The HIV-1 envelope glycoprotein (Env) mediates cell entry and is the target of the host humoral immune response. Functional Env is a trimer of noncovalent gp120-gp41 heterodimers. Rational trimer design has transformed the HIV-1 vaccine research field and has helped understand Env structure and immunogenicity. Uncleaved prefusion-optimized (UFO) trimers have been shown to stabilize diverse HIV-1 Env glycoproteins.