Approach to a retrovirus vaccine: immunization of mice against Friend virus disease with a replication-defective Friend murine leukemia virus.

Abstract

In an initial attempt to test the ability of replication-defective retroviruses to immunize against immunologically related pathogenic viruses, we have worked with the erythroleukemogenic Friend retrovirus complex (FV), which consists of a replication-competent helper component, Friend murine leukemia virus (FMuLV), and a related defective pathogenic component, spleen focus-forming virus (SFFV). An 81-base-pair deletion was introduced into the plSE-encoding region of the env gene of an otherwise replication-competent molecular clone of the FMuLV provirus. After transfection of this clone into cells that package the viral RNA in MuLV coats, infectious virus was released into the culture medium. Mouse fibroblasts infected with this virus, here called AFMuLV, expressed the truncated viral env gene products in their cytoplasm but not on cell surfaces, and culture fluids from these cells did not transmit the infection to fresh mouse fibroblasts. In preliminary experiments, immunization of mice of H-2-congenic BALB/c strains with AFMuLV conferred levels of inmnunity to FV dise ranging from weak to relatively strong.Immunized mice developed anti-FV IgM and IgG antibodies and cytotoxic T cells. Mice observed for 15 weeks after the first of two immunizations showed no detectable pathology, but AFMuLV DNA was detectable in livers of some immunized mice for at least 3-6 weeks. These results suggest that our approach to development ofretrovirus vaccines may be a useful one.

Induction of complex immune responses and strong protection against retrovirus challenge by adenovirus-based immunization depends on the order of vaccine delivery

“…Numerous different strategies have been employed in the FV model to date, including attenuated F-MuLV or FV [ 10 , 16 , 32 , 94 ], replication-defective [ 34 ] or inactivated virus [ 35 ], protein- and peptide-based vaccines [ 36 – 39 , 42 ], cell-based vaccines, and gene-based vaccines such as plasmid DNA-based [ 43 ], vaccinia virus-based [ 44 , 46 ] or adenovirus-based vaccines [ 26 – 31 ]. While comparisons of all these vaccine approaches are complicated by the use of different mouse strains and widely differing FV challenge doses, it can be determined from these studies that the vaccines that conferred strong protection from FV challenge are the attenuated viruses [ 10 , 16 , 32 , 94 ], inactivated virus delivered with complete Freund’s adjuvant [ 35 ], a peptide-based vaccine delivering F-MuLV-derived peptides in calcium phosphate nanoparticles together with CpG-containing oligodeoxynucleotides as adjuvant [ 42 ], and viral vector based vaccines such as an envelope-encoding vaccinia virus [ 46 ] or some of the adenovirus-based vectors developed by us [ 27 , 30 , 31 ].…”

“…Many vaccines have been described before for the immunization against FV, the vaccines tested include attenuated N-tropic F-MuLV-N or FV-N [ 10 , 16 , 32 , 33 ], replication-defective [ 34 ] or inactivated F-MuLV [ 35 ], protein [ 36 , 37 ] and peptide vaccines [ 38 – 40 ], cell-based vaccines such as FV-derived tumor cells [ 33 ] or F-MuLV- or peptide-loaded dendritic cells [ 41 ], nano-particle-based vaccines [ 42 ], or gene-based vaccines such as DNA-based vectors [ 43 ], vaccinia-based vectors [ 44 – 46 ], or the adenovirus-based vectors developed by us [ 26 – 31 ]. While comparisons are sometimes difficult due to the different mouse strains and widely differing FV challenge doses that were employed in the various studies, it has to be noted that until now, only the immunization with attenuated F-MuLV conferred complete protection to FV-susceptible mice.…”

Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-viral immunity during chronic retroviral infection

“…This is associated with the expansion and activation of Tregs [ 19 ], which down-regulate virus-specific cytotoxic CD8 + T cell activity [ 6 ], a conspicuous feature which in fact was also seen in HIV infection [ 20 ]. As no appropriate mouse model for studying HIV infection exists, the well-described FV infection model has been accepted to be suitable to understand basic concepts in retroviral immunity and to test novel vaccination strategies [ 21 – 24 ].…”

Vaccination with an Adenoviral Vector That Encodes and Displays a Retroviral Antigen Induces Improved Neutralizing Antibody and CD4+T-Cell Responses and Confers Enhanced Protection

“…The only vaccine that has been shown to confer complete protection from FV disease in highly FV-susceptible mice so far is attenuated F-MuLV (7,32), with which survival and absence of infected cells after FV challenge were demonstrated. Vaccination of highly susceptible CB6F1 mice with a peptide containing a CD4 ϩ T-cell epitope emulsified in complete Freund's adjuvant resulted in ϳ80% survival of mice after FV challenge, but not sterile immunity (19,21).…”