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

TitleCD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies.
Publication TypeJournal Article
Year of Publication2014
AuthorsMadani N, Princiotto AM, Schön A, LaLonde J, Feng Y, Freire E, Park J, Courter JR, Jones DM, Robinson J, Liao H-X, M Moody A, Permar S, Haynes B, Smith AB, Wyatt R, Sodroski J
JournalJ Virol
Volume88
Issue12
Pagination6542-55
Date Published06/01/2014
ISSN1098-5514
KeywordsAIDS Vaccines, Animals, Antigens, CD4, Antiviral Agents, Cell Line, Female, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Neutralization Tests, Rabbits
Abstract

UNLABELLED: 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.

DOI10.1128/JVI.00540-14
Alternate JournalJ. Virol.
PubMed ID24696475
PubMed Central IDPMC4054336
Grant ListAI090682 / AI / NIAID NIH HHS / United States
AI100645 / AI / NIAID NIH HHS / United States
AI24755 / AI / NIAID NIH HHS / United States
GM56550 / GM / NIGMS NIH HHS / United States
P01 GM056550 / GM / NIGMS NIH HHS / United States
R37 AI024755 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
CHAVI-ID: 
1
Cover Picture: