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INSIGHTS | PERSPECTIVES

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antibody response and thus represent bot-
tlenecks in generating bnAbs ( 9 ). Two previ-
ously described bnAbs, DH270 and CH235
( 10 , 11 ), the lineages of which were previ-
ously characterized and shown to harbor
improbable mutations that are important
for HIV-1 neutralization ( 9 ), were studied by
Saunders et al. On the basis of Env-DH270
lineage bnAb structures, an Env immuno-
gen was designed that bound the inferred
unmutated common ancestor (UCA) anti-
body with submicromolar affinity and, criti-
cally, also bound an affinity-maturation in-
termediate bnAb harboring rare mutations
with greater than fourfold increased affin-
ity. After six immunizations with a nanopar-
ticle-Env immunogen, physiologically rele-
vant neutralizing activity of modest breadth
was achieved in mice harboring B cells en-
gineered to express the DH270-UCA bnAb
precursor antibody. This Env immunogen
recruited DH270-UCA–expressing B cells

that incorporated rare mutations critical
for neutralization, an important advance on
the path to bnAb generation.
In additional experiments, inferred
CH235-UCA antibody genes were again used
to produce mice that, when immunized with
Env immunogen, generated HIV-1 neutral-
izing antibodies also carrying CH235 rare
mutations. Inducing physiologically rele-
vant HIV-1 neutralization in mouse models
is noteworthy, although tempered, in these
studies because the mice were engineered to
harbor supraphysiological (10 to 15%) initial
precursor B cell populations that were ca-
pable of responding. However, rhesus ma-
caques immunized with the CH235-eliciting
Env immunogen elicited HIV-1 neutralizing
antibodies after at least two immunizations.
Macaques presumably harbor a physiologi-
cally relevant low frequency of immuno-
gen-binding B cells, although this was not
evaluated. Thus, the findings in nonhuman
primates highlight an important hallmark in

eliciting HIV-1 neutralizing antibodies from

a natural B cell repertoire.

Steichen et al. similarly achieve an im-

portant goal in the development of an ef-

fective HIV-1 vaccine investigating the

BG18 bnAb lineage that leads to a potent

bnAb recognizing the V3 glycan neutral-

izing epitope on Env ( 12 ). However, this

study focuses on the available B cell anti-

body specificities in a healthy individual.

Because each of the hundreds of millions

of B cells in the body express a unique anti-

body specificity, the frequency of precursor

B cells that can recognize a bnAb-eliciting

immunogen is important to determine

when considering which precursor bnAb

lineage to target ( 13 ). Although the BG18

bnAb sequence is 30% mutated from the

inferred UCA, this bnAb lacks nucleotide

deletions or insertions that are consid-

ered more difficult to elicit through affin-

ity maturation. Informed by the BG18-Env

structure, Steichen et al. designed a precur-

sor antibody that carried 11% of the muta-

tions while retaining two-thirds the BG18

neutralizing breadth. On the basis of this

minimally mutated antibody sequence and

antibody-Env structure, next-generation

DNA sequencing data from 14 healthy indi-

viduals were examined to identify Ig heavy

chain–encoding sequences from each do-

nor with similar BG18 HCDR3 length and

Ig gene usage; 28 common BG18-like pre-

cursor antibodies were identified.

Common precursor antibodies were pro-

duced and used to iteratively select Env im-

munogens with appreciable affinities to the

common BG18 precursor antibodies. These

immunogens were then used to immunize

mice engineered to harbor B cells express-

ing the BG18-UCA Ig heavy chain that could

pair with different mouse Ig light chains. To

better reflect physiological precursor B cell

frequencies, BG18-UCA+ B cells were adop-

tively transferred into wild-type hosts at a

ratio of seven BG18-UCA+ B cells per million

host B cells. These mice were immunized

with nanoparticle-presented Env immuno-

gen, and rare BG18-UCA+ precursor B cells

were shown to respond, including their dif-

ferentiation into plasma cells secreting IgG

antibodies with increased affinities for the

immunogen. Steichen et al. further used

these BG18-UCA immunogens to assess re-

activity among human B cells from 16 dif-

ferent donors and found that immunogen-

reactive B cells were present at a frequency

of ~0.001% within a healthy B cell antibody

repertoire. These data thus document the

feasibility of engineering HIV-1 immuno-

gens that can recruit precursor bnAb B cells

into an antibody response from a physiolog-

ically relevant rare subset.

Development of an HIV vaccine remains

a daunting task. The studies of Saunders et

al. and Steichen et al., together with a recent

report from Escolano et al. demonstrating

the ability of a distinct HIV-1 Env immuno-

gen to recruit precursor bnAb-expressing B

cells into an appropriate antibody response

in wild-type mice, rabbits, and macaques

( 14 ), demonstrate meaningful progress. A

number of issues remain important to con-

sider in future studies, including identify-

ing which of the bnAb lineages to replicate

in a vaccine and the ability of any new im-

munogen to also generate B cell memory

and long-lived plasma cells, as well as better

characterization of the breadth of neutral-

izing activity elicited. Inherent to reaching

these goals will be a more careful evalua-

tion of the manner in which immunogens

are presented in a vaccine as well as the

timing and mode of vaccine administration

( 15 ). Finally, considering that many HIV

bnAbs cross-react with self-antigens, it will

also be important to evaluate whether vac-

cine strategies targeting these lineages also

promote autoimmunity. j

REFERENCES AND NOTES

1. K. O. Saunders et al., Science 366 , eaay7199 (2019).


2. J. M. Steichen et al., Science 366 , eaax4380 (2019).


3. P. D. Kwong, J. R. Mascola, Immunity 37 , 412 (2012).


4. P. D. Kwong, J. R. Mascola, Immunity 48 , 855 (2018).


5. M. Bonsignori et al., Immunol. Rev. 275 , 145 (2017).


6. B. F. Haynes et al., Cell Host Microbe 19 , 292 (2016).


7. A. Escolano, P. Dosenovic, M. C. Nussenzweig, J. Exp.
   Med. 214 , 3 (2017).


8. J. E. Crowe Jr., Cell 166 , 1360 (2016).


9. K. Wiehe et al., Cell Host Microbe 23 , 759 (2018).


10. M. Bonsignori et al., Sci. Transl. Med. 9 , eaai7514 (2017).


11. M. Bonsignori et al., Cell 165 , 449 (2016).


12. N. T. Freund et al., Sci. Transl. Med. 9 , eaal2144 (2017).


13. R. K. Abbott et al., Immunity 48 , 133 (2018).


14. A. Escolano et al., Nature 570 , 468 (2019).


15. K. M. Cirelli et al., Cell 177 , 1153 (2019).

ACKNOWLEDGMENTS

We acknowledge R. Pelanda for helpful comments. R.M.T is

funded by the National Institutes of Health (NIH, AI136534),

and A.A. was funded by the NIH (T32 AR007534).

10.1126/science.aaz8647

B cell

Env structure–based serial immunogens

Critical mutations

UCA antibody

Env, envelope; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light chain; UCA, unmutated common ancestor.

IgH

IgL

Afnity

maturation

Afnity

maturation

Afnity

maturation

HIV neutralization and breadth

Broadly neutralizing

antibody

Staged HIV-1 immunization
Serial immunizations with distinct immunogens of the Env epitope of HIV-1 favor affinity maturation
of antibodies toward broadly neutralizing activity in mice and macaques.

1198 6 DECEMBER 2019 • VOL 366 ISSUE 6470

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