| During 2003, three million people have died due to the global HIV/AIDS epidemic and five million more acquired human immunodeficiency virus (HIV). Currently, approximately 40 million people are infected with HIV (www.unaids.org). Control of this epidemic will come from research elucidating immunologic control of lentivirus replication and the development of successful lentiviral vaccines. Utilizing the caprine arthritis encephalitis virus (CAEV) animal model, the present research investigated antibody responses to the surface glycoprotein (SU) of CAEV induced by infection or SU immunization.; The first study evaluated the hypothesis that disease progression in CAEV infected goats is associated with Th2 immune responses, whereas Th1 responses restrict virus replication and development of arthritis. Anti-SU IgG isotypes were determined chronologically in infected goats and during initial CAEV infection. Arthritic goats (progressors) had predominantly IgG1 anti-SU antibodies, while SU antibodies of long term nonprogressor (LTNP) goats were biased toward IgG2. Initial IgG1 dominated SU antibody responses correlated with development of pre-clinical joint lesions, while the absence of joint lesions was associated with an IgG2 bias. Thus, the isotype of anti-SU antibodies initially induced by CAEV infection predicted disease outcome. Results support induction of Th1 immune responses as a means of immunotherapy or vaccine development.; The second study evaluated the hypothesis that masking immunodominant non-neutralization epitopes of SU by glycosylation will enhance neutralizing antibody responses. Two modified SU were constructed. SU-M contained two glycans within targeted linear epitopes by R539S and E542N mutations. SU-T was truncated at 518A, upstream from target epitopes, by introduction of termination codons at 519Y and 521Y. Multiple immunizations of goats with SU-M, SU-T or wild-type SU-W induced type-specific neutralizing antibodies to CAEV-63) and cross-reactive antibodies that neutralized CAEV-Co and CAEV-1g5. Compared to SU-W immunized goats, goats immunized with SU-T had significantly lower neutralizing antibody titers. In contrast, immunization with SU-M resulted in reduced recognition of glycosylated linear epitopes and significantly higher neutralizing antibody titers. Thus, masking of linear immunodominant non-neutralization epitopes by glycosylation, but not epitope removal, is an effective immunization strategy to enhance neutralizing antibody responses. |
