Neutralizing antibody-mediated control of lentivirus infection

Sandra Dawn Taylor

Vaccines preventing HIV-1 infection will likely elicit antibodies that neutralize diverse strains. However, the capacity for lentiviruses to escape broadly neutralizing antibodies (nAbs) is not completely understood, nor is it known whether nAbs alone can control heterologous infection. In the first experiment, we determined that convalescent immune plasma from a horse (A2150) persistently infected with equine infectious anemia virus (EIAV) neutralized homologous virus and several envelope variants containing heterologous principal neutralizing domains (PND). Plasma was infused into foals affected with severe combined immunodeficiency (SCID), followed by challenge with a homologous EIAV stock. Treated SCID foals were protected against clinical disease, with complete prevention of infection occurring in one foal. In three SCID foals, a novel neutralization-resistant variant, designated EIAVWSU5-V55, arose that was found to pre-exist at a low frequency in the challenge inoculum. In contrast, SCID foals infused with non-immune plasma developed acute disease associated with high levels of the predominant challenge virus. Following transfer to an immunocompetent horse, EIAVWSU5-V55 induced a single febrile episode and was subsequently controlled in the absence of type-specific nAb. Long term control was associated with the presence of cytotoxic T lymphocytes (CTL). The goal of the second study was to determine if purified plasma immunoglobulin (PPIG) with more potent and broadly neutralizing activity than the plasma used in the first study would prevent homologous and heterologous infection in SCID foals. Thus, plasma or PPIG from horse A2140 was infused into five experimental SCID foals prior to homologous EIAV challenge. Four of these foals were completely protected from infection, while one demonstrated partial protection. However, PPIG infused into an additional SCID foal followed by heterologous EIAVPND5 challenge failed to protect against infection. In the final experiment, pseudoviruses expressing specific variable regions of EIAVWSU5-V55 were tested for neutralization by PPIG from horses A2150 and A2140 to identify SU regions that contribute to neutralization resistance. Our results suggest that although high-titered, broadly nAb can prevent homologous infection in the absence of CTL, they may not be sufficient to prevent heterologous infection. Therefore, a protective lentivirus vaccine will likely require immunogens that elicit broadly nAb and CTL.

Neutralizing antibody-mediated control of lentivirus infection

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