Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG.

We have tested three human monoclonal antibodies (MAbs) IgG1b12, 2G12, and 2F5) to the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1), and a tetrameric CD4-IgG molecule (CD4-IgG2), for the ability to neutralize primary HIV-1 isolates from the genetic clades A through F and from group O. Each of the reagents broadly and potently neutralized B-clade isolates. The 2F5 MAb and the CD4-IgG2 molecule also neutralized strains from outside the B clade, with the same breadth and potency that they showed against B-clade strains. The other two MAbs were able to neutralize a significant proportion of strains from outside the B clade, although there was a reduction in their efficacy compared with their activity against B-clade isolates. Neutralization of isolates by 2F5 correlated with their possession of the LDKW motif in a segment of gp41 near the membrane-spanning domain. The other two MAbs and CD4-IgG2 recognize discontinuous binding sites on gp120, and so no comparison between genetic sequence and virus neutralization was possible. Our data show that a vaccine based on the induction of humoral immunity that is broadly active across the genetic clades is not impossible if immunogens that express the epitopes for MAbs such as 2F5, 2G12, and IgG1b12 in immunogenic configurations can be created. Furthermore, if the three MAbs and CD4-IgG2 produce clinical benefit in immunotherapeutic trials in the United States or Europe, they may also do so elsewhere in the world.

Lack of greater seroconversion of rhesus monkeys after subcutaneous inoculation of dengue type 2 live-virus vaccine combined with infection-enhancing antibodies.

Four groups of six nonimmune male rhesus monkeys were inoculated subcutaneously with formulations of dengue type 2 vaccine virus DEN-2/S-1. Group A received 1.9 x 10(4) plaque-forming units of vaccine in normal human serum albumin diluent. Group B received the same dose combined with a dengue type 2-immune human serum diluted 1:1,600, beyond its neutralization endpoint of 1:300, but having an immune enhancement titer of 250,000. Groups C and D received 10-fold dilutions of these respective formulations. No migration-inhibitory factor was found when peripheral blood mononuclear leukocytes obtained on day 68 post-immunization from monkeys of all experimental groups were tested. No viremia was detected in any of the monkeys when sera taken on postvaccination days 1 through 12 were inoculated into adult Toxorhynchites amboinensis mosquitoes and LLC-MK2 cells. By day 89, four of the six monkeys had seroconverted by the neutralization test in each of groups A, B, and C, and three of five monkeys in group D (one monkey died from cardiac collapse after anesthesia) had seroconverted. Immune enhancement of dengue virus infection is known to occur in humans and monkeys circulating heterologous flavivirus antibodies. In this study, there was no enhancing effect when antibody was mixed with dengue type 2 vaccine virus and injected subcutaneously.