CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies

Abstract

Approaches to prevent human immunodeficiency virus (HIV-1) transmission are urgently needed. Difficulties in eliciting antibodies that bind conserved epitopes exposed on the unliganded conformation of the HIV-1 envelope glycoprotein (Env) trimer represent barriers to vaccine development. During HIV-1 entry, binding of the gp120 Env to the initial receptor, CD4, triggers conformational changes in Env that result in the formation and exposure of the highly conserved gp120 site for interaction with the coreceptors, CCR5 and CXCR4. The DMJ compounds (+)-DMJ-I-228 and (+)-DMJ-II-121 bind gp120 within the conserved Phe 43 cavity near the CD4-binding site, block CD4 binding, and inhibit HIV-1 infection. Here we show that the DMJ compounds sensitize primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies directed against CD4-induced (CD4i) epitopes and the V3 region, two gp120 elements involved in coreceptor binding. Importantly, the DMJ compounds rendered primary HIV-1 sensitive to neutralization by antisera elicited by immunization of rabbits with HIV-1 gp120 cores engineered to assume the CD4-bound state. Thus, small molecules like the DMJ compounds may be useful as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies.

Importance: Preventing HIV-1 transmission is a priority for global health. Eliciting antibodies that can neutralize many different strains of HIV-1 is difficult, creating problems for the development of a vaccine. We found that certain small-molecule compounds can sensitize HIV-1 to particular antibodies. These antibodies can be elicited in rabbits. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

FIG 1

Effects of NBD-556 and analogues on HIV-1 infection. The infection of Cf2Th-CCR5-CD4 cells by recombinant HIV-1 expressing firefly luciferase was measured in the presence of the indicated concentrations of NBD-556 (A), (±)-MAE-II-120 (B), (+)-DMJ-I-228 (C), and (+)-DMJ-II-121 (D). The viruses contained the HIV-1 JR-FL or A-MLV envelope glycoproteins. The values are represented as a percentage of the level of target cell luciferase observed for each virus in the absence of the compound. The means and standard deviations of the results obtained in triplicate samples are shown. The results are representative of those obtained in 3 to 21 independent experiments.

FIG 2

(+)-DMJ-II-121 sensitizes HIV-1 JR-FL to neutralization by the 17b and 39F antibodies. (A and B) The neutralization of HIV-1 JR-FL by the CD4-induced antibody 17b (A) and the V3-directed antibody 39F (B) in the presence of the indicated concentrations of (+)-DMJ-II-121 is shown. (C and D) Neutralization of virus with the A-MLV envelope glycoprotein by the 17b (C) or 39F (D) antibody in the presence or absence of 50 μM (+)-DMJ-II-121 is shown. (E and F) Infection by viruses with HIV-1 JR-FL or A-MLV envelope glycoproteins in the presence of the indicated concentrations of 17b (E) or 39F (F) antibody and 100 μM NBD-556. All viral infection data shown are normalized to the level of infection seen in the absence of antibody at the indicated concentrations of (+)-DMJ-II-121 (A to D) or NBD-556 (E and F). The means and standard deviations of the results obtained in triplicate samples are shown. The results are representative of those obtained in 4 to 10 independent experiments.

FIG 3

(+)-DMJ-II-121 sensitization of HIV-1 to neutralization by a CD4-induced antibody from an HIV-1-infected individual and a rabbit antiserum elicited by the 3CC stabilized HIV-1 gp120 core. A concentration of (+)-DMJ-II-121 that reduced infection of HIV-1 JR-FL by approximately 50% was used in these experiments. The effects of increasing concentrations of rabbit antiserum elicited by the 3CC stabilized gp120 core on infection by HIV-1 JR-FL (A) or the A-MLV-pseudotyped HIV-1 control (B) are shown. The infection of the B5 transmitted/founder virus in the presence of the indicated concentrations of the 17b antibody, in the absence and presence of 50 μM (+)-DMJ-II-121, is shown (C). The effects of increasing concentrations of the CD4-induced antibody CH08, which was derived from an HIV-1-infected individual (88), on infection by HIV-1 JR-FL (D) and the A-MLV-pseudotyped HIV-1 control (E), in the absence and presence of 50 μM (+)-DMJ-II-121, are shown. All viral infection data shown are normalized to the level of infection seen in the absence of antibody at a 50 μM concentration of (+)-DMJ-II-121. The means and standard deviations of the results obtained in triplicate samples are shown. The results are representative of those obtained in 2 to 20 independent experiments.