Immunovirology and Pathogenesis Program

The Immunovirology and Pathogenesis Program (IVPP) was formed in 2005, resulting from the amalgamation of the Laboratory Support and Primary HIV Infection Research Programs. The group works very closely with the Immunovirology group at the St Vincent’s Centre for Applied Medical Research. The activities of the IVPP can be divided into three categories. A substantial proportion of laboratory-based activity is directed towards providing routine or semi-routine laboratory support essential for the successful conduct of clinical trials and epidemiological studies conducted by NCHECR, through specimen processing and conduct of specialised immunological and virological assays. These include immunogenicity assays for vaccine trials. The second component is the conduct of clinical trials and natural history studies in pathogenically informative populations of patients with HIV-infection such as those identified with primary infection and long term non-progressors. Finally, senior scientists and academics within the Program are responsible for their own research projects on pathogenesis and development of therapeutics.

Immunopathogenesis work currently relates to CD4 T-cell function in early HIV infection and in natural controllers of the disease. Novel methodologies for the characterisation of antigen-specific T cells and T regulatory cell have been established allowing the functional and molecular characterisation of these difficult to study cells. These novel methodologies have substantial implications for the understanding of the immunopathogenesis of a range of infections apart from HIV infection, including Hepatitis C and autoimmune diseases. It has also allowed us to gain insights into the location of reservoirs of HIV infections. The effect of early therapeutic intervention with integrase inhibitors and other anti-retroviral regimens on these reservoirs is one of the major current focuses within the laboratory.

We have also described a novel way of knocking down HIV replication using promoter targeted siRNAs which induce transcriptional gene silencing. This novel approach induces prolonged and profound suppression of viral replication by inducing a repressive chromatin structure in the integrated forms of both HIV-1 and SIV. Current efforts in this project focus on assessing effective delivery systems for these constructs and understanding the mechanisms underlying the induction and maintenance of this state that is similar to viral latency.

The IVPP works collaboratively with the other NCHECR programs, the St Vincent’ NSW HIV Reference laboratory and a number of Australian and international groups both in the first world with current productive collaborations with groups based in the North America, UK and Japan, and with groups in the developing world, particularly in Thailand.

The IVPP is located in a purpose built facility on the St Vincent’s Research campus. Its facilities include a state of the art PC3 laboratory. The group has the capacity to perform advanced multi-parameter flow cytometry, and to safely perform biologically contained multi-parameter cell sorting. This allows the functional and molecular characterisation of lymphocyte populations. The laboratory is well equipped for both cellular and molecular work. The access to material from both natural history studies and clinical trials conducted by both the IVPP and other programs within NCHECR means that much of this work is conducted on clinically relevant material. The group has successfully trained and mentored a large number of PhD and honours students.

Publications - selected recent publications IVPP

Defining T cell responses to Viral Infections:

De Rose R, Mason RD, Loh L, Peut V, Smith MZ, Fernandez CS, Alcantara S, Amarasena T, Reece J, Seddiki N, Kelleher AD, Zaunders JJ & Kent SJ. Safety, immunogenicity and efficacy of peptide-pulsed cellular immunotherapy in macaques. J Med Primatol. 2009; 37 (Suppl 2)69-78.

Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring M T, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES & Walker BD. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol. 2007; 8(7):1246-54.

Kestens LA, Seddiki N, Bohjanen B & Paul RC. Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy. Current Opinion in HIV & AIDS. 2008; 3(4):419-424.

King C, Ilic A, Koelsch K & Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004;117(2): 265-77.

Mason RD, Rose RD, Seddiki N, Kelleher AD & Kent SJ. Low pre-infection levels and loss of central memory CD4+ T cells may predict rapid progression in SIV-infected pigtail macaques. Virology. 2008;381(1) 11-5.

Munier CM, Zaunders JJ, Ip S, Cooper DA & Kelleher AD. A culture amplified multi-parametric intracellular cytokine assay (CAMP-ICC) for enhanced detection of antigen specific T-cell responses. J Immunol Methods. 2009; (inpress)

Santner-Nanan B, Seddiki N, Zhu E, Quent V, Kelleher AD, De St Groth BF & Nanan R. Accelerated age-dependent transition of human regulatory T cells to effector memory phenotype. Int Immunol. 2008; 20(3):375-83.

