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A New Lease on Life for an HIV-Neutralizing Antibody Class and Vaccine Target COMMENTARY Dennis R

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A New Lease on Life for an HIV-Neutralizing Antibody Class and Vaccine Target COMMENTARY Dennis R COMMENTARY A new lease on life for an HIV-neutralizing antibody class and vaccine target COMMENTARY Dennis R. Burtona,b,1 Neutralizing antibodies (nAbs), in the time of COVID- dependent effect in TZM-bl cells was not due to 19, have received much attention in the lay press ow- phagocytosis of virus and it was proposed that a ing to their association with vaccine protection against “kinetic effect” was responsible. Thus, it was suggested severe acute respiratory syndrome coronavirus 2. The that bnAb bound to FcR would be prepositioned to attention is well-deserved and the association of nAbs bind more effectively to the MPER, which is probably with protection is true for many viruses (1). For HIV, we only fully displayed once initial contact of virus with eagerly await the results of the antibody-mediated target cells has been made. Overall, the possibility protection trial investigating the ability of the HIV broadly then arose that an early event in infection in NHPs neutralizing antibody (bnAb) VRC01 to prevent infection might involve FcRI-bearing cells, most likely mononu- in humans (https://ampstudy.org/). Meanwhile, passively clear phagocytes or dendritic cells, and MPER bnAbs administered and vaccine-induced nAbs have been were thereby advantaged in protection terms. A com- shown to provide protection against mucosal viral chal- plicating factor in this mechanism is the high serum lenge in nonhuman primates (NHPs) (2). A recent anal- concentration of monomeric immunoglobulin G (IgG) ysis of a large number of NHP protection studies that will compete with specific IgG for FcRI binding, and showed a good correlation between serum neutraliza- indeed 5% serum was shown to abolish the FcRI effect tion titer and protection (3). However, one set of bnAbs, for MPER bnAbs (6). However, it was argued that condi- those directed to the membrane proximal external re- tions operating in vivo may still allow the enhancement gion (MPER) of the HIV envelope spike, appeared to be effect. outliers and offered greater protection at lower serum A report in PNAS (11) identifies a class of nAbs neutralizing titers. This phenomenon was first described demonstrating the phenomenon of hugely enhanced for MPER bnAbs 2F5 and 4E10 (4) and was also tenta- neutralization of FcR-bearing target cells as compared tively noted for MPER bnAb 10E8 (5) and has been re- to the corresponding cells lacking FcR. Miller et al. ferred to colloquially as MPER bnAbs “punching above previously described a bnAb, D5, a number of years their weight.” ago that recognizes the N-terminal heptad repeat A very interesting related observation with regard (NHR) region of gp41 (12). The region is conserved, to the phenomenon had earlier been made by Perez being a part of the HIV fusion machinery, but is only et al., who showed that neutralization was greatly transiently exposed during the process in which the enhanced in target cells (TZM-bl cells) engineered to virus membrane fuses with that of the target cells pre- express Fc receptors, particularly FcRI and to a lesser ceding the transfer of viral genetic information to the extent FcRIIb, on their surface as compared to wild- target cell (13, 14). The NHR is a validated clinical tar- type target cells (6). The enhancement was shown to get for the drug enfuviritide (15). However, D5 primar- be dependent on the Fc region of the bnAbs. This ily only neutralizes highly sensitive HIV isolates (tier-1 result was consistent with some observations made viruses) and is very weak against more neutralization- even earlier by Holl et al. (7–9), who noted that the resistant viruses (tier 2), characteristic of human infec- MPER bnAbs 2F5 and 4E10 showed hugely enhanced tion and transmission. Therefore, interest in the anti- ability to neutralize viruses infecting mononuclear body per se and its epitope as a vaccine target has phagocytes and monocyte-derived dendritic cells been limited. In this report, it is demonstrated that D5 and a link to FcRI expression. They likewise showed neutralizes a range of tier-2 viruses effectively in TZM-bl the dependence of the effect on the Fc part of the Ab target cells expressing human FcRI. The enhancement molecule. A later study (10) showed that the FcR- effect in certain cases is estimated to be of the order of aDepartment of Immunology and Microbiology, IAVI Neutralizing Antibody Center, Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037; and bRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139 Author contributions: D.R.B. wrote the paper. The author declares no competing interest. Published under the PNAS license. See companion article, “The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat,” 10.1073/pnas.2018027118. 