Characterization of the Outer Domain of the gp120 Glycoprotein from Human Immunodeficiency Virus Type 1

Abstract

The core of the gp120 glycoprotein from human immunodeficiency virus type 1 (HIV-1) is comprised of three major structural domains: the outer domain, the inner domain, and the bridging sheet. The outer domain is exposed on the HIV-1 envelope glycoprotein trimer and contains binding surfaces for neutralizing antibodies such as 2G12, immunoglobulin G1b12, and anti-V3 antibodies. We expressed the outer domain of HIV-1 YU2 gp120 as an independent protein, termed OD1. OD1 efficiently bound 2G12 and a large number of anti-V3 antibodies, indicating its structural integrity. Immunochemical studies with OD1 indicated that antibody responses against the outer domain of the HIV-1 gp120 envelope glycoprotein are rare in HIV-1-infected human sera that potently neutralize the virus. Surprisingly, such outer-domain-directed antibody responses are commonly elicited by immunization with recombinant monomeric gp120. Immunization with soluble, stabilized HIV-1 envelope glycoprotein trimers elicited antibody responses that more closely resembled those in the sera of HIV-1-infected individuals. These results underscore the qualitatively different humoral immune responses elicited during natural infection and after gp120 vaccination and help to explain the failure of gp120 as an effective vaccine.

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

“…The antibodies elicited by gp140 react relatively more to the non-neutralization sites within the gp120 than gp41 [73,74]. Furthermore, important neutralizing epitopes in gp41 are absent from soluble gp140 protein immunogens because of protein aggregation attributed to the hydrophobic properties of the MPER [51,75].…”

High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection

“…Glycans 234 and 241 are spatially close to each other and are located on the ␤-sandwich structure of the HIV-1 Env protein (20,39,64). The ␤-sandwich is located in the gp120 inner domain and is important for trimeric association between the gp41 and gp120 subunits (63).…”

Design of an Escherichia coli Expressed HIV-1 gp120 Fragment Immunogen That Binds to b12 and Induces Broad and Potent Neutralizing Antibodies

“…Because full-length or core gp120 does not elicit significant amounts of b12-like antibodies, an alternative target would be an outer domain (OD) only immunogen. However, previous immunizations with a glycosylated, wild-type version of the OD did not yield neutralizing sera (45). An engineered, non-glycosylated OD performed somewhat better with sera that showed improved but modest neutralization relative to animals immunized with monomeric gp120 (20).…”