INSIGHTS | PERSPECTIVES
eric immunodeficiency viruses (SHIVs)
with TF Envs (12). Importantly, bnAbs are
highly effective in protecting against retro-virus transmission when passively administered to monkeys challenged with SHIVs.
A fundamental problem is the inability of
current vaccines to induce high titers of
bnAbs to the relatively conserved sites of
vulnerability on HIV-1 Env.
The roadblocks to inducing bnAbs are
multiple. The immunogen must be optimized to display the precise epitope recognized by the bnAb, requiring information
at the molecular level. A soluble gp140
SOSIP trimer enabled crystallization and
cryo–electron microscopy (cryo-EM) to
determine its structure (9). Concordance
between this structure and the cryo-EM
structure of a membrane-bound trimer
(9) was an important step in the evaluation of the native trimer structure. Because
stabilization of the SOSIP trimer has been
achieved, Envs can now be routinely made
that do not expose non-neutralizing and potentially diverting epitopes. Unfortunately,
immunization of rabbits and monkeys with
SOSIP trimers alone did not induce bnAbs
(8), indicating that additional strategies are
needed. In addition, bnAb evolution has
been observed only after extensive virus
Env diversification (10). This suggests that
multiple sequential Envs may be required
to induce bnAbs through vaccination.
Another obstacle is that HIV Env is one
of nature’s most heavily glycosylated proteins. The conserved Env sites to which
bnAbs bind are heavily masked by glycans,
yet most bnAbs must interact with, or at
least accommodate, Env glycans (see the
figure). Unfortunately, Env glycans are
derived from the host, are poorly immunogenic, and can be quite heterogeneous,
providing further challenges for bnAb elicitation and recognition.
To recognize epitopes, bnAbs typically
have one or more unusual traits, including
long heavy-chain third complementarity-
determining regions (HCDR3s), high levels
of somatic mutations, high frequency of
insertions and deletions (indels), and reac-
tivity with self or environmental antigens
(autoreactivity or polyreactivity) (5, 6, 11).
Mice engineered to express some bnAb Ig
heavy-chain variable domain (VH) and light-
chain variable domain (VL) genes display
central tolerance (deletion), receptor edit-
ing, antibody reversion (loss of reactivity to
target epitope), and peripheral anergy (self-
reactive T cells become nonresponsive), all
of which control bnAb development (13).
Immune tolerance control of bnAbs can
reduce the pool of bnAb-producing B cells
capable of responding to a vaccine and
may increase the propensity of bnAb B cell
lineages to divert “off track” during anti-
gen stimulation and affinity maturation.
Typically, bnAb B cell lineages—even when
they arise in HIV-infected individuals, and
certainly in vaccination—are subdominant
and therefore disfavored (11–14).
Another challenge is that germline versions of bnAbs frequently do not bind
to most Env proteins, suggesting either
the design of specific germline-targeting
molecules or the very careful choice of a
sequence of TF Env molecules (perhaps informed by antibody-virus coevolution studies) to initiate a bnAb response. Targeting
naive B cell receptors (which correspond
to bnAbs that the B cells produce) can indeed activate and expand bnAb precursor B
cells. Moreover, Env antigens have successfully induced bnAbs in near-germline bnAb
B cell receptor–expressing mice (15). What
has yet to be accomplished is to induce
bnAbs in outbred nonhuman primates
or in human clinical trials. An additional
proposal is vaccine transient immune
modulation, in which vaccination occurs
in concert with inhibitors of immune tolerance to allow bnAb-producing precursor
B cells to survive and to activate anergic
B cells in peripheral immune sites (11). To
avoid systemic breaks in tolerance, specific
stimulators of protective antibodies are being defined, as well as specific inhibitors of
those controls that prevent the stimulation
and maturation of bnAb-producing B cells.
What are the preferred targets for bnAb
induction? Sites toward the “top” of the
Env spike are advantageous in that they
frequently trigger an antibody response
in natural infection, often relatively early,
and have relatively low levels of somatic
hypermutation. However, such antibodies
require glycan recognition, albeit to rela-
tively homogeneous high-mannose glycans.
Those bnAbs that target the CD4 binding
site of the Env protein typically have high
levels of somatic hypermutation but do not
require direct glycan recognition. BnAbs
that recognize the envelope glycoprotein
41 (gp41)–gp120 interface usually involve
binding to complex heterogeneous glycans
and so may be disadvantaged. Experimen-
tal approaches will be crucial in deciding
the best targets.
Overall, degrees of protection from HIV,
SIV, and SHIV transmission have been seen
with vaccination; thus, we know that development of a protective HIV vaccine is, in
principle, possible. What is not known is
how studies in monkeys will translate into
humans. Critical questions for HIV vaccine
development include (i) What are strategies for improving vaccine efficacy seen in
the RV144 trial? (ii) Can human attenuated
CMV or other vectors that induce atypical
CD8 T cell responses clear acute HIV infection similar to rhesus CMV vectors? (iii)
What are the preferred structures, forms,
and sequences of Env immunogens that
are needed to induce bnAbs? (iv) How are
bnAbs regulated as compared with easily
induced non-neutralizing or neutralizing
antibodies to very sensitive viruses? Answering these questions in the coming years
should yield promising vaccine candidates
to be tested in human clinical trials and
bring us closer to a practical HIV vaccine. j
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This work was supported by the National Institute of Allergy and
Infectious Diseases, the Division of AIDS, the Centers for HIV/
AIDS Vaccine Immunology–Immunogen Discovery Grants at
Duke School of Medicine, Durham, NC (AI000645) and at The
Scripps Research Institute, La Jolla, CA (AI 100663); and the Bill
& Melinda Gates Foundation with Collaboration for AIDS Vaccine
Discovery Grants OPP52282, OPP1114721, and OPP1094352 to
B.F.H., and OPP1084519 to D.R.B. Many important references
were not cited because of space limitations. See the supplementary materials for additional references.
1130 17 MARCH 2017 • VOL 355 ISSUE 6330
Protomers (third hidden) Glycans
The HIV envelope trimer
The structure of a recombinant trimer has been shown
to closely resemble that of the membrane-associated
molecule. The trimer is the sole target of bnAbs, and
most bnAbs either bind to or accommodate glycans.