Seddiki N & Kelleher AD. Regulatory T cells in HIV Infection: Who's Suppressing What? Curr Infect Dis Rep. 2008;10 (3): 252-258.

Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A & De St Groth BF. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006; 203(7): 1693-700.

Seddiki N, Santner-Nanan B, Tangye SG, Alexander SI, Solomon M, Lee S, Nanan R & Fazekas de Saint Groth B. Persistence of naïve CD45RA+ regulatory T cells in adult life. Blood. 2006; 107(7): 2830-38.

Seddiki N, Sassson SC, Santner-Nanan B, Munier M, Van Bockel D, Ip S, Marriott D, Pett S, Nanan R, Cooper DA, Zaunders JJ & Kelleher AD. Proliferation of weakly suppressive regulatory CD4+ T cells is associated with over-active CD4+ T-cell responses in HIV-positive patients with mycobacterial immune restoration disease. Eur J Immunol 2009; 39(2): 391-403.

Venturi V, Chin HY, Asher TE, Ladell K, Scheinberg P, Bornstein E, van Bockel D, Kelleher AD, Douek DC, Price DA & Davenport MP. T cell receptor b-chain sharing in human CD8+ Tcell responses to cytomegalovirus and Epstein-Barr virus. Journal of Immunology. 2008; 181 (11):7853-62.

van Bockel D, Price DA, Asher TE, Venturi V, Suzuki K, Warton K, Davenport MP, Cooper DA, Douek DC & Kelleher AD. Validation of RNA-based molecular clonotype analysis for virus-specific CD8+ T-cells in formaldehyde-fixed specimens isolated from peripheral blood. J Immunol Methods. 2007; 326 (1-2): 127-38.

Zaunders JJ, Dyer WB, Munier ML, Ip S, Liu J, Amyes E, Rawlinson W, De Rose R, Kent SJ, Sullivan JS, Cooper DA & Kelleher AD. CD127+CCR5+CD38+++ CD4+ Th1 effector cells are an early component of the primary immune response to vaccinia virus and precede development of interleukin-2+ memory CD4+ T cells. J Virol. 2006; 80 (20): 10151-61.

Zaunders JJ, Ip S, Munier ML, Kaufmann DE, Suzuki K, Brereton C, Sasson SC, Seddiki N, Koelsch K, Landay A, Grey P, Finlayson R, Kaldor J, Rosenberg ES, Walker BD, Fazekas De St Groth B, Cooper DA & Kelleher AD. Infection of CD127+ (interleukin-7 receptor+) CD4+ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection. J Virol. 2006; 80 (20): 10162-72.

Zaunders JJ, Munier M, Kaufmann DE, Ip S, Grey P, Smith D, Ramacciotti T, Quan D, Finlayson R, Kaldor J, Rosenberg ES, Walker BD, Cooper DA & Kelleher AD on behalf of the PHAEDRA Study Team. Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection. Blood. 2005;1(106): 1660-7.

Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Zhenjun C, Kier-Nielsen L, Mifsud NA, Tait AW, Holdsworth R, Almeida CA, Nolan D, Macdonald WA, Archbold JK, Kelleher AD, Marriott D, Mallal S, Bharadwaj M, Rossjohn J & McCluskey J. Human leukocyte antigen class 1-restricted activation of CD8+ T Cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity. 2008; 28(6): 822-832.

Sasson S, Zaunders J, Zanetti G, King E, Merlin K, Smith D, Stanley K, Cooper DA & Kelleher AD. Increased plasma IL-7 correlates with decreased CD127 and increased CD132 extracellular
expression on T-cell subsets in HIV-1 infection. J Infect Dis. 2006; 193(4): 505-14.

Viral escape from Immune pressure and viral evolution:

Brumme ZL, Brumme CJ, Carlson J, Streeck H, John M, Eichbaum Q, Block BL, Baker B, Kadie C, Markowitz M, Jessen H, Kelleher AD, Rosenberg E, Kaldor J, Yuki Y, Carrington M, Allen TM, Mallal S, Altfeld M, Heckerman D & Walker, BD. Marked epitope and allele-specific differences in rates of escape in HIV-1 Gag, Pol and Nef CTL epitopes in acute/early HIV-1 infection. J. Virol. 2008; 82(18) : 9216-9227.

