Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.


Potency needs constancy

In a finding that highlights ways to optimize the efficacy of antibody-based therapeutics and vaccines, the activity of potent HIV-1-neutralizing antibodies has been confirmed to depend on cellular binding to the antibodies' Fc regions.

Protection conferred against virus infection by licensed antiviral vaccines is mostly due to the generation of 'neutralizing' antibodies that bind to virus particles in such a way that they block their entry into a cell1. Current strategies for designing treatments and vaccines for HIV-1 focus on such antibodies, particularly on the highly potent, broadly neutralizing antibodies that are produced during the immune responses of rare infected individuals2,3 and which bind to the envelope protein (a highly variable protein) of multiple strains of the virus. However, it is becoming clear that the impact of these antibodies is not limited to direct viral neutralization through binding. Writing in Cell, Bournazos et al.4 show that in vivo activity of even the most potent broadly neutralizing anti-HIV-1 antibodies relies on antiviral functions that are triggered by binding of cellular receptors — the Fcγ receptors — to the 'tail' region of antibodies of the immunoglobulin G class, binding that was previously found5 to be crucial for sustaining the in vivo activity of less-potent neutralizing antibodies.

Despite showing promising neutralizing activity in vitro, attempts to use broadly neutralizing antibodies to control HIV-1 infections in vivo have had limited success. Up to now, only the most potent neutralizing antibodies, used at high dose and often only in combination, have yielded measurable control of HIV-1, and this effect rapidly declines with waning antibody levels and as a result of mutations that allow the virus to 'escape' antibody binding6,7,8,9. Difficulties with tissue penetration10 and reduced neutralizing activity during cell-to-cell viral transmission11 may also contribute to the lower efficacy of these antibodies in vivo and necessitate the maintenance of antibody levels orders of magnitude above those sufficient in vitro6,7,8,9.

Antibodies are notable for their capacity to link the adaptive and innate arms of the immune response: the variable domains of an antibody specifically recognize different targets, and their constant tail domain, the Fc region, stimulates an array of immune defences. The Fc region is bound by proteins of the complement system, which activate signalling pathways to induce inflammatory responses and destruction of antibody-bound cells or viruses. The Fc region of immunoglobulin G is also recognized by activating and inhibitory Fcγ receptors (FcγRs) on effector cells of the immune system, such as monocytes, macrophages, dendritic cells, neutrophils and natural killer cells. Fc binding provides these cells with essential stimulatory and regulatory signals12. FcγR-mediated effector-cell functions include antibody-dependent cellular cytotoxicity (in which antibodies bind to viral proteins expressed on the infected cell, triggering its killing by effector cells), phagocytic clearance (cellular engulfment and destruction of viruses), and the release of soluble antimicrobial and immunomodulatory factors, such as cytokines and chemokines (Fig. 1).

Figure 1: Antibody-mediated viral control.

a, Binding of certain (blue) but not other (red) antibodies' variable regions to an HIV-1 virus particle can directly neutralize the virus if all envelope proteins required for cell entry are inhibited. b, However, Bournazos et al.4 show that the antiviral activity of these neutralizing antibodies in vivo depends on effects elicited when the constant (Fc) regions of immunoglobulin G antibody molecules are bound by Fcγ receptors (FcγRs) on the surface of effector cells of the immune system. These effects include engulfment and destruction (phagocytosis) of antibody-bound virus particles (including neutralized and non-neutralized particles); the secretion of soluble factors that stimulate other immune activities; and direct killing (antibody-dependent cellular cytotoxicity; ADCC) of virus-infected cells.

Recruitment of effector functions has long been a focus in the harnessing of antibody-based protection against HIV-14,5,12,13,14, but the precise contributions of direct antibody-mediated virus neutralization, activity of the complement system and FcγR-mediated effector functions remain unresolved13. Pioneering work indicated that neutralizing antibodies require FcγR functions for their in vivo activity5, whereas non-neutralizing antibodies that act solely through effector functions have shown limited in vivo activity against HIV-113,15, suggesting that a combination of both neutralization and effector-mediated activity is needed. By contrast, complement action seems dispensable, at least when neutralizing antibodies are used as a pre-exposure prophylaxis (to try to prevent infection)5. Now, Bournazos et al. expand on the previous finding that FcγR-dependent mechanisms are required5 by investigating the effect of antibody treatment on HIV-1 infection in mice in the presence or absence of Fc–FcγR interactions, either by modulating the antibodies' Fc region or by using mice lacking FcγRs.

Particularly notable is the authors' finding that, despite their superior potency, even the action of broadly neutralizing antibodies is largely dependent on interactions with activating FcγRs. When the researchers engineered the antibodies to improve the strength of Fc–FcγR binding, they observed increased viral control in vivo, highlighting the potential of antibody improvement for therapeutic use. On reflection, however, this dependence on FcγR functions might prove to be a crucial limitation on the use of engineered molecules designed to inhibit HIV entry to cells by targeting viral envelope proteins, because such molecules lack the ability to recruit immune effector functions.

