Superfibronectin, a multimeric form of fibronectin, increases HIV infection of primary CD4+ T lymphocytes.

The ability of viruses and bacteria to interact with the extracellular matrix plays an important role in their infectivity and pathogenicity. Fibronectin is a major component of the extracellular matrix in lymph node tissue, the main site of HIV deposition and replication during the chronic phase of infection. Therefore, we asked whether matrix fibronectin (FN) could affect the ability of HIV to infect lymphocytes. To study the role of matrix FN on HIV infection, we used superfibronectin (sFN), a multimeric form of FN that closely resembles in vivo matrix FN. In this study we show that HIV-1IIIB efficiently binds to multimeric fibronectin (sFN) and that HIV infection of primary CD4+ lymphocytes is enhanced by >1 order of magnitude in the presence of sFN. This increase appears to be due to increased adhesion of viral particles to the cell surface in the presence of sFN, followed by internalization of virus. Enzymatic removal of cell surface proteoglycans inhibited the adhesion of HIV-1IIIB/sFN complexes to lymphocytes. In contrast, Abs to integrins had no effect on binding of HIV-1IIIB/sFN complexes to lymphocytes. The III1-C peptide alone also bound HIV-1IIIB efficiently and enhanced HIV infection, although not as effectively as sFN. HIV-1IIIB gp120 envelope protein binds to the III1-C region of sFN and may be important in the interaction of virus with matrix FN. We conclude that HIV-1IIIB specifically interacts with the III1-C region within matrix FN, and that this interaction may play a role in facilitating HIV infection in vivo, particularly in lymph node tissue.

Efficacy evaluation of prime-boost protocol: canarypoxvirus-based feline immunodeficiency virus (FIV) vaccine and inactivated FIV-infected cell vaccine against heterologous FIV challenge in cats.

OBJECTIVE: To evaluate the immunogenicity and prophylactic efficacy of immunization schemes employing a recombinant canarypoxvirus ('ALVAC')-based feline immunodeficiency virus (FIV) vaccine alone or in combination with an inactivated FIV-infected cell vaccine against homologous and heterologous FIV challenges in cats. METHODS: Specific pathogen-free cats were given a total of three immunizations with subtype A vaccines and challenged 4 weeks after the final immunization with 50 median animal infectious doses (ID50) of FIV-Petaluma, a subtype A isolate. Following the initial challenge, protected cats received a second challenge with 75 ID50 of FIV-Bangston, a subtype B isolate. FIV-specific humoral and cell-mediated responses were measured to determine the immune correlates of protection. RESULTS: Two of three cats immunized with the ALVAC FIV recombinants alone were protected from homologous FIV challenge in the presence of FIV-specific cytotoxic T-lymphocyte (CTL) responses but in the absence of FIV-specific humoral responses. All three cats immunized with the ALVAC-FIV recombinant and boosted with FIV-infected cell vaccine were also protected from homologous FIV challenge in the presence of both FIV-specific CTL and humoral responses. Partial to full protection was observed in ALVAC-FIV/FIV-infected cell vaccine-immunized cats against a heterologous FIV challenge given 8 months after the initial challenge. Two out of three cats had transient infection and the remaining cat had no sign of FIV infection at a dose at which all three control cats were readily infected. CONCLUSIONS: Immunization schemes employing ALVAC-based FIV vaccines in combination with inactivated FIV-infected cell vaccine generate protective immune responses that can cross-react with FIV isolates that are genetically distinct from the vaccine strains.

Perspectives on FIV vaccine development.

Feline immunodeficiency virus (FIV), discovered a decade ago, is the causative agent of feline immunodeficiency syndrome (FAIDS), a chronically degenerative, fatal disease in domestic cats. Our understanding of the immunopathogenesis of FIV has improved but the development of an effective therapy and prophylaxis has been slow, reflecting the remarkable adaptability of the virus to modern medical intervention. FIV vaccine development has had its successes and failures similar to those encountered in human immunodeficiency virus (HIV) vaccine research. This review summarizes the status of FIV vaccine research, including trials of conventional, recombinant subunit and recombinant vector-based vaccines, and potential mechanisms of vaccine protection. The lessons learned from the FIV model should provide new insights for the approaches toward the development of HIV vaccines.

Development of FIV-specific cytolytic T-lymphocyte responses in cats upon immunisation with FIV vaccines.

Vaccine protection has been achieved in cats against experimental infection with feline immunodeficiency virus (FIV). Such protection has been attributed to FIV-specific humoral immunity, as well as cellular immunity of unknown mechanism(s). Since cell-mediated immunity plays a crucial role in the clearance of viral infections, this study evaluated the role of FIV-specific CTL in vaccine prophylaxis. Cats were immunised with inactivated FIV vaccines, reported to have > 90% vaccine efficacy. Significant levels of specific CTL activity were detected following the third immunisation. CTL activity persisted for several months and could be enhanced through a booster immunisation. The levels of CTL activity were comparable to those induced by a recombinant canarypoxvirus based FIV vaccine. These results suggest a possible role for CTL-mediated immunity in vaccine protection against FIV infection in cats.

Mechanism(s) of FIV vaccine protection.

Infection of domestic cats with the feline immunodeficiency virus (FIV) represents an important veterinary health problem and a useful animal model for the development of vaccines against AIDS. Two experimental FIV vaccines have been developed: one consisting of fixed infected cells and the other of inactivated whole virus. Both vaccines elicited strong CTL responses to FIV and high virus neutralizing (VN) antibody titers. Over 90% of vaccinated cats were protected against intraperitoneal infection with 10 cat infectious dose 50% (10 CID50) of either homologous FIVPet or heterologous FIVDix. As a means to evaluate the mechanism of vaccine protection, cats were either passively immunized with serum antibodies or transfused with peripheral blood cells from FIV-vaccinated cats. Cats passively immunized with vaccine sera or purified vaccine antibodies were protected from homologous FIV infection at a challenge doses which infected all control cats (5 and 10 CID50). Such passive protection was not achieved against heterologous FIV challenge. More importantly, cats transfused with washed blood cells from half-matched vaccinated cat were protected from FIV challenge (20 and 50 CID50). As expected, protection was not observed in cats transfused with cells from either unmatched vaccinated or half-matched unvaccinated cats. Further, only peripheral-blood cells from vaccinated cats had FIV-specific CTL responses to both autologous and half-matched target cells. Overall, these findings suggest that both humoral and cellular immunity are required for optimal vaccine protection.