Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV...Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined. In this paper, we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses. No difference in the neutralizing activities between the plasma from LTNP and TP was found, which was consistent with the most recent reports. In addition, no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found. The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.展开更多
Recent studies have demonstrated that the membrane-proximal external region （MPER） of human immunodeficiency virus 1 （HIV-1） glycoprotein 41 contains a series of epitopes for human monoclonal antibodies, including...Recent studies have demonstrated that the membrane-proximal external region （MPER） of human immunodeficiency virus 1 （HIV-1） glycoprotein 41 contains a series of epitopes for human monoclonal antibodies, including 2F5, Zl3el, 4El0, and 10E8, which were isolated from HIV-l-infected individuals and show broad neutralizing activities. This suggests that MPER is a good target for the development of effective HIV-1 vaccines. However, many studies have shown that it is difficult to induce antibodies with similar broad neutralizing activities using MPER-based peptide antigens. Here, we report that 10E8-1ike neu- tralizing antibodies with effective anti-HIV-1 activity were readily induced using a precisely designed conformational immu- nogenic peptide containing the 10E8-specific epitope. This immunogenic peptide （designated T10HE） contains a 15-mer MPER-derived 10E8-specific epitope fused to T-helper-cell epitopes from tetanus toxin （tt）, which showed a significantly sta- bilized a-helix structure after a series of modifications, including substitution with an （S）-c^-（2＇-pentenyl） alanine containing an olefin-bearing tether and ruthenium-catalyzed olefin metathesis, compared with the unmodified T10E peptide. The stabilized （x-helix structure of T10HE did not affect its capacity to bind the 10E8 antibody, as evaluated with an enzyme linked immuno- sorbent assay （ELISA） and surface plasmon resonance binding assay （SPR assay）. The efficacies of the T10HE and T10E epitope vaccines were evaluated after a standard vaccination procedure in which the experimental mice were primed with ei- ther the T10HE or T10E immunogen and boosted with HIV-1 JRFL pseudoviruses. Higher titers of 10E8-1ike antibodies were induced by T10HE than that by T10E. More importantly, the antibodies induced by T10HE showed enhanced antiviral potency against HIV-1 strains with both X4 and R5 tropism and a greater degree of broad neutralizing activity than the antibodies in- duced by T10E. These results indicate that a 10E8-epitope-based structure-specific peptide immunogen can elicit neutralizing antibodies when used as a vaccine prime.展开更多
基金supported in part by the National Key S&T Special Projects on Major Infectious Diseases (Grant No. 2008ZX10001-002, 2008ZX10001-012)the National Natural Science Foundation of China (No. 30700706)
文摘Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined. In this paper, we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses. No difference in the neutralizing activities between the plasma from LTNP and TP was found, which was consistent with the most recent reports. In addition, no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found. The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.
基金supported by Ministry of Science and Technology of China(2012ZX10001-009)
文摘Recent studies have demonstrated that the membrane-proximal external region （MPER） of human immunodeficiency virus 1 （HIV-1） glycoprotein 41 contains a series of epitopes for human monoclonal antibodies, including 2F5, Zl3el, 4El0, and 10E8, which were isolated from HIV-l-infected individuals and show broad neutralizing activities. This suggests that MPER is a good target for the development of effective HIV-1 vaccines. However, many studies have shown that it is difficult to induce antibodies with similar broad neutralizing activities using MPER-based peptide antigens. Here, we report that 10E8-1ike neu- tralizing antibodies with effective anti-HIV-1 activity were readily induced using a precisely designed conformational immu- nogenic peptide containing the 10E8-specific epitope. This immunogenic peptide （designated T10HE） contains a 15-mer MPER-derived 10E8-specific epitope fused to T-helper-cell epitopes from tetanus toxin （tt）, which showed a significantly sta- bilized a-helix structure after a series of modifications, including substitution with an （S）-c^-（2＇-pentenyl） alanine containing an olefin-bearing tether and ruthenium-catalyzed olefin metathesis, compared with the unmodified T10E peptide. The stabilized （x-helix structure of T10HE did not affect its capacity to bind the 10E8 antibody, as evaluated with an enzyme linked immuno- sorbent assay （ELISA） and surface plasmon resonance binding assay （SPR assay）. The efficacies of the T10HE and T10E epitope vaccines were evaluated after a standard vaccination procedure in which the experimental mice were primed with ei- ther the T10HE or T10E immunogen and boosted with HIV-1 JRFL pseudoviruses. Higher titers of 10E8-1ike antibodies were induced by T10HE than that by T10E. More importantly, the antibodies induced by T10HE showed enhanced antiviral potency against HIV-1 strains with both X4 and R5 tropism and a greater degree of broad neutralizing activity than the antibodies in- duced by T10E. These results indicate that a 10E8-epitope-based structure-specific peptide immunogen can elicit neutralizing antibodies when used as a vaccine prime.