1Email: [email protected]. Published January 27, 2021. PNAS 2021 Vol. 118 No. 7 e2026390118 https://doi.org/10.1073/pnas.2026390118 | 1of3 Downloaded by guest on September 28, 2021 greatly increases the effective concentration of antibody when virus engages target cell receptors, leading to much more effective neutralization (Fig. 1). The key question now is whether the FcR-dependent property described can be exploited either in the use of passive antibodies antivirally or in vaccine development. As proposed by the authors, an important experiment is now to determine whether D5 punches above its weight in protection experiments in NHPs— that is, does it offer protection at relatively low serum neutralizing titers to mucosal challenge? If it does, then this would suggest that D5, especially if engineered to have higher affinity for its target epitope (16), could find prophylactic and possibly thera- peutic application given its breadth of neutralization. The NHR would also then be a possible attractive vaccine target. Impor- tantly, a positive result, together with existing MPER bnAb pro- tection, would also be suggestive of the involvement of FcRI- bearing cells, such as mononuclear phagocytes, at a crucial stage in the infection process in NHPs. As noted by the authors, the identity of the cells involved first in the very early stages of trans- Fig. 1. Modeling of the interaction of FcRI-bound IgG to the NHR mission is uncertain but there is evidence that FcRI-bearing cells region of gp41 of HIV envelope during viral entry (compare figure 5 of ref. 11). It is hypothesized that, during viral entry and the such as macrophages and dendritic cells can transmit virus to interaction of HIV envelope with CD4 and CCR5 on target cells, the CD4+ T cells (17, 18), which will of course become the predom- NHR is exposed for recognition by antibody D5 complexed to FcRI on inant cell type infected with HIV in the developing course of in- the target cells. Prepositioning of D5 in this way greatly enhances the fection. A positive result for D5 protection in NHPs would inspire ability of the antibody to inhibit viral entry. The modeling used known further work in the animal model on vaccine-induced protection structures and interaction sites where available. The Fc portion of a human FcγR I/Fc complex (Protein Data Bank [PDB] ID code 4W4O, and the possibilities of translating findings to humans. red) was superimposed on the Fc of human IgG (IgG b12, modified Finally, the enhanced neutralization described by bringing from PDB ID code 1HZH, dark and light blue) and extracted. The NHR is nAbs in close proximity to the membrane of target cells may have represented by the coordinates of a gp41 NHR trimer mimetic (PDB ID utility in terms of bifunctional antibody constructs combining code 6R2G, orange) and the rest of gp41 is represented schematically as in figure 5 of ref. 11. To avoid structural clashes, the immunoglobulin specificity for HIV with specificity for a target cell antigen. Indeed, Fab arms are bent away from the bound FcRI, and the Fc portion is lain one such “CrossMAb” incorporating the MPER bnAb 10E8 and flat parallel to the surface of the host cell membrane (pink). The figure anti-CD4 has been described and is now under clinical evaluation can be compared to the tight space modeled for the interaction of an (19). The anti-CD4 specificity in that construct is as an active in- FcRIIa-bound IgG molecule bound to the envelope proteins of an hibitor of viral entry but also tethers the MPER Ab to the target cell alphavirus (20). Modeling and three-dimensional rendering by Christina Corbaci and Lars Hangartner. surface at precisely the location for viral entry on the cell mem- brane. A similar result is found for 10E8 linked to an anti-CCR5 specificity. Following the studies described here, more tethering 5,000. The effect is shown to be dependent on the Fc region of constructs could be readily envisaged and evaluated. the antibody. Furthermore, immunization of guinea pigs with an NHR-based immunogen generates antisera that show neutralizing Acknowledgments I thank Lars Hangartner and Christina Corbaci for help with the figure. I activity dependent upon FcR expression on the target cells. The acknowledge the financial support of the National Institute of Allergy and explanation for the results, similar to the MPER bnAbs, is that the Infectious Diseases, the Bill and Melinda Gates Foundation, the International prepositioning of the D5 and polyclonal NHR Abs on the FcR AIDS Vaccine Initiative, and the James B. Pendleton Charitable Trust. 1 P. J. Klasse, Neutralization of virus infectivity by antibodies: Old problems in new perspectives. Adv. Biol. 2014, 157895 (2014). 2 A. J. Hessell, D. C. Malherbe, N. L. Haigwood, Passive and active antibody studies in primates to inform HIV vaccines. Expert Rev. Vaccines 17,127–144 (2018).
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