Most human immunodeficiency virus type 1 (HIV-1) infected individuals develop an HIV-specific neutralizing antibody (NAb) response which selects for escape variants of the virus. Here, we studied autologous NAb responses in 5 typical R5 progressors in relation to viral NAb escape and molecular changes in the viral envelope (Env) in the period from seroconversion until after AIDS diagnosis. In serum from 3 patients, high-titer neutralizing activity was observed against the earliest autologous virus variants, followed by declining humoral immune responses against subsequent viral escape variants. Autologous neutralizing activity was undetectable in sera from 2 patients. Patients with high titer neutralizing activity in serum showed the strongest positive selection pressure on Env early in infection. In the initial phase of infection, gp160 length and number of potential N-linked glycosylation sites (PNGS) increased in viruses from all patients. Over the course of infection, positive selection pressure declined as the NAb response subsided, coinciding with reversions of changes in gp160 length and number of PNGS. A number of identical amino acid changes were observed over the course of infection in the viral quasispecies of different patients. Our results indicate that although neutralizing autologous humoral immunity may have limited effect on disease course, it is an important selection pressure in virus evolution early in infection, while declining HIV specific humoral immunity in later stages may coincide with reversion of NAb-driven changes in Env. 10.1128/JVI.00757-08