Background:  Natural human infection with HIV-1 usually results in a highly strain-specific neutralizing antibody response. Antibodies that neutralize the infecting strain in 1 infected individual typically exhibit little or no neutralizing activity against other primary isolates of HIV-1. This strain specificity of the neutralizing antibody response has been observed in simian immunodeficiency virus (SIV) infection as well as HIV. It is reasonable to think that the variable loops of the envelope glycoprotein, gp120, are responsible for this strain specificity of the neutralizing antibody response; however, this has not yet been formally demonstrated. Additionally, which variable loop(s) may be principally responsible for the strain specificity has not been defined.

Methods:  Sequential sera were obtained from monkeys 2.5 to 6 months after infection with cloned SHIV-DH12 or cloned SHIV-KB9 (89.6P). Neutralization assays were developed for these 2 viruses that utilize secreted engineered alkaline phosphatase (SEAP) as a reporter for infection of C8166 cells. Neutralization assays were conducted to investigate the extent of the strain-specific neutralizing antibody activity in the simian/human immunodeficiency virus (SHIV)-infected monkey sera samples against each of the 2 SHIV clones.

Results:  Sera from monkeys infected with SHIV-KB9 neutralized SHIV-KB9 to titers greater than 1:1280, but they did not detectably neutralize SHIV-DH12. These same sera also did not neutralize 2 pathogenic SHIV-DH12 derivatives, clone 7 and clone 8. Similarly, sera from monkeys infected with SHIV-DH12 neutralized SHIV-DH12 to titers greater than 1:1280, but they did not detectably neutralize SHIV-KB9.

Conclusions:  These neutralization studies demonstrated exquisite strain specificity to the neutralizing response that parallels the strain specificity seen during natural human infection with HIV-1. The SHIV-DH12 and SHIV-KB9 have distinct envelope glycoproteins, with the vast majority of amino acid sequence variation confined to discrete variable regions. To discern which loops may be contributing to this strain specificity, chimeric viruses have been designed in which the V1/V2 loops, V3 loop, or V4 loop are exchanged between SHIV-DH12 and SHIV-KB9 alone and in combination. Neutralization analyses of these chimeric viruses with KB9-postive sera and DH12-positive sera will clarify the role of the variable loops in the strain specificity of neutralization and may help identify the contribution of each loop to this strain specificity.