HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Abstract

Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env1, in the setting of analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg kg−1 infusions of 3BNC117, separated by 3 or 2 weeks, respectively, are generally well tolerated. Infusions are associated with a delay in viral rebound for 5–9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals, emerging viruses show increased resistance, indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml−1, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9–19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.

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).…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Whether individuals who have developed bnAbs exhibit a reduced susceptibility to HIV‐1 super‐infection has not been addressed, although as bnAbs constitute only part of the overall HIV‐specific antibody response they may not reach sufficient titers to do so. The lack of clinical impact of bnAbs is consistent with early bnAb infusion studies in animal models68 and humans69 that did not show a lasting impact on HIV‐1 viral loads, although newer, more potent bnAbs appear to have a more persistent impact on viral load70, 71, 72 and subsequent antibody development 73. At this time, ongoing clinical trials are being conducted to determine if bnAb infusion can augment other anti‐HIV‐1 therapies.…”

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.…”