Cross-Subtype Neutralizing Antibodies Induced In Baboons By A Subtype E Gp120 Immunogen Based On An R5 Primary Human Immunodeficiency Virus Type 1 Envelope

Global human immunodeficiency virus type 1 (HIV-1) diversity may require engineering vaccines to express antigens representing strains prevalent in the target population of vaccine testing. The majority (90%) of Incident infections in Thailand are genetic subtype E, with a small percentage of subtype B infections in the intravenous drug user populations. We have evaluated and compared the binding and HIV-1 neutralizing properties of serum antibodies induced in baboons by CHO cell-expressed monomeric gp120 derived from a CCR5-using (R5) subtype E primary HIV-1(CM235) or a CXCR4-using (X4) subtype B T-cell line-adapted (TCLA) HIV-1(SF2) isolate. In contrast to the subtype-specific HIV-1 neutralizing antibodies induced with recombinant HIV-1(SF2) gp120 (rgp120(SF2)), rgp120(CM235) immunization induced antibodies capable of neutralizing both subtype E and subtype B TCLA HIV-1 isolates. However, neither immunogen induced antibodies capable of neutralizing primary HIV-1 isolates. Antibody induced by rgp120(CM235) preferentially bound natively folded gp120 and retained strong cross-reactivity against multiple gp120 strains within subtype E as well as subtype B. In contrast, antibody responses to rgp120(SF2) were directed predominantly to linear epitopes poorly exposed on native gp120 and had more limited cross-recognition of divergent gp120, Fine epitope mapping revealed differences in antibody specificities. While both rgp120(CM235) and rgp120(SF2) induced antibodies to regions within C1, V1/V2, V3, and C5, unique responses were induced by rgp120(CM235) to multiple epitopes within C2 and by rgp120(SF2) to multiple epitopes within C3, V4, and C4. These data demonstrate that strain and/or phenotypic differences of HIV-1 subunit gp120 immunogens can substantially alter antibody binding specificities and subsequent HIV-1 neutralizing capacity.