Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent

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.

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

“…Cell-to-cell infection is mediated by adhesive cell-cell contacts that form between infected and uninfected CD4 ϩ T cells (called "virological synapses" [VS]). Cell-to-cell infection through VS is more efficient than cell-free infection in vitro (1,2) and has been found to resist neutralizing antibodies (NAbs) to a greater extent than infection by the same viral clone when it is presented as cell-free virus (1,(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

“…However, several new-generation bNAbs with remarkable potency and breadth have been found to block cell-to-cell infection considerably less effectively than cell-free infection and this is even clearer in examining HIV-1 primary isolates (3-7, 9, 10). The magnitude of resistance is dependent on both the targeted epitopes and the viral strains (7). The mechanisms that promote resistance of cell-associated HIV-1 to neutralization by bNAbs are still unclear.…”

New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

“…Overall, the T/F Envs tended to show greater disparities in cell-to-cell versus cell-free susceptibility to bnAb neutralization than the more commonly used laboratory strains, highlighting the need for caution in interpreting results solely on the basis of laboratory isolates. Furthermore, studies of bnAb cell-to-cell infection have been carried out mainly with clade B HIV-1 Envs, and inclusion of more genetically diverse variants that are representative of other globally significant subtypes will be important (37). As discussed previously, the decreased effectiveness against cell-to-cell infection was consistent, but the magnitude ranged widely depending on the Env variant and epitope targeted by the bnAb.…”

“…In fact, chronically infected cells appear to transfer virus more directly, via Env-mediated fusion at the plasma membrane (38), while acutely transfected cells seem to require the endocytosis of immature virions following membrane fusion (39). These findings have important implications for neutralizing antibody-based vaccination and therapeutic strategies (1), as there might be an increased probability of bnAb resistance mutations in cell-cell compared to cell-free virus spread, further highlighting the importance of understanding the decreased susceptibility of cell-to-cell HIV-1 infection to neutralization (37).…”

“…Even a slight decrease in susceptibility in vivo could result in a substantial effect on virus production in amplification over multiple rounds of replication. Studies have consistently shown that HIV-1 broadly neutralizing antibodies can block cell-to-cell infection but that much higher concentrations or bnAb combinations are frequently required (33)(34)(35)(36)(37). All of those studies reported that differences between cell-free neutralization and cell-associated neutralization were seen across virus strains and antibody epitopes.…”