Mutations in HIV-1 envelope that enhance entry with the macaque CD4 receptor alter antibody recognition by disrupting quaternary interactions within the trimer.

Publication Type:

Journal Article


Journal of virology, Volume 89, Issue 2, p.894-907 (2015)


Adaptation, Biological, Animals, Antigens, CD4, CD4-Positive T-Lymphocytes, env Gene Products, Flow Cytometry Core Facility, Genomics Core Facility, Human Immunodeficiency Virus, Epitopes, HIV Antibodies, HIV-1, Humans, Macaca, Models, Molecular, Mutant Proteins, Mutation, Missense, Protein Conformation, Virus Internalization


Chimeric simian immunodeficiency virus (SIV)/human immunodeficiency virus (HIV) (SHIV) infection of macaques is commonly used to model HIV type 1 (HIV-1) transmission and pathogenesis in humans. Despite the fact that SHIVs encode SIV antagonists of the known macaque host restriction factors, these viruses require additional adaptation for replication in macaques to establish a persistent infection. Additional adaptation may be required in part because macaque CD4 (mCD4) is a suboptimal receptor for most HIV-1 envelope glycoprotein (Env) variants. This requirement raises the possibility that adaptation of HIV-1 Env to the macaque host leads to selection of variants that lack important biological and antigenic properties of the viruses responsible for the HIV-1 pandemic in humans. Here, we investigated whether this adaptation process leads to changes in the antigenicity and structure of HIV-1 Env. For this purpose, we examined how two independent mutations that enhance mCD4-mediated entry, A204E and G312V, impact antibody recognition in the context of seven different parental HIV-1 Env proteins from diverse subtypes. We also examined HIV-1 Env variants from three SHIVs that had been adapted for increased replication in macaques. Our results indicate that these different macaque-adapted variants had features in common, including resistance to antibodies directed to quaternary epitopes and sensitivity to antibodies directed to epitopes in the variable domains (V2 and V3) that are buried in the parental, unadapted Env proteins. Collectively, these findings suggest that adaptation to mCD4 results in conformational changes that expose epitopes in the variable domains and disrupt quaternary epitopes in the native Env trimer.