The high-affinity interaction of the retroviral nucleocapsid (NC) protein with the packaging signal (y) region of the viral genome is critical for viral RNA packaging and virion assembly. In HIV-1, the y-site spans a four stem-loop region, with the loops known as SL1 through SL4 and NC binding to the loop regions of SL2 and SL3. While the nucleocapsid proteins of HIV-1 and HIV-2 share considerable amino acid sequence homology, the y-sites vary considerably between the two viruses. This suggests that the NC of HIV-2, despite the sequence homology with HIV-1 NC, may bind to a different type of structural element or bind in a different region of the genome.

HIV-1 NC binds to a conserved tetraloop motif in SL2 and SL3 that is not found in any of the HIV-2 stem-loops in the corresponding region. Preliminary ITC and NMR data suggest that HIV-2 NC does bind with high affinity to at least one site within the region corresponding to the HIV-1 y-site, as well as a second moderate-affinity site located immediately upstream of this region. Both of these binding sites are within linkers connecting two stem-loops rather than in the loops, as seen in HIV-1.

Currently, structural studies are underway on the complex of HIV-2 NC and the high-affinity binding site located within the y-site. The relative RNA packaging ability of these two viruses, mediated by the NC-y interaction, has significant implications regarding their different transmission rates as well as their potential as lentiviral vectors for gene therapy.