Decoding the glycan shield: Immune recognition and response to the HIV-1 envelope trimer

The HIV-1 envelope glycoprotein (Env) is essential for viral entry and infection of host cells. Composed of a trimer of the gp120-gp41 heterodimeric glycoproteins, the Env trimer is the primary target for neutralizing antibodies. Extensive research over the past 40 years has focused on developing advanced immunogens, specifically recombinant, native-like Env trimers and structure-guided, germline-targeting constructs, to elicit protective antibody responses. The Env trimer is encased by up to 90 N-linked glycosylation sites, whose occupancy effectively shields the underlying protein from immune surveillance. While it is well established that glycosylation of HIV-1 gp120 affects antibody responses in infected individuals and that many broadly neutralizing antibodies depend on glycan-specific epitopes, the capacity of Env-derived glycopeptides to act as unconventional CD4⁺ T-cell epitopes and shape helper T-cell responses remains comparatively underexplored. This review examines the adaptive immune responses triggered by HIV Env, with an emphasis on how Env glycosylation simultaneously constrains B-cell recognition and contributes to antigen processing and T-cell-mediated immune responses, aiming to lay the groundwork for future vaccine development and to inform strategies that elicit robust and lasting protection against HIV-1 infection.