CONCISE COMMUNICATION

Broadly neutralizing HIV-1 antibody reactivity in HIV

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tests: implications for diagnostics

wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/22/2023

Tara Smitha,b, Silvina Masciotrac, Wei Luoc, Vickie Sullivanc,

William M. Switzerc, Jeffrey A. Johnsonc and Walid Heneinec

Objective: Passive immunization with broadly neutralizing antibodies (bNAbs) is

under evaluation for HIV prevention. BNAbs target gp120 or gp41, two HIV envelope
antigens commonly present in diagnostic tests. Depending on bNAb type and dose
administered to humans, serum levels can reach nearly 1 mg/ml and wane over several
weeks to months. We investigated the reactivity of bNAbs in HIV serological tests to
inform diagnostic testing practices for persons treated with these products.
Design and methods: The antigp120 bNAbs VRCO1, PGT121, PGT145, 3BNC117,
10–1074 and N6 and antigp41 bNAbs 10E8 and 10E8v4 were tested with the
laboratory-based Bio-Rad Ag/Ab Combo assay, the point-of-care single-use Determine
Combo, OraQuick, Reveal G4, SureCheck, Uni-Gold, INSTI and DPP HIV-1/2 assays,
and the supplemental Geenius and HIV-1 Western Blot assays.
Results: At 1 mg/ml, all bNAbs were nonreactive in four screening tests. OraQuick,
SureCheck, Reveal G4 and INSTI detected at least two bNAbs each; SureCheck exhibited
reactivity to six bNAbs. Geenius was HIV-1 indeterminate (gp160þ) with all bNAbs
except PGT121, which was HIV antibody-negative. HIV-1 Western Blot was indetermi-
nate (gp41þ/gp160þ) with 10E8 and 10E8v4 and negative with the remaining bNAbs.
There was no correlation between the test antigen construct(s) and bNAb reactivity.
Conclusion: We identified a laboratory-based Ag/Ab EIA and three single-use rapid
HIV tests that are nonreactive against a panel of bNAbs supporting some diagnostic tests
can distinguish HIV-1 infection events among persons receiving bNAb immunopro-
phylaxis. Evaluation of HIV diagnostic tests prior to clinical use may identify suitable
serologic assays for persons administered bNAbs.
Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved.

AIDS 2021, 35:1561–1565

Keywords: antiretroviral therapy, broadly neutralizing antibodies, HIV, HIV

diagnostics, HIV rapid testing, HIV supplemental test

Introduction ‘Ending the HIV Epidemic: A Plan for the United States’
initiative launched by the United States Department of
Preexposure prophylaxis (PrEP) with antiretroviral drugs Health and Human Services [1]. However, inadequate
is a recommended HIV prevention strategy in the adherence to daily PrEP can reduce its effectiveness,

a
Oak Ridge Institute for Science and Research, Oak Ridge, TN, bICF, and cDivision of HIV/AIDS Prevention, National Center for
HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Correspondence to Tara Smith, 1600 Clifton Rd NE MS-A25, Atlanta, GA 30329, USA.
Tel: +1 404 639 2724; e-mail: kra8@cdc.gov
Received: 16 October 2020; revised: 16 February 2021; accepted: 12 March 2021.

