Adeno-associated virus (AAV) vectors that express HIV-1 broadly neutralizing antibodies (bNAbs) have had limited success owing to the large proportion of HIV-1 isolates that remain partially or wholly resistant to bNAbs. Gardner et al. now present a new approach in which bNAbs are replaced with a fusion protein that mimics the virus receptor CD4 and its co-receptor CCR5, which bind to the two most conserved epitopes in the HIV-1 Env protein, thereby facilitating host-cell entry. Compared with a CD4 mimic alone, the fusion protein resulted in a 20–200-fold increase in viral neutralization, and the targeting of only the most conserved epitopes resulted in the neutralization of a diverse panel of HIV-1, HIV-2 and SIV isolates. A 40-week trial of this new AAV vector in rhesus macaques demonstrated durable protection against SHIV with no adverse effects.