Xu et al. and Julg et al. extend the potential use of bnAbs for HIV-1 prevention. Julg
et al. demonstrated complete protection of
rhesus macaques from a swarm of SHIV
variants by a bnAb “cocktail” of PGT121
(targets the V3 glycan) and PGDM1400
(targets the V1-V2 glycan). PGT121 or
PGDM1400 alone failed to protect rhesus
macaques from the SHIV swarm employed.
Xu et al. used structural information
derived from years of intensive study of
bnAbs to construct synthetic trispecific
bnAbs directed concomitantly to the CD4
binding site, MPER, and the V1-V2 glycan.
The trispecific antibody prototype selected
for further development demonstrated
considerably greater potency and breadth
than any known single human bnAb. The
trispecific antibody protected NHPs from
a mixture of SHIVs that “overwhelmed”
several other bnAbs. Should the trispecific
antibody prove safe and effective in clinical trials, it would herald a new class of
One of the concerns seen with long-term
infusion of human monoclonal antibodies is antidrug antibodies that may reduce
activity and/or lead to allergy-type reactions over time ( 11). The construction of a
trispecific bnAb introduces more synthetic
components, thus increasing the potential
for these reactions. Only clinical testing of
such a drug can evaluate this concern.
The first human clinical trials of a bnAb
to prevent HIV-1 acquisition are under way
[“antibody-mediated prevention” (AMP)
trials, NCT02716675 and NCT02568215].
These trials provide intravenous infusions of the bnAb VRC01 (which blocks the
HIV-1 CD4 binding site) every 8 weeks to
4500 high-risk HIV-1–negative subjects at
47 sites in 11 countries. The VRC01 bnAb
neutralizes about 90% of HIV-1 variants at
concentrations that will be achieved in the
blood of trial participants ( 4). The AMP
trials are designed to determine if VRC01
can prevent HIV-1 acquisition, to establish the concentrations of bnAbs required
for protection, and to define the relationship between any “breakthrough infections” and in vitro sensitivity to VRC01. If
VRC01 works as anticipated, breakthrough
variants should be resistant to this bnAb,
whereas sensitive variants should be eliminated at the mucosa or at sites distant to
the mucosa ( 12).
The feasibility of infusion of bnAbs in the
clinic is challenged by the requirement for
frequent treatments. An important advance
in antibody engineering has been the introduction of selective mutations in the Fc
portion of the antibody. These mutations
improve binding to the neonatal Fc receptor
that protects against antibody degradation,
thereby increasing the concentration of antibody in serum for longer periods of time.
In addition, Fc receptor mutations appear
to enhance mucosal localization of VRC01
in the genital tract of NHPs ( 13). Both Fab
and Fc effector functions have been shown
to be important, providing different mechanisms to prevent viral acquisition in antibody-mediated protection ( 13).
The rapid growth of bnAb use in HIV-1
prevention is a great example of how important clinical observations led to new
technologies and a concerted basic science program to identify targets for HIV-1
vaccine design, and now new products for
the treatment and prevention of HIV-1 ( 4,
8–10). These are early days in bnAb development with a focus on proof-of-concept
studies, such as the AMP trials. Improved
delivery methods to allow long-term generation of bnAbs may prove revolutionary.
For example, bnAbs can be delivered as
an alternative to a vaccine for constitutive
production in people through adeno-as-sociated virus gene transfer. This method
was used to produce the CD4 binding site
bnAb VRC07 (a broader-specificity antibody than VRC01) in vivo, which offered
protection from SHIV infection in NHPs
( 14). More recently, studies of the evolution of bnAbs have led to the identification
of candidate gp120 antigens that, through
sequential exposures, led to the formation
of bnAbs CH103 and CH235, which block
the CD4 binding site ( 3, 15). A clinical trial
(HVTN 115, NCT03220724) is underway in
which sequential injections of immunogens are administered to mimic the B cell
mutations observed during the ontogeny
of CD4 binding site bnAb generation ( 3,
15). The history, scope, and depth of bnAb
research emphasize the hope that use of
such antibodies will affect the trajectory of
the HIV-1 pandemic. j
REFERENCES AND NOTES
1. J. R. Mascola et al., J. Virol. 79, 10103 (2005).
2. L. Stamatatos et al., Nat. Med. 15, 866 (2009).
3. H.-X. Liao et al., Nature 496, 469 (2013).
4. A. Pegu et al., Immunol. Rev. 275, 296 (2017).
5. L. Xu et al., Science 358, 85 (2017).
6. N. A. Doria-Rose etal. , J.Virol. 90, 76 (2015).
7. B.Julg et al., Sci. Transl. Med. 9,eaao4235(2017).
8. L. E. McCoy, D. R. Burton, Immunol. Rev. 275, 11 (2017).
9. A.Escolano et al., J. Exp. Med. 214, 3(2017).
10. K. J. Bar et al. , N. Engl. J. Med. 375, 2037 (2016).
11. L. Doessegger, M. L. Banholzer, Clin. Transl. Immunol. 4,
12. J. Liu et al. , Science 353, 1045 (2016).
13. S.-Y. Ko et al., Nature 514, 642 (2014).
14. K.O.Saunders etal., J.Virol. 89,8334(2015).
15. M. Bonsignori et al. , Cell 165, 449 (2016).
This work was supported by the U.S. National Institute of Allergy
and Infectious Diseases, the Division of AIDS, the HIV Prevention
Trials Network (U01-AI068619), the UNC Center for AIDS
Research (CFAR P30-AI50410), the HIV Vaccine Trials Network
(UM1-AI068614-12), and the U.S. National Institute of Diabetes
and Digestive and Kidney Diseases (R01-DK108424 to M.S.C.).
bnAbs in epithelial mucosa
A mixture of two bnAbs,
PGDM1400 and PGT121, or a
trispeci0c bnAb prevent infection
of CD4 T cells from HIV-1.
bnAbs in deeper tissue
bnAbs can also protect tissues from
HIV-1 infection through natural killer
cells or other phagocytic cells, with no
latent or persistent viral replication in
CD4 T cell
killer cell Dendritic cell
6 OCTOBER 2017 • VOL 358 ISSUE 6359 47
bnAbs prevent HIV-1
Combinations of bnAbs and a trispecific antibody can bind to virions and prevent HIV-1 mucosal infection and
elicit antiviral responses in deeper tissue. It is hoped this multitarget approach will prevent resistant breakthrough.