17 MARCH 2017 • VOL 355 ISSUE 6330 1129 SCIENCE sciencemag.org
that systems will soon be commercially available. Vacuum transfer alone—from a glove
box, reaction chamber, or focused ion beam
instrument—allows the study of air-sensitive
materials or processes that occur in environments other than air. Corrosion, for example,
has an enormous economic impact. Vacuum-transfer tools allow surfaces to be exposed to
specific environments (gaseous or aqueous)
and transferred directly to the atom probe in
order to allow direct high-resolution examination of the phases that form at the surface in
the early stages of corrosion. The insights will
allow the design of new strategies for corrosion prevention. In another example, catalyst
design for the conversion of biomass-based
feedstocks to liquid fuels is one of the most
promising sustainable alternatives to our
dwindling fossil fuel reserves. Understanding
the reactions that take place at surfaces in different chemical environments is essential for
this work. Again, vacuum transfer allows the
direct examination of surfaces after reactions
have taken place. Other applications might
include the study of highly corrosive air-sensitive alloys, such as lightweight magnesium
alloys and battery materials.
Hydrogen and water play a profound role
in corrosion and catalysis processes, and
cryo-transfer systems will allow an understanding of the mechanisms through which
these processes occur, in which D2O can be
used to study aqueous environments. Access
to information about hydrogen will also be
useful for the development of fuel cells and
hydrogen storage materials. For certain alloys, cryogenic transfer also opens up the
possibility of investigating phase transformations that take place below or occur rapidly at
room temperature (such as precipitation or
Perhaps most excitingly, these transfer
systems hold the potential to examine vitrified organic materials, or even to study water
itself, opening up the powerful technique of
atom probe to the life sciences field, complementing recent developments in cryo–
electron microscopy (10) and providing new 3D
information about the composition of the
hidden machinery of life. j
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4. B. Gault, M. P. Moody, J. M. Cairney, S. P. Ringer, Atom Probe
Microscopy (Springer, 2012).
5. R.Gemma, T.Al-Kassab, R.Kirchheim,A.Pundt,Scripta
Mater. 67, 903 (2012).
6. J. Takahashi,K.Kawakami, Y.Kobayashi, T. Tarui,Scripta
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By Barton F. Haynes1
and Dennis R. Burton2,3
In 2015, 17 million HIV-infected individ- uals worldwide were on antiretroviral drug therapies, which are remarkably effective in suppressing the virus. Yet, 6000 people a day became newly in- fected, making the quest for an effective and safe HIV vaccine a major global
priority. However, developing a vaccine has
been difficult for reasons related to the nature of the virus and its life cycle, including early integration into the host genome
and the highly glycosylated, compact, and
sequence-variable nature of the envelope
(Env) “spike” that is the sole target of neutralizing antibodies (and typically associated with vaccine protection). Where are
we, then, on the path to a vaccine?
From 1987 to 2013, all of the six HIV vaccine efficacy trials failed except for one.
The RV144 trial in Thailand that used a
viral vector prime (expressing three HIV
genes, env, gag, and pro) and a boost with
HIV’s glycoprotein gp120 (a constituent of
the viral spike) showed a modest estimated
31.2% vaccine efficacy at 42 months (1).
Antibodies to the second variable loop of
gp120 as well as antibody-dependent cellular cytotoxicity (ADCC) correlated with decreased transmission risk, whereas a high
immunoglobulin (Ig) A antibody response
to Env (which may inhibit ADCC) correlated with increased transmission risk (1).
Although the RV144 trial showed putative
short-lived vaccine efficacy, it was not suf-
ficient for vaccine deployment. Nonethe-
less, from RV144 (1) and studies in animal
models (2), a hypothesis gained ground
that ADCC and other non-neutralizing
functions of Fc receptor (FcR)–bearing im-
mune cells could contribute to protection
against HIV transmission. New trials have
been designed to improve RV144 vaccine
efficacy by using new adjuvants and Env
proteins (1). Thus, one track of vaccine de-
velopment is to investigate easy-to-induce,
non-neutralizing antibodies that have FcR-
mediated anti-HIV effector functions in
vitro for their ability to prevent HIV trans-
mission in vivo.
Another path for vaccine development
derives from observations that CD8 cytolytic T cells (CTLs) can control HIV viral
load by killing HIV-infected CD4 T cells.
Prime and boost regimens with conserved
or mosaic HIV gene vector inserts designed
to overcome viral diversity have induced
considerable breath in human CTL recognition of HIV and have shown efficacy in
monkey models that mimic human exposure
to the virus (3). Remarkably, vaccination of
macaques with simian immunodeficiency virus (SIV) gag inserted into an attenuated rhesus
cytomegalovirus (rhCMV) vector cleared SIV-infected cells after initial rounds of infection
in about 50% of vaccinated monkeys (4). Interestingly, attenuated rhCMV induced an
extraordinary breadth of CTLs, and target
cell–killing was mediated by atypical CD8
CTL recognition of antigen (4). Efforts are
under way to determine whether similar immune responses can be induced in humans.
Receiving much attention is the idea of
inducing broadly neutralizing antibodies
(bnAbs)—those that neutralize a diversity
of global HIV isolates (5, 6). This approach
has been reinvigorated by the isolation of
many potent bnAbs from infected individuals (7); the generation of a stable HIV
Env spike (which is a trimer) (8) and the
determination of its structure at high resolution (9); the description of how bnAbs
interact with the trimer at the molecular
level, leading to the design of new immunogens (9); the discovery of how bnAbs
evolve in infected individuals (10); insight
into host constraints on the induction of
bnAbs (6, 11); insight into the nature of
transmitted-founder (TF) viruses (6); and
the development of simian-human chim-
Developing an HIV vaccine
What are the paths and obstacles to a practical vaccine?
1Duke Human Vaccine Institute, Duke Center for HIV/AIDS
Vaccine Immunology–Immunogen Discovery, Duke University
School of Medicine, Durham, NC, USA. 2Department of
Immunology and Microbiology, Scripps Center for HIV/AIDS
Vaccine Immunology–Immunogen Discovery, International
AIDS Vaccine Initiative Neutralizing Antibody Center, The
Scripps Research Institute, La Jolla, CA, USA. 3Ragon Institute
of Massachusetts General Hospital, Massachusetts Institute
of Technology, and Harvard University, Cambridge, MA, USA.
Email: email@example.com; firstname.lastname@example.org
“...6000 people a day became
newly infected, making
the quest for an effective
and safe HIV vaccine
a major global priority.”