Abstract
An increasing number of broadly neutralizing antibodies (bnAbs) are considered leads for HIV-1 vaccine development and novel therapeutics. Here, we systematically explored the capacity of bnAbs to neutralize HIV-1 prior to and post-CD4 engagement and to block HIV-1 cell-cell transmission. Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection. Selection of bnAbs that are capable of suppressing HIV irrespective of the transmission mode therefore needs to be considered to ascertain their in vivo activity in therapeutic use and vaccines. Employing assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission to T cells, we probed a panel of 16 bnAbs for their activity against 11 viruses from subtypes A, B and C during both transmission modes. Over a wide range of bnAb-virus combinations tested, inhibitory activity against HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs. In rare bnAb-virus combinations, inhibition for both transmission modes was comparable but no bnAb potently blocked cell-cell transmission across all probed virus strains. Mathematical analysis indicated an increased probability of bnAb resistance mutations to arise in cell-cell rather than free virus spread, further highlighting the need to block this pathway. Importantly, the capacity to efficiently neutralize prior to CD4 engagement correlated with the inhibition efficacy against free virus but not cell-cell transmitted virus. Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner. In summary, bnAb activity against divergent viruses varied depending on the transmission mode and differed depending on the window of action during the entry process, underscoring that powerful combinations of bnAbs are needed for in vivo application.
Highlights
Identified highly potent broadly neutralizing HIV antibodies are considered as lead components for vaccines and immunotherapeutics and extensive characterization of these bnAbs in vitro and in vivo is underway to select the most promising candidates [6]
Considering that HIV-1 can utilize free virus and cell-cell transmission to infect, the efficacy of neutralizing antibodies in vivo may depend on their ability to block both pathways
To enable a controlled comparison of bnAb neutralization activity in free virus and cell-cell transmission, we sought to employ an assay format, in which i) both free virus and cell-cell transmission are studied using Env-pseudotyped viruses to limit the infection to a single round, ii) target cells used for free virus and cell-cell transmission are identical and yield results comparable to primary T cell (PBMC) infection, iii) the assays are scalable and can be used to evaluate larger antibody and virus panels
Summary
Identified highly potent broadly neutralizing HIV antibodies (bnAbs) are considered as lead components for vaccines and immunotherapeutics (reviewed in [1,2,3,4,5]) and extensive characterization of these bnAbs in vitro and in vivo is underway to select the most promising candidates [6]. Cell-cell transmission systems described to date vary in respect to donor and target cells, HIV strains and infection systems (multiple–round and single round infection), virus input and readouts used (reporter assays, direct detection of HIV-1 antigens, single cell and bulk cell analysis) and these differences are thought in part to have led to contradicting observations in respect to neutralizing antibody and ART activity during cell-cell transmission [25,26,27,46,47,50,51,52,53,54] Despite these discrepancies, there is agreement that cell-cell transmission, at least in vitro, is vastly more efficient than free virus spread and leads to multiple infection of target cells [36,37,38]. Functional differences of the entry process [49], the maturation status of the virus during cell-cell transmission [49] and the stage of the entry process blocked by neutralizing antibodies [25,30] have been proposed as factors that influence antibody activity during cellcell transmission
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