Matthews PC, Leslie AJ, Katzourakis A, Crawford H, Payne R, Prendergast A, Power K, Kelleher AD, Klenerman P, Carlson J, Heckerman D, Ndung'u T, Walker BD, Allen TM, Pybus OG & Goulder PJ. HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering. J Virol. 2009 May;83(9):4605-15.

Schneidewind A, Brumme ZL, Brumme CJ, Power KA, Reyor LL, O'Sullivan K, Gladden A,
Hempel U, Kuntzen T, Wang YE, Oniangue-Ndza C, Jessen H, Markowitz M, Rosenberg ES, Sekaly RP, Kelleher AD, Walker BD & Allen TM. Transmission and long-term stability of compensated CD8 escape mutations. J Virol. 2009 Apr;83(8):3993-7.


Schneidewind A , Brockman MA, Adam RI, Li B, Le Gall S, Goulder PJR, Rinaldo CA, Allgaier R, Kuntzen T, McMichael AJ, Brander C, Kelleher AD, and Allen TM. Late escape from a dominant gag-specific CTL response in HLA-B27 HIV+ subjects is associated with a dramatic cost to HIV-1 fitness. J Virol. 2007; 81(22): 12382-93.

Streeck H, Lichterfeld M, Alter G, Meier A, Teigen N, Yassine-Diab B, Sidhu HK, Little S, Kelleher AD, Routy JP, Rosenberg ES, Sekaly RP, Walker BD, Altfeld M. Recognition of a defined regime within p24gag by CD8+Tcells during Primary HIV-1 Infection in individuals expressing protective HLA class I alleles. J Vrol. 2007; 81(14): 7725-31.

Li B, Allen T, Gladden A, Altfeld M, Kelleher AD, Cooper DA & Kaldor J. Rapid Reversion of Sequence Polymorphisms Dominates Early HIV-1 Evolution. J Virol. 2007; 81(1):193-201.

Furutsuki T, Hosoya N, Kawana-Tachikawa A, Tomizawa M, Odawara T, Goto M, Kitamura Y, Nakamura T, Kelleher AD, Cooper DA & Iwamoto A. Frequent transmission of CTL-escape HIV-1 in highly HLA A24 positive Japanese population. Journal of Virology 2004; 78: 8437-8445.

Ammaranond P, van Bockel D, Zaunders J, Cooper DA & Kelleher AD. A new variant CTL escape mutation in HLA-B27 positive individuals infected with HIV-1. AIDS Research and Human Retroviruses 2005; 21(5): 395-7.

Viral reservoirs:

Lewin SR, Murray JM, Solomon A, Wightman F, Cameron PU, Purcell DJ, Zaunders JJ, Grey P, Bloch M, Smith D, Cooper DA & Kelleher AD. Virological determinants of success following structured treatment interruptions of antiretrovirals in acute HIV infection. JAIDS. 2008; 47(2): 140-147.

Havlir DV, Koelsch KK, Strain MC, Margot N, Lu B, Ignacio CC, Miller MD & Wong JK Predictors of residual viremia in HIV-infected patients successfully treated with efavirenz and lamivudine plus either tenofovir or stavudine. J Infect Dis. 2005; 191, 1164-8.

Koelsch KK, Liu L, Haubrich R, May S, Havlir D, Gunthard HF, Ignacio CC, Campos-Soto P, Little SJ, Shafer R, Robbins GK, D’Aquila RT, Kawano Y, Young K, Dao P, Spina CA, Richman DD & Wong J K. Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis 2008; 197, 411-9.

Koelsch KK, Smith DM, Little SJ, Ignacio CC, Macaranas TR, Brown AJ, Petropoulos CJ, Richman DD & Wong JK. Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus. Aids. 2003; 17, F11-6

Smith DM, Wong JK, Hightower GK, Ignacio CC, Koelsch KK, Daar ES, Richman DD & Little SJ. Incidence of HIV superinfection following primary infection. Jama 2005; 292(10): 1177-8.

