Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection

Abstract

Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression.

HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells

“…Vaccination or other strategies that enhance the humoral response to HIV gp120 at the CD4-binding site relative to binding of other HIV envelope epitopes may have therapeutic potential in reducing immune activation. In addition, mAbs directed against HIV are being tested currently in clinical trials to prevent HIV rebound following discontinuation of ART and are being considered in HIV prevention trials (47)(48)(49)(50). Our data demonstrate that the effects of mAb on pDC production of IFN should be considered prior to mAb selection for clinical trials because mAbs that enhance pDC production of IFN might increase immune activation.…”

Des anticorps qui détruisent les cellules infectées par le VIH-1

“…Si la conception d'un vaccin capable d'induire des bNAb semble encore difficile, des immunothérapies passives, réalisées par injection d'anticorps recombinant, sont en cours d'essai clinique aux États-Unis. Ainsi, l'injection du bNAb 3BNC117 ou du VRC01, qui se fixent tous les deux sur le CD4 binding site, permet de diminuer la charge virale de 10 à 100 fois pendant 28 jours chez des patients infectés [7,8]. Le mécanisme d'action in vivo de ces anticorps reste mal compris.…”

“…La plupart de ces anticorps inhibent la transmission du virus de cellule à cellule [12]. Un test révélateur de l'activation de la voie initiée par le récepteur CD16, qui est la voie de signalisation de l'ADCC dans les cellules NK, a été essais cliniques des bNAb (3BNC117 et VRC01) ne montrent pas de diminution spectaculaire de la charge en ADN viral, un marqueur de la taille du réservoir, lorsque ces anticorps sont utilisés en monothéra-pie [7,8]. Figure 2B).…”

CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies

“…The breadth and potency of NIH45-46 were increased through a G54W mutation (NIH45-46 G54W ), where the tryptophan targets the Phe-43 cavity of the CD4-binding site on gp120 (11). Importantly, these highly potent broadly neutralizing antibodies (bNAbs) can protect from HIV-1 challenge and reduce viral loads in infected humanized mice and rhesus macaques and in HIV-infected individuals (12)(13)(14)(15)(16)(17).…”