HIV-1 matrix protein p17 modulates in vivo preactivated murine T-cell response and enhances the induction of systemic and mucosal immunity against intranasally co-administered antigens.
HIV-1 p17 is a viral cytokine that acts on preactivated, but not on resting, human T cells promoting proliferation, proinflammatory cytokines release and HIV-1 replication, after binding to a cellular receptor (p17R). Here, we demonstrate that p17Rs are expressed on activated murine T cells, which respond to p17 stimulation similarly to their human counterpart. We developed a mouse model of abortive HSV-1 infection to induce T cell activation in vivo. Preactivated cells expressed p17Rs and were highly susceptible to p17 stimulation, which triggered proinflammatory cytokines release and promoted CD4+ T cell survival and expansion. Coculture of in vivo activated splenocytes with macrophages in the presence of p17 further increased their ability to produce IFN-gamma. The presence of macrophages and activated T cells at mucosal sites prompted us to investigate the immunomodulatory activities of p17 in vivo. Intranasal coadministration of p17 with beta-galactosidase (beta-gal) resulted in improved beta-gal specific cellular and humoral immune responses at systemic and mucosal levels. It is well established that HIV-1 replication is driven in an autocrine/paracrine manner by endogenously produced proinflammatory cytokines. Our results highlight the role of p17 in sustaining cellular activation and inflammation, thereby promoting a permissive microenvironment for HIV-1 replication. In addition, p17 is a promising candidate antigen, exhibiting immunomodulatory/adjuvant properties, that need to be exploited in the development of HIV/AIDS vaccines.
Fiorentini
Simona
S
Section of Microbiology, Department of Experimental and Applied Medicine, Medical School, University of Brescia, Brescia, Italy. sfiorent@med.unibs.it
Becker
Pablo D
PD
Marini
Elena
E
Marconi
Peggy
P
Avolio
Manuela
M
Tosti
Giorgio
G
Link
Claudia
C
Manservigi
Roberto
R
Guzman
Carlos A
CA
Caruso
Arnaldo
A
D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000818:Animals; D002522:Chlorocebus aethiops; D005260:Female; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus
D000276:Adjuvants, Immunologic; D015683:Gene Products, gag; D015488:HIV Antigens; D011956:Receptors, Cell Surface; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1