Mucosal Immunology and Sexual Transmission of HIV

Lab head: Andrew Harman
Location: Centre for Virus Research, The Westmead Institute for Medical Research

Lab members: Andrew Harman Kirstie Bertram Heeva Baharlou Hafsa Rana Jake Rhodes
Funding: NHMRC
Research approach equipment: Our group has acquired access to all the tissues that make up the human anogenital tracts (labia, vagina, cervix, foreskin, glans penis, anus and rectum). We use these tissue to define the immune environment of these tissue and examine their role in sexual transmission of HIV.

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production.

Harman AN, Lai J, Turville S, Samarajiwa S, Gray L, Marsden V, Mercier S, Jones K, Nasr N, Rustagi A, Cumming H, Donaghy H, Mak J, Gale M Jr, Churchill M, Hertzog P, Cunningham AL.

Blood. 2011 Jul 14;118(2):298-308. Epub 2011 Mar 16.

Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton.

Cameron PU, Saleh S, Sallmann G, Solomon A, Wightman F, Evans VA, Boucher G, Haddad EK, Sekaly RP, Harman AN, Anderson JL, Jones KL, Mak J, Cunningham AL, Jaworowski A, Lewin SR.

Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16934-9. Epub 2010 Sep 13.

Manipulation of dendritic cell function by viruses.

Cunningham AL, Donaghy H, Harman AN, Kim M, Turville SG.

Curr Opin Microbiol. 2010 Aug;13(4):524-9. Epub 2010 Jul 2. Review.

HIV-1-infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase.

Harman AN, Kraus M, Bye CR, Byth K, Turville SG, Tang O, Mercier SK, Nasr N, Stern JL, Slobedman B, Driessen C, Cunningham AL.

Blood. 2009 Jul 2;114(1):85-94. Epub 2009 May 12.

Oligomerization of the macrophage mannose receptor enhances gp120-mediated binding of HIV-1.

Lai J, Bernhard OK, Turville SG, Harman AN, Wilkinson J, Cunningham AL.

J Biol Chem. 2009 Apr 24;284(17):11027-38. Epub 2009 Feb 17.

Role for plasmacytoid dendritic cells in the immune control of recurrent human herpes simplex virus infection.

Donaghy H, Bosnjak L, Harman AN, Marsden V, Tyring SK, Meng TC, Cunningham AL.

J Virol. 2009 Feb;83(4):1952-61. Epub 2008 Dec 10.

Determination of suitable housekeeping genes for normalisation of quantitative real time PCR analysis of cells infected with human immunodeficiency virus and herpes viruses.

Watson S, Mercier S, Bye C, Wilkinson J, Cunningham AL, Harman AN.

Virol J. 2007 Dec 3;4:130.

DC-SIGN 'AIDS' HIV immune evasion and infection.

Cunningham AL, Harman AN, Donaghy H.

Nat Immunol. 2007 Jun;8(6):556-8. No abstract available.

[PubMed - indexed for MEDLINE]

HIV induces maturation of monocyte-derived dendritic cells and Langerhans cells.

Harman AN, Wilkinson J, Bye CR, Bosnjak L, Stern JL, Nicholle M, Lai J, Cunningham AL.

J Immunol. 2006 Nov 15;177(10):7103-13.

Investigating The Role of Mononuclear Phagocytes in Sexual Transmission of HIV

Primary supervisor: Andrew Harman

Research Background: Mononuclear phagocytes (MNP) present in the anogenital tracts are one of the first cells to encounter invading pathogens during sexual intercourse which they detect via C-type lectin receptors (CLR) expressed on their surface. MNPs play a crucial role in transmission of HIV as they take up the virus and then efficiently pass it onto T cells in which it explosively replicates. The anogenital tracts consist of various tissues which are all anatomically different and are likely to differ in the MNP subsets they contain. For example the vagina, foreskin and anus contain a robust multilayered stratified squamous epithelial layer which contains a single MNP subset (Langerhans cells). Deep to this tissue is dermis which contains at least six MNP subsets. The rectum and cervix contain and thin and fragile columnar epithelial monolayer which is devoid of MNPs however MNPs are present in the underlying lamina propria which extend processes through to the lumen and sample incoming pathogens. However lamina propria MNPs in humans are poorly characterised. Furthermore the specific MNP subsets found in different anogenital tissues (e.g. vagina vs foreskin or cervix vs rectum) have yet to be determined, especially in terms of the pathogen binding receptors they express. This project will examine the tissue specific differences in DCs subsets and characterise their role in sexual transmission of HIV.

Research Aims and Plan: We have formed collaborations with colorectal and plastic surgeons as well as sexual health specialists, such that we have access to allthe tissues that HIV encounters during sexual transmission (vagina, cervix, foreskin, rectum anus).

AIM 1. To determine MNP subsets present in different anogenital tissues: You will use state of the art deconvolution microscopy to determine which dendritic cell subsets are present in these tissues. We will then treat these samples with HIV-1 and identify which of these subsets take up the virus.

AIM 2. To identify HIV binding receptors on anogenital MNP subsets: You will extract MNPs from the tissue samples by enzymatic digestion and use multicolour flow cytometry to distinguish between each MNP subset and thoroughly characterise them for surface CLR expression andother markers.

AIM 3. To measure the kinetics of transfer of HIV from MNPs to T cells: You will treat MNPs extracted from the anogenital tissues with different strains of HIV-1 and then measure the relative efficiency by which they can transfer the virus to T cells. This work we will make significant steps in determining which MNP subsets play the key role in sexual transmission of HIV. This has relevance to the design of microbicides and mucosal vaccines to block sexual transmission of the virus.

Discipline: Applied Medical Sciences, Westmead
Co-supervisors: Kirstie Bertram, Anthony Cunningham
Keywords: Cell biology, Immunology, HIV infection