ABSTRACT The error-prone replication machinery of HIV-1 continuously generates new variants of the envelope glycoproteins (Envs). Antibody selection pressures applied in the host can limit their persistence. The target specificity of antibodies elicited in different hosts varies considerably. Whether some specificities are shared and have affected the population-level evolution of Env structure is still unclear. We examined the historical changes in amino acid sequence of the gp41 fusion peptide proximal region (FPPR), which is not exposed on the Env trimer. For three FPPR positions, the residue found in the clade B ancestor was mainly replaced by alanine. However, the changes in alanine frequency at these positions between 1979 and 2016 followed different patterns; two positions maintained a historically-constant frequency whereas the third showed a gradual increase. To understand these patterns, we introduced alanine substitutions in the FPPR of primary HIV-1 strains and examined their fitness and antigenicity relative to the clade-ancestral form. The evolutionary patterns could not be explained by effects on Env fitness. Instead, the FPPR variants with a historically-constant alanine frequency exhibited a unique open-at-the-base conformation of the trimer that exposes partially-cryptic epitopes. These Envs were modestly but significantly more sensitive to poorly-neutralizing sera from HIV-infected individuals than the clade-ancestral form. Our findings suggest that weakly-neutralizing antibodies targeting the base of the trimer are commonly elicited. Such low-level antibody pressures do not exert catastrophic effects on the emerging variants but rather determine their set-point frequency in the population and historical patterns of change. IMPORTANCE HIV-1 infection elicits antibodies that target the Env proteins of the virus. The specific targets of these antibodies vary between infected individuals. It is unclear whether some target specificities are shared between the antibody responses of different individuals. Our data suggest that antibodies against the base of the Env protein are commonly elicited during infection and are contained in sera with low neutralization efficacy. Such antibody pressures are weak. As a result, they do not completely eliminate the sensitive Env forms from the population, but rather maintain their frequency at a low level that has not increased during the past 40 years.

The fusion peptide proximal region of the HIV-1 envelope glycoproteins regulates exposure of immunogenic epitopes at the trimer base