Intriguingly, in experiments using HIV particles that can complete only one round of infection, such that newly infected cells do not express HIV envelope proteins and hence lack binding sites for antibodies, Bournazos et al. still saw FcγR-dependent antibody-mediated viral control. This suggests that classical antibody-dependent cellular cytotoxicity can be ruled out as a sole driving force, and that effector-cell release of soluble antiviral factors and the phagocytic clearance of viral particles may be decisive.

Nevertheless, a central question that remains is, why would a potent neutralizing antibody need to rely on fast, FcγR-mediated removal of antibody-bound viral particles? There are several possible explanations. Neutralization can be reversible if the antibody binding has a high off-rate16,17,18, and if an antibody fails to irreversibly neutralize the virus, it may be crucial to eliminate these viruses rapidly before they regain infectivity. Tissue penetration may be another limiting factor10: lower antibody doses at certain sites may mean that not all envelope proteins on the virus are immediately bound and neutralized.

How many envelope proteins HIV carries, how many of these are needed to infect (and in turn must be neutralized), and how many antibody molecules are needed to trigger irreversible neutralization of envelope proteins will all also contribute to the rate of virus inactivation19. Alongside these stoichiometric requirements, the kinetics of neutralization will be steered by the on-rate of antibody binding. Considering all these factors, enhanced clearance of antibody-bound viral particles may become relevant in situations in which the virus is not fully neutralized, either because the threshold of neutralizing-antibody binding required for inactivation has not been reached, or because the specific neutralizing antibody fails to irreversibly block the virus. In support of the idea that quantity of antibody, and hence antibody occupancy, plays a part, Bournazos and colleagues observed that eliciting FcγR effector functions had an additive effect on viral control at lower, but not higher, antibody doses.

Further work will be needed to precisely quantify the impact of phagocytic clearance, and to define if only one or a combination of FcγR-mediated functions is needed to achieve in vivo control of HIV-1 by neutralizing antibodies. Several technical challenges may arise in attempts to investigate this. HIV-1 infection is commonly monitored by quantifying levels of viral RNA, but this approach does not assess the infectivity of the viral particles present, and so both neutralized and non-neutralized virions will be counted. Thus, short-term experiments in which the effects of neutralizing antibodies are assessed solely on the basis of a reduction in RNA levels will not be able to quantify the contribution of Fc-mediated effects. Long-term monitoring of infections, as performed by Bournazos et al.4 and in previous work5, in combination with measurements of circulating infectious virus and infected cells, will be key to quantifying the influence of FcγR-dependent mechanisms.


  1. 1

    Koff, W. C. et al. Science 340, 1232910 (2013).

    Article  Google Scholar 

  2. 2

    Burton, D. R. et al. Cell Host Microbe 12, 396–407 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Mascola, J. R. & Montefiori, D. C. Annu. Rev. Immunol. 28, 413–444 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Bournazos, S. et al. Cell 158, 1243–1253 (2014).

    CAS  Article  Google Scholar 

  5. 5

    Hessell, A. J. et al. Nature 449, 101–104 (2007).

    CAS  ADS  Article  Google Scholar 

  6. 6

    Barouch, D. H. et al. Nature 503, 224–228 (2013).

    CAS  ADS  Article  Google Scholar 

  7. 7

    Klein, F. et al. Nature 492, 118–122 (2012).

    CAS  ADS  Article  Google Scholar 

  8. 8

    Trkola, A. et al. Nature Med. 11, 615–622 (2005).

    CAS  Article  Google Scholar 

  9. 9

    Poignard, P. et al. Immunity 10, 431–438 (1999).

    CAS  Article  Google Scholar 

  10. 10

    Ko, S.-Y. et al. Nature (2014).

  11. 11

    Abela, I. A. et al. PLoS Pathog. 8, e1002634 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Ackerman, M. E., Dugast, A. S. & Alter, G. Annu. Rev. Med. 63, 113–130 (2012).

    CAS  Article  Google Scholar 

  13. 13

    Ackerman, M. E. & Alter, G. Curr. HIV Res. 11, 365–377 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Huber, M. et al. PLoS Med. 3, e441 (2006).

    Article  Google Scholar 

  15. 15

    Burton, D. R. et al. Proc. Natl Acad. Sci. USA 108, 11181–11186 (2011).

    CAS  ADS  Article  Google Scholar 

  16. 16

    Platt, E. J., Gomes, M. M. & Kabat, D. Proc. Natl Acad. Sci. USA 109, 7829–7834 (2012).

    CAS  ADS  Article  Google Scholar 

  17. 17

    Ruprecht, C. R. et al. J. Exp. Med. 208, 439–454 (2011).

    CAS  Article  Google Scholar 

  18. 18

    Yasmeen, A. et al. Retrovirology 11, 41 (2014).

    Article  Google Scholar 

  19. 19

    Magnus, C., Rusert, P., Bonhoeffer, S., Trkola, A. & Regoes, R. R. J. Virol. 83, 1523–1531 (2009).

    CAS  Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Alexandra Trkola.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Trkola, A. Potency needs constancy. Nature 514, 442–443 (2014).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing