Induction of HIV-1 specific immunity after vaccination with apoptotic HIV-1/MuLV infected cells.

Spetz A.-L¹., Sörensen A.¹, Walther-Jallow L.¹, Wahren B.², Andersson J.¹, Holmgren L.³, Hinkula J². ¹Center for Infectious Medicine, ²Microbiology and Tumor Biology Center, ³Cancer Center Karolinska Hospital, Karolinska Institutet, Stockholm (Sweden).

Background: Antigen-presenting dendritic cells present viral antigens to T cells after uptake of apoptotic bodies derived from virus-infected cells in vitro. It is unclear however whether apoptotic virus-infected cells are capable of generating immunity in vivo. Material and Methods: Syngeneic apoptotic HIV-1/murine leukaemia virus (MuLV) infected (dose equivalent of 0.84 + 0.15 ng p24), MuLV infected or non-infected cells were inoculated i.p. Mice were sacrificed after one or two immunizations with three-week intervals. In challenge experiments, mice were immunized twice before receiving the infectious dose of 1 X 10⁵ tissue culture ID₅₀ HIV-1/MuLV contained in 10⁶ live cells i.p. Splenocytes were re-stimulated in vitro with p24 or Nef antigen and proliferation was measured by 3H-thymidine uptake or CFSE labelling followed by flow cytometry. ELISA was used to measure secretion of IFN-gamma into culture supernatants. Serum Ig G and Ig A as well as mucosa-associated Ig A (fecal and bronkoalveolar lavage) was measured by ELISA. Results: Here we show that inoculation of mice with apoptotic HIV-1/MuLV infected cells induces HIV-1 specific immunity. Immunization with apoptotic HIV-1/MuLV-infected syngeneic splenocytes resulted in strong Nef- specific CD8⁺ T cell proliferation and p24-induced CD4⁺ and CD8⁺ T cell proliferation as well as IFN-gamma production. In addition, systemic IgG and IgA as well as mucosa associated IgA responses were generated. Moreover, mice vaccinated with apoptotic HIV-1/MuLV cells were protected against challenge with live HIV-1/MuLV infected cells, whereas mice vaccinated with apoptotic non-infected or MuLV-infected splenocytes remained susceptible to HIV-1/MuLV. Conclusion: These data show that intraperitoneal immunization with apoptotic HIV-1 infected cells induces high levels of HIV-1 specific systemic immunity, primes for mucosal immunity and induces protection against challenge with live HIV-1 infected cells in mice. These findings may have implications for the development of therapeutic and prophylactic HIV-1 vaccines.