Envelope glycoprotein determinants of neutralization resistance in a simian-human immunodeficiency virus (SHIV-HXBc2P 3.2) derived by passage in monkeys

The simian-human immunodeficieny virus SHIV-HXBc2 contains the envelope gly coproteins of a laboratory-adapted, neutralization-sensitive human immunode ficiency virus type 1 variant, HXBc2. Serial in vivo passage of the nonpath ogenic SHIV7-HXBc2 generated SHIV KU-1, which causes rapid CD4(+) T-cell de pletion and an AIDS-Iike illness in monkeys, A molecularly cloned pathogeni c SHIV, SHIV-HXBc2P 3.2? was derived from the SHIV KU-1 isolate and differs from the parental SHIV-HXBc2 by only 12 envelope glycoprotein amino acid r esidues. Relative to SHIV-HXBc2, SHIV-HXBc2P 3.2 was resistant to neutraliz ation by all of the antibodies tested with the exception of the 2G12 antibo dy. The sequence changes responsible for neutralization resistance were loc ated in variable regions of the gp120 exterior envelope glycoprotein and in the gp-ll transmembrane envelope glycoprotein. The 2G12 antibody, which ne utralized SHIV-HXBc2 and SHIV-HXBc2P 3.2 equally, bound the HXBc2 and HXBc2 P 3,2 envelope glycoproteins on the cell surface comparably. The ability of the other tested antibodies to achieve saturation was less for the HXBc2P 3.2 envelope glycoproteins than for the HXBc2 envelope glycoproteins. even though the affinity of the antibodies for the two envelope glycoproteins wa s similar, Thus, a highly neutralization sensitive SHIV, by modifying both gp120 and gp41 glycoproteins, apparently achieves a neutralization-resistan t state by decreasing the saturability of its envelope glycoproteins by ant ibodies.