The Walter and Eliza Hall Institute of Medical Research

Therapies to promote immune mediated clearance of HIV, hepatitis B virus and tuberculosis

Project type

Honours and/or PhD

Supervisor(s)	Division	Email
Dr Marc Pellegrini (Primary)	Infection and Immunity	.(JavaScript must be enabled to view this email address)
Dr Gabrielle Belz (Co-supervisor)	Molecular Immunology	.(JavaScript must be enabled to view this email address)
Dr Axel Kailles (Co-supervisor)	Molecular Immunology	.(JavaScript must be enabled to view this email address)

 

Details of project

Research opportunities for Honours or PhD projects are available around several recent discoveries in our laboratory. The projects involve targeting genes using conventional or lentiviral silencing approaches in hosts and investigating the consequence of such host immune gene manipulation during the course of infection. The infection models that will be used include HIV, Hepatitis B and TB.

Additionally the results obtained in animal models will be translated to human samples collected from patients with HIV, Hepatitis B or TB. Current molecular pathways that are being investigated for their role in preventing or promoting immune mediated clearance of infection include apoptosis, necroptosis, NFκB, E3 ubiquitination and proteasomal degradation and Stat and Socs signalling networks.

Project references

1. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR, Shahinian A,Lang PA, Lang KS, Morre M, Assouline B, Lahl K, Sparwasser T, Tedder TF, Paik JH,DePinho RA, Basta S, Ohashi PS, Mak TW. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell. 2011 Feb 18;144(4):601-13. Epub 2011 Feb 3. PubMed PMID: 21295337.
2. Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D,Dhanji S, Nguyen LT, Gronski MA, Morre M, Assouline B, Lahl K, Sparwasser T,Ohashi PS, Mak TW. Adjuvant IL-7 antagonizes multiple cellular and molecularinhibitory networks to enhance immunotherapies. Nat Med. 2009 May;15(5):528-36.Epub 2009 Apr 26.PubMed PMID: 19396174.
3. Calzascia T, Pellegrini M, Hall H, Sabbagh L, Ono N, Elford AR, Mak TW, OhashiPS. TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice. J Clin Invest. 2007 Dec;117(12):3833-45. PubMed PMID: 17992258; PubMed Central PMCID: PMC2066188.
4. Pellegrini M, Bouillet P, Robati M, Belz GT, Davey GM, Strasser A. Loss of Bimincreases T cell production and function in interleukin 7 receptor-deficientmice. J Exp Med. 2004 Nov 1;200(9):1189-95. Epub 2004 Oct 25. PubMed PMID:15504823; PubMed Central PMCID: PMC2211860.
5. Pellegrini M, Belz G, Bouillet P, Strasser A. Shutdown of an acute T cellimmune response to viral infection is mediated by the proapoptotic Bcl-2 homology3-only protein Bim. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14175-80. Epub 2003 Nov 17. PubMed PMID: 14623954; PubMed Central PMCID: PMC283565.

Research interests

Infectious diseases caused by HIV, Hepatitis B and Hepatitis C virus are responsible for approximately 4 million deaths per year. The global health burden posed by these infections is underscored by their prevalence. More than 2 billion people have been infected with HBV and currently 170 million and 33 million people are infected with HCV and HIV respectively. Two billion people are infected with Mycobacterium tuberculosis and 1.5 million people die of tuberculosis (TB) each year.

Although antivirals and antibiotics have had a major impact on morbidity and mortality, the rapid emergence of pathogen resistance limits their efficacy. Furthermore, none of our HIV therapies are able to cure infection and we are now beginning to see many long term complications of persistent inflammation / treatment. This highlights the urgent need to develop new therapies that focus on augmenting host immunity.

Identifying host immune inhibitory networks is critical for the rational design of therapies that promote adaptive immunity in HIV-1, HBV and TB infection. These fundamental insights are also useful in vaccine design. Targeted and reversible inhibition of host immune regulatory networks offers a common therapeutic platform to treat diverse chronic overwhelming infections and these types of therapies would be refractory to traditional pathogen resistance mechanisms.

Our laboratory focuses on defining that factors that limit or antagonise immune responses in chronic infections using models of HIV infection in human immune system reconstituted mice and hepatitis B and TB infections in animals. We use molecular techniques including lentivrial regulatable knock down techniques to indentify targets that can be translated to human therapies.

Selected publications

1. Pellegrini M, Mak TW, Ohashi PS. Fighting cancers from within: augmenting tumor immunity with cytokine therapy. Trends Pharmacol Sci. 2010Aug;31(8):356-63. Epub 2010 Jun 17. Review. PubMed PMID: 20561689.
2. Pellegrini M, Mak TW. Tumor immune therapy: lessons from infection and implications for cancer - can IL-7 help overcome immune inhibitory networks? Eur J Immunol. 2010 Jul;40(7):1852-61. Review. PubMed PMID: 20518034.
3. Strasser A, Pellegrini M. T-lymphocyte death during shutdown of an immune response. Trends Immunol. 2004 Nov;25(11):610-5. Review. PubMed PMID: 15489190.
4. O'Connell RM, Balazs AB, Rao DS, Kivork C, Yang L, Baltimore D. Lentiviralvector delivery of human interleukin-7 (hIL-7) to human immune system (HIS) mice expands T lymphocyte populations. PLoS One. 2010 Aug 6;5(8):e12009. PubMed PMID:20700454; PubMed Central PMCID: PMC2917362.
5. Huang LR, Wu HL, Chen PJ, Chen DS. An immunocompetent mouse model for thetolerance of human chronic hepatitis B virus infection. Proc Natl Acad Sci U S A.2006 Nov 21;103(47):17862-7. Epub 2006 Nov 9. PubMed PMID: 17095599; PubMed Central PMCID: PMC1635544.

Research theme

Infectious diseases

Scientific discipline

• Biochemistry
• Cell Biology
• Genetics
• Immunology
• Microbiology
• Molecular Biology
• Pathology
• Physiology
• Stem Cell Biology

Keywords

HIV, hepatitis B, immunotherapy, TB