Immune checkpoint modulation enhances HIV-1 antibody induction.
Todd BradleyMasayuki KuraokaChen-Hao YehMing TianHuan ChenDerek W CainXuejun ChenCheng ChengAli H EllebedyRobert ParksMaggie BarrLaura L SutherlandRichard M ScearceCindy M BowmanHilary Bouton-VervilleSampa SantraKevin WieheMark G LewisAne OgbePersephone BorrowDavid MontefioriMattia BonsignoriM Anthony MoodyLaurent VerkoczyKevin O SaundersRajesh M ValanparambilJohn R MascolaGarnett KelsoeFrederick W AltBarton F HaynesPublished in: Nature communications (2020)
Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.
Keyphrases
- hiv infected
- antiretroviral therapy
- hiv positive
- human immunodeficiency virus
- hiv testing
- hiv aids
- hepatitis c virus
- men who have sex with men
- mouse model
- south africa
- type diabetes
- induced apoptosis
- dna methylation
- radiation therapy
- metabolic syndrome
- adipose tissue
- squamous cell carcinoma
- cancer therapy
- transcription factor
- insulin resistance
- skeletal muscle
- cell proliferation
- oxidative stress
- signaling pathway
- cell death