DOI:10.1097/QAD.0000000000002898

ISSN 0269-9370 Copyright Q 2021 Wolters Kluwer Health, Inc. All rights reserved. 1561
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
 1562 AIDS 2021, Vol 35 No 10
creating an interest in developing long-acting prevention
products to simplify adherence [2]. Potent, broadly
neutralizing antibodies (bNAbs) develop naturally in
approximately 1% of persons living with HIV and target
the HIV envelope (Env) glycoproteins gp120 (CD4-
binding site, V1-V2 and V3 loops) and gp41 [3,4]. bNAbs
have been considered for HIV prevention and as a
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potential treatment for persons with HIV [5]. Although
bNAbs have not indicated better clinical outcome in
humans so far, when administered to nonhuman primates
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/22/2023
they have been shown to protect against infection and
reduce plasma viral loads [6–15].
The bNAb VRC01, identified in 2010, was found to
neutralize 90% of viruses in a panel of 190 HIV-1 Env
viruses with a mean IC50 of 0.33 mg/ml [16]. Following
VRC01, several other antibodies have been identified to
improve neutralization and half-life in serum. Among the
most clinically advanced are 3BNC117, VRC07–523LS,
N6, 10–1074, PGT121 (targeting the V3 loop and
surrounding glycans) and 10E8 (targeting the membrane
proximal external region of gp41) [15]. Two multina-
tional clinical trials, known as AMP (antibody-mediated
prevention), are evaluating the ability of VRC01 to
prevent the acquisition of HIV: one in heterosexual
women in sub-Saharan Africa, and another in MSM and
transgender persons who have sex with men in North
America, South America and Switzerland
(NCT02568215, NCT02716675) [17]. Depending on
the bNAb type and dosing strategy, appreciable serum
levels (up to 1 mg/ml) of bNAbs can be maintained in
humans for several weeks [18–21]. In the AMP trial,
infusions of 30 mg/kg of VRC01 led to peak serum
concentrations of approximately 600 mg/ml, declining
rapidly to approximately 12 mg/ml by the end of the 8-
week infusion cycle [22]. The prophylactic use of bNAbs
for HIV prevention in seronegative persons may pose
challenges in diagnostic testing for breakthrough HIV
infections because the Env antigens targeted by bNAbs
for neutralization are commonly present in diagnostic
tests. The AMP trial showed 75% efficacy against
infection with viruses that are sensitive to VRC01 at
IC80 less than 1 mg/ml, providing proof-of-concept of
HIV prevention by bNAbs. However, overall, no
protective efficacy was found because only nearly 30%
of circulating viruses exhibited IC80 less than 1 mg/ml
[23]. Therefore, combination bNAbs may be needed to
improve coverage of HIV variants and will require
identifying diagnostic tests with no reactivity to multiple
bNAbs. Although bNAbs are also being evaluated for
treatment of persons with HIV [9,18–20,24–28], the use
of diagnostic tests would not be relevant for
this population.
To better inform diagnostic testing during the develop-
ment and evaluation of bNAbs for HIV prevention, we
assessed candidate bNAbs to determine their reactivity in
eight screening and two supplemental HIV diagnostic
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
tests approved by the US Food and Drug Administration
(FDA). We found that bNAbs did not express reactivity to
HIV diagnostic tests in a predictable manner, despite the
antigens they were purported to target. Overall, the
observed lack of reactivity in some tests evaluated does
identify suitable assays for diagnostic monitoring of
immunoprophylaxed persons.
Materials and methods
bNAbs against gp120 (VRC01, PGT121, PGT145,
3BNC117, 10–1074 and N6) and against gp41 (10E8 and
10E8v4) were acquired from the NIH AIDS Reagent
Program (https://www.aidsreagent.org) and were
diluted to 50 mg/ml in negative serum, and 100 mg/ml
and 1 mg/ml in phosphate-buffered solution (PBS) pH
7.4. These dilutions were selected to potentially mimic
the high serum concentrations within weeks post infusion
and the diminished concentrations over time. The
dilutions in PBS allowed for assessing the reactivity of
each bNAb against both the anti-HIV Ab diagnostic and
protein A anti-IgG control indicators when present in the
single-use rapid test examined. bNAb reactivity was
evaluated using the laboratory-based Bio-Rad GS HIV
Combo Ag/Ab (BRC) screening assay, and in seven
single-use rapid tests: Alere Determine HIV-1/2 Ag/Ab
Combo (DC), OraQuick Advance Rapid HIV-1/2
Antibody Test (OQ), Medmira Reveal G4 Rapid
HIV-1 antibody test (G4), Chembio SURE CHECK
HIV 1/2 Assay (SureCheck), Trinity Biotech Uni-Gold
Recombigen HIV-1/2 test (Uni-Gold), BioLytical
INSTI HIV-1/2 rapid antibody test (INSTI) and
Chembio DPP HIV 1/2 Assay (DPP). A rapid test with
the highest reactivity was further tested with bNAb
dilutions to determine a limit of detection. The bNAbs
were also evaluated with two supplemental HIV tests: the
Bio-Rad Geenius HIV 1/2 Supplemental Assay (Gee-
nius) at all concentrations, and the Bio-Rad GS HIV-1
Western Blot (WB) at 1 mg/ml.
Results
At concentrations of 50 mg/ml in serum, none of the
bNAbs had anti-HIV Ab reactivity in the rapid tests and
BRC. At 100 mg/ml in PBS, only PGT145 was reactive
in SureCheck on only the test line. Geenius was HIV-1
indeterminate for 10–1074, 10E8v4, and 10E8 at both 50
and 100 mg/ml. At the higher concentration of 1 mg/ml
in PBS, none of the bNAbs produced anti-HIV Ab
reactivity on the BRC, DC, Uni-Gold and DPP single-
use rapid tests. Of note, Uni-Gold and DC showed
reactivity in the control line with PBS alone, though this
is expected based on the design of these assays. Table 1
summarizes the reactivity of the eight bNAbs at 1 mg/ml
 HIV bNAbs: implications for diagnostics Smith et al. 1563

