against invading pathogens at mucosal surfaces and may provide a vital link to appropriate priming of adaptive immune responses. We have evaluated the role of Toll like receptors (TLRs) in triggering innate cytokine responses and modulating HIV-1 replication in human cervicovaginal tissue.

METHODS: Human cervicovaginal tissue explants were exposed to a wide range of TLR ligands in culture and their effects on cytokine output (23 analytes by Luminex) and HIV-1 replication determined. Specific responses were further characterized using proteomic and microarray technology.

RESULTS: Of the TLR ligands tested (TLR 2-9), all provided a discrete cytokine profile, with TLR 3 and 4 ligands inducing the strongest proinflammatory responses. Only TLR7 ligand loxoribine enhanced HIV replication when given 2 hours before infection. Interestingly CpG B and C (but not A) oligonucleotides inhibited HIV replication in cervicovaginal tissue. This innate response appeared to be independent of TLR signaling and could be induced by a range of specific non-CpG containing oligonucleotides in the low uM range. This response appeared to be tissue specific as none of the oligonucleotides inhibited R5 HIV-1BaL infection of PBMC and demonstrated little activity in an R5 Cell-cell fusion assay. Tissue resistance to HIV-1 infection could be transferred by a soluble inhibitor factor of >100kd. Proteomic analysis of inhibitory supernatant and cDNA microarray profiling of resistant tissue have generated a list of potential inhibitory factors that will require further characterization.

CONCLUSIONS: We have characterized the innate cytokine response to a wide range of TLR ligands, such data could provide important insight into their potential use as mucosal adjuvants. Furthermore, we have identified specific triggers of innate R5 HIV-1 resistance in genital mucosa.

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2007-07-22
MOPDA02
Models for Mucosal Immunity and Transmission

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