An exploration of how broadly neutralizing antibodies might induce HIV remission: the ‘vaccinal’ effect

Abstract

Purpose of reviewBroadly neutralizing antibodies (bNAbs) are a potential new therapeutic strategy to treat HIV infection. This review explores possible mechanisms of action of bNAbs and summarizes the current evidence supporting their immunomodulatory properties, which might lead to sustained virological remission --the 'vaccinal effect'. Recent findingsAntiretroviral therapy (ART) is required to confer lasting HIV suppression; stopping ART almost invariably leads to HIV recrudescence from a persistent pool of virally infected cells --the HIV reservoir. HIV-specific broadly neutralizing antibodies (bNAbs) may confer viral control after ART cessation predominantly through blockade of viral entry into uninfected target cells. In some human and animal studies, HIV bNAbs also conferred lasting viral suppression after therapeutic bNAb plasma levels had declined. Immune-modulatory mechanisms have been postulated to underlie this observation --the 'vaccinal effect'. Hypothesized mechanisms include the formation of immune complexes between bNAbs and HIV envelope protein, thereby enhancing antigen presentation and uptake by immune cells, with boosted adaptive immune responses subsequently controlling the HIV reservoir. SummaryThere is emerging evidence for potent antiviral efficacy of bNAb therapy. Whether bNAbs can induce sustained viral suppression after dropping below therapeutic levels remains controversial. Mechanistic data from on-going and future clinical trials will help answer these questions.

Directing HIV-1 for degradation by non-target cells, using bi-specific single-chain llama antibodies

“…Conventional antibodies bind to HIV through two variable domains and require engagement of the immune system through their constant domains (Fc), before finally the viruses are cleared. This takes time and is most likely the reason that neutralizing antibodies are required 8,63 . EGFR is ubiquitously expressed on many (non-immune) cells in the body.…”

“…Treatment interruption results in renewed viral replication and a rapid viral rebound from these latent reservoirs [3][4][5] . For this reason, lifelong daily adherence to cART is required in infected individuals, which is costly, associated with side effects and can result in selection of multidrug-resistant escape mutants.HIV-1 specific broadly neutralizing antibodies (bNAbs) present an immune therapy based alternative for cART [6][7][8][9][10][11][12] . bNAbs have been isolated from the sera of some HIV-1 infected individuals.…”

“…HIV-1 specific broadly neutralizing antibodies (bNAbs) present an immune therapy based alternative for cART [6][7][8][9][10][11][12] . bNAbs have been isolated from the sera of some HIV-1 infected individuals.…”

Polyfunctionality of broadly neutralizing HIV-1 antibodies

“…Therefore, the impact on viral replication in dense areas such as lymph nodes is probably limited as compared to neutralization alone, but this phenomenon may be of outmost importance to generate immunomodulatory ICs. bNAbs are studied for their capacity to promote endogenous immune responses (the so-called ‘vaccinal effect’) via Env-containing immune complexes (for a review, see [46]). However, the origin of these immunogens is unknown.…”

“…More recently, the vaccinal effect has emerged as a possible mechanism underlying the efficacy of bNAbs therapies, and as a mean to improve and extend their utilization (for a review see [46]). FcRn engagement in the lysosome of dendritic cells is required to target engulfed antibodies to cross-presentation pathways [56].…”