Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption

Abstract

BACKGROUND The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 μg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P = 0.04 by a two-sided Fisher’s exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher’s exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization–resistant virus. CONCLUSIONS VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326.)

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

“…Thus, Q 2 VOA differs from bulk cultures in that it enables measurement of the genetic and phenotypic diversity of the replication-competent reservoir. Finally, the observation that bNAb neutralization-sensitive and -resistant clones coexist in the reservoir provides an explanation for the observation that combination therapy will likely be required to maintain suppression (27,28).…”

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.…”

Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption

“…While ADCC has not been formally proven to be a mechanism of viral control in subjects treated with bNAbs, many bNAbs have been shown to mediate ADCC in vitro (33)(34)(35) and in vivo in HIV-1-infected humanized mouse models (36)(37)(38). The passive transfer of single bNAbs in the setting of ATI in chronically infected individuals has also been examined, with VRC01 and 3BNC117 delaying viral rebound by several weeks compared to that in historical controls (39,40). However, in most individuals, viral suppression was not maintained and bNAb-resistant rebound viruses emerged as bNAb levels waned.…”

“…However, in most individuals, viral suppression was not maintained and bNAb-resistant rebound viruses emerged as bNAb levels waned. Careful consideration will need to be taken for bNAbs to be used as an antilatency approach, as preexisting viruses that are resistant to some bNAbs may reside within the latent reservoir (39,41), and broad reactivation of genetically diverse HIV-1 proviruses can be induced by LRAs in vivo (42). The complex task of prescreening individuals for bNAbresistant viruses and the combinatorial use of multiple bNAbs targeting different epitopes on Env may be necessary for bNAbs to be effective as an antilatency approach (36).…”