The survival and replication of viruses depends on their ability to control, hijack, and profit from the activity of the host cell. Deciphering the interaction between the virus and the host cell throughout its life cycle is instrumental not only for the identification of novel potential opportunities for antiviral intervention but also for a deeper mechanistic knowledge of the cellular machinery. We are interested in both aspects: exploring the way viruses interact with host cellular components and improving our understanding of the host pathways involved.
Despite decades of intense research, many features of HIV and other retroviruses remain obscure. Virus replication is regulated by the complex and not always well understood activity of multifunctional viral proteins to gain optimal advantage of the host machinery. On the other hand, as a result of its co-evolution with viral parasites, the host cell has developed mechanisms to interfere with the viral replication. We are exploring both aspects of this host-parasite relationship.
Retroviral factors which promote virus replication
Nef-like infectivity factors. Nef is a multifunctional regulatory protein expressed by primate lentiviruses, crucial for HIV replication and progression to AIDS. Among its activities, Nef potentiates the infectivity of HIV using a mechanism which still remains unexplained. While this was thought to be an exclusive prerogative of primate lentiviruses, we have discovered that a regulatory protein (glycosylated gag) expressed by gammaretroviruses has a similar activity on the infectivity of the retrovirus particle, providing a compelling example of convergent evolution within two divergent groups of retroviruses. We are exploring the molecular mechanisms triggered by these factors and investigating the presence of yet undetected Nef-like virus infectivity factors in other virus groups.
A novel activity of Nef-like proteins. The ability to mount a neutralizing immune response is key to control viral infections. In addition to their activity on virus infectivity, we have identified the ability of Nef and glycosylated Gag to increase retrovirus resistance to neutralizing antibodies targeting the membrane proximal external region of the HIV-1- envelope glycoprotein. We are therefore now exploring how Nef alters HIV-1 susceptibility to neutralization and the role of such activity in the course of natural infection.
Host factors which inhibit retrovirus replication
In the last decade, several cellular factors have been identified, capable of inhibiting retrovirus replication at different stages of the viral life cycle. Such cell factors often have a species-specific activity and play an important role in preventing cross-species infection. We are currently exploring these mechanisms of retrovirus restriction and investigating the existence of further cross-species anti-retroviral barriers.
- Massimo Pizzato, PI
- Ajit Chande, postdoctoral fellow
- Serena Ziglio, postdoctoral fellow
- Emilia Cristiana Currurullo, PhD student
- Annachiara Rosa, PhD student
- Jeremy Luban, University of Massachusetts Medical School, USA
- Oliver Fackler, University Hospital Heidelberg, Germany
- Paul Gorry, Burnet Institute, Melbourne, Australia
Miyamoto, T., Nakayama, E.E., Yokoyama, M., Ibe, S., Takehara, S., Kono, K., Yokomaku, Y., Pizzato, M., Luban, J., Sugiura, W., Sato, H., Shioda, T. (2012), The carboxyl-terminus of human immunodeficiency virus type 2 circulating recombinant form 01_AB capsid protein affects sensitivity to human TRIM5alpha. Plos One, in press.
Lai, P.J., Yan, J., McClure, M.O., Heeney, J.L., Gottlinger, H.G., Luban, J., Pizzato, M. (2011) Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41. Plos Pathog. 7: e1002442.
Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, Reinhard C, Uchil P, Chatel L, Bisiaux A, Albert M, Strambio-De-Castillia C, Mothes W, Pizzato M, Grütter M, and J Luban. (2011) TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature, 472: 361-5.
Pizzato, M., MLV glycosylated-Gag is an infectivity factor that rescues Nef-deficient HIV-1. (2010) Proc Natl Acad Sci U S A. 107:9364-9.
Sokolskaja, E., Olivari, S., Zufferey, M., Strambio-De-Castillia, C., Pizzato, M., Luban J. (2010) Cyclosporine blocks incorporation of HIV-1 envelope glycoprotein into virions. J Virol, 84:4851-5.
Pizzato, M., Erlwein, O., Bonsall, D., Kaye, S., Muir, D., McClure, M.O. (2009) A one-step SYBR Green I-based product-enhanced reverse transcriptase assay for the quantitation of retroviruses in cell culture supernatants. J Virol Methods, 156: 1-7.
Takeuchi, Y., McClure, M.O., Pizzato, M. (2008) Identification of gammaretroviruses constitutively released from cell lines used for human immunodeficiency virus research. J Virol, 82:12585-8.
Pizzato, M., Popova, E., Göttlinger, H.G. (2008) Nef can enhance the infectivity of receptor-pseudotyped human immunodeficiency virus type 1 particles. J Viro, 82(21):10811-9.
Pizzato, M., Helander, A., Popova, E., Calistri, A., Zamborlini, A., Palù, G., Göttlinger, H.G. (2007) Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef , Proc Natl Acad Sci U S A, 104: 6812-7.