Smith DM, Wong JK, Hightower GK, Ignacio CC, Koelsch KK, Daar ES, Richman DD & Little SJ. HIV drug resistance acquired through superinfection. Aids. 2005; 19(12): 1251-6.


siRNA induced Transcriptional Gene silencing of HIV:

Lim HGW, Suzuki K, Cooper DA, Kelleher AD. Promoter-targeted siRNA’s induce gene silencing of simian immunodeficiency virus (SIV) infection in vitro. Mol Ther. 2008; 16(3):565-570.


Suzuki K, Juelich T, Lim H, Ishida T, Watanebe T, Cooper DA, Rao S & Kelleher AD. Closed chromatin architecture is induced by an RNA duplex targeting the HIV-1 promoter region. J Biol Chem. 2008; 283(34): 23353-63.

Suzuki K, Shijuuku T, Fukamachi T, Zaunders J, Guillemin G, Cooper DA & Kelleher A. Prolonged transcriptional silencing and CpG methylation induced by siRNAs targeted to the HIV-1 promoter region. Journal of RNAi and Gene Silencing. 2005; 1(2): 66-78.

Yamagishi M, Ishida T, Miyaki A, Cooper DA, Kelleher AD, Suzuki K & Watanabe T. Retroviral delivery of Promoter-targeted shRNA induces long-term silencing of HIV-1 transcription. Microbes Infect. 2009; 11(4): 500-8.

Vaccines for HIV:

Emery S, Kelleher AD, Workman C, Puls RL, Bloch M, Baker D, Anderson J, Hoy J, Ip S, Nalliah K, Ward LD, Law MG, and Cooper DA. Influence of IFN-ã co-expression on the safety and antiviral efficacy of recombinant fowlpoxvirus HIV therapeutic vaccines following interruption of antiretroviral therapy. Human Vaccines. 2007; 4: 260-267.

De Rose, Sullivan M, Dale C, Kelleher AD, Emery S, Cooper DA, Ramshaw I, Boyle D, Kent S. Dose-response relationship of DNA and recombinant fowlpox virus prime-boost HIV vaccines: implications for future trials. For the Australian Thai HIV Vaccine Consortium. Human Vaccines 2006; 2(3): 134-136.

Kelleher AD, Puls R, Bebbington M, Boyle D, Ffrench R, Kent S, Kippax S, Purcell D, Thomson S, Wand H, Cooper DA & Emery S. A Randomised, Placebo-controlled Phase I Trial of DNA Prime, Recombinant Fowlpox Virus Boost Prophylactic Vaccine for HIV-1. AIDS. 2006; 20(2): 294-7.

Emery S, Workman C, Puls RL, Bloch M, Baker D, Bodsworth N, Anderson J, Crowe S, French MAH, Hoy J, Aichelberg A, Ward LD, Boyle DB, Law MG, Kelleher AD & Cooper DA on behalf of the NCHVR01 study team. Randomised, placebo-controlled, Phase I/IIa evaluation of the safety and immunogenicity of fowlpox virus expressing HIV gag-pol and interferon-gamma in HIV-1 infected subjects. Human Vaccines. 2005;1(6): 232-238.

Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, Gilbert PB, Marmor M, del Rio C, Gottesdiener KM, Corey L, Johnston MI, Dieffenbach CW, Robertson MN, and the STEP Study Team* AD Kelleher (member). Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008; 372 (9653):1881-93.

McElrath MJ, De Rosa SC, Moodie Z, Dubey S, Kierstead L, Janes H, Defawe OD, Carter DK, Hural J, Akondy R, Buchbinder SP, Robertson MN, Mehrotra DV, Self SG, Corey L, Shiver JW, Casimiro DR and the Step Study Protocol Team* Kelleher AD (member).HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet. 2008; 372 (9653): 1894-905

Other Publications:

Mallon PWG, Sedwell R, Rogers G, Nolan D, Unemori P, Hoy J, Samaras K, Kelleher AD, Emery S, Cooper DA & Carr A for the Rosey investigators. The effect of rosiglitazone on PPAR gene expression in human adipose tissue is limited by antiretroviral drug-induced mitochondrial dysfunction. Journal of Infectious Diseases. 2008; 198(12):1794-1803.

Swaminathan S, Zaunders J, Wilkinson J, Suzuki K, Kelleher AD. Does the presence of anti-HIV miRNAs in monocytes explain their resistance to HIV-1 infection? Blood 2009; (inpress)