Immunology, Transplantation and Infectious diseases
Immunobiology of HIV
This unit focuses on the structure-immunogenicity applied to the host-virus relationship and in particular we study alterations of self repertoire associated to reduced susceptibility to HIV infection or development of tumors. The analyses of the immune factors involved in immune controls could be extremely relevant to generate strategies able to prevent viral transmission. CCR5 cellular protein is the main coreceptors for HIV and natural antibodies (Abs) to CCR5 showed HIV-blocking properties, both in CD4+ T lymphocytes and in epithelial cells, thus interfering with mucosal HIV transmission. The mechanism of action of these Abs is different from that reported for other CCR5 specific molecules. Natural Abs to CCR5 specifically inhibit HIV replication by inducing a full and long lasting CCR5 downregulation with a very slow kinetic (48h). In an experimental BalB/c mouse model, full in vivo CCR5 downregulation, as well as receptor back-regulation, follow a very slow kinetics that was gradually recovered in 4 weeks after immunization.
Research activity
Research activity is aimed at creating an immune barrier by targeting the host rather than the virus establishing a durable elimination of CCR5. The receptor internalization by anti-CCR5 Abs requires β-arrestin2, which may couple ligand-activated receptors to clathrin, and lead to a cytoplasmatic CCR5 accumulation with consequent activation of ERK1. Such signalosoma turn from Class A trafficking short term pattern, normally used for its internalization with natural modulating molecules (RANTES), into a long lasting Class B type specifically induced by stimulation with anti-CCR5 Abs. This new pathway is relevant not only to study in depth the molecular basis of all pathologies where CCR5 is involved but also to generate new antidody-based therapeutics and vaccines. The unit is also involved in the identification of hepatocarcinoma (HCC) specific mutated self-proteins and development of monoclonal antibodies against new HCC epitopes.
Venuti A, Pastori C, Pennisi R, Riva A, Sciortino MT, Lopalco L. Class B β-arrestin2- dependent CCR5 signalosome retention with natural antibodies to CCR5. Sci. Rep. 2016; 6,39382.
Venuti A, Pastori C, Siracusano G, Riva A, Sciortino MT, Lopalco L. ERK-1 based pathway as a new selective mechanism to modulate CCR5 with natural antibodies. J Immunol. 2015 Oct 1;195(7):3045-57.
Pastori C, Diomede L, Venuti A, Fisher G, Jarvik JW, Bomsel M, Sanvito F, Lopalco L. Induction of HIV blocking anti-CCR5 IgA in Peyer’s Patches without histopathological alterations. J Virol. 2014 Apr;88(7):3623-35.
Ganor Y, Drillet-Dangeard AS, Lopalco L, Tudor D, Tambussi G, Barry Delongchamps N, Zerbib M, Bomsel M. Calcitonin gene-related peptide inhibits Langerhans cell-mediated HIV-1 transmission. J Exp Med. 2013 Oct 21;210(11):2161-70.
Tudor D, Yu H, Maupetit J, Drillet AS, Schwartz-Cornil I, Lopalco L, Tuffery P, Bomsel M. The immunoglobulin CH1 constant region of the anti-HIV-1 broadly neutralizing 2F5 human antibody contributes extensively to epitope specificity, affinity and antiviral activities. PNAS. 2012 Jul 31;109(31):12680-5.
Diomede L, Nyoka S, Scotti L, Pastori C, Zambon A, Sherman G, Gray C, Sarzotti- Kelsoe M, Lopalco L. Passively transmitted gp41 antibodies in babies borm from subtype C HIV-1 seropositive women:correlation between finer specificity and protection. J Virol. 2012 Apr;86(8):4129-38.
Pastori C, Tudor D, Diomede L, Drillet AS, Jegerlehner A, Rohn T, Bomsel M, Lopalco L. Virus like particle based strategy to elicit antibodies targeting HIV protective antibodies within conserved regions of gp41. Virology 2012 Sept;431(1):1-11.
Bomsel M, Tudor D, Drillet AS, Alfsen A, Ganor J, Roger MG, Mouz N, Amacker M, Zurbriggen M, Diomede L, Devillier G, Cong Z, Wei Q, Gao H, Qin C, Yang GB, Chalifour A, Lopalco L, Fleury S. Mucosal antibodies induced by immuno-focused immunization with HIV-1 gp41-antigens coupled to virosomes provide protection against repeated vaginal SHIV challenges in non-human primate. Immunity 2011 Feb 25;34(2):269-80.
Pastori C, Weiser B, Barassi C, Uberti-Fopa, Ghezzi S, Longhi R, Calori G, Burger H, Kemal K, Lazzarin A, Lopalco L. Long lasting CCR5 internalization by antibodies in a subset of Long Term Non Progressors: a possible protective effect against disease progression. Blood 2006 Jun 15;107(12):4825-33.
Barassi C, Soprana E, Pastori C, Longhi R, Lillo F, Grasso M, Marenzi, C, Lazzarin A, Siccardi A.G, Lopalco L. Induction of murine mucosal CCR5-reactive antibodies as anti-HIV strategy. J Virol. 2005 Jun; 79(11): 6848–6858.