Table 1. Reactivity of eight broadly neutralizing antibodies at 1 mg/ml on eight screening HIV tests.

BRC DCa Uni-Golda DPP OQ G4 SureCheck INSTI

HIV antigen gp41, gp41, gp41, gp41, gp41, gp120

in test gp160 gp41 gp120 gp120 gp41 gp120 gp120 fragment

Reactive against gp120

VRCO1 NR NR NR NR NR NR NR invalid
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PGT121 NR NR NR NR NR R NR invalid
3BNC117 NR NR NR NR R NR R invalid
PGT145 NR NR NR NR NR NR invalid invalid
10-1074 NR NR NR NR R NR R invalid
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N6 NR NR NR NR NR NR R R
Reactive against gp 41
10E8 NR NR NR NR R R R NR
10E8v4 NR NR NR NR R NR R NR

Bio-Rad GS HIV Combo Ag/Ab (BRC), Alere Determine HIV-1/2 Ag/Ab Combo (DC), Trinity Biotech Uni-Gold Recombigen HIV-1/2 test (Uni-
Gold), Chembio DPP HIV 1/2 Assay (DPP), OraQuick Advance Rapid HIV-1/2 Antibody Test (OQ), Medmira Reveal G4 Rapid HIV-1 antibody test
(G4), Chembio SURE CHECK HIV 1/2 Assay (SureCheck) and BioLytical INSTI HIV-1/2 rapid antibody test (INSTI). Dilutions were made in PBS pH
7.4. Invalid, absence of control line; NR, nonreactive; R, reactive.
a
Uni-Gold and DC showed reactivity in the control line with PBS alone.

on the eight evaluated screening tests. SureCheck was the Discussion

most reactive rapid test overall, with reactivity against
three antigp120 and two antigp41 bNAbs. In addition,
PGT145, an antigp120 bNAb, was strongly reactive on
the antigen-specific line but no reactivity was observed on
the anti-IgG control line (invalid result). INSTI displayed
no reactivity on either the control spot or the diagnostic
Ab spot with five of the eight bNAbs (invalid result).
When analysing bNAb reactivity on supplemental tests,
Geenius results were all HIV-1 indeterminate with only
gp160 reactivity, except for PGT121, which was HIV
antibody-negative. All antigp120 bNAbs were WB-
negative and the two antigp41 bNAbs, 10E8 and 10E8v4,
were indeterminate with reactivity to gp160 (þ) and gp41
(þ/) proteins. For SureCheck, the RT that showed the
most reactivity, all bNAbs except for VRCO1 and
PGT121 were further diluted in PBS and evaluated (Table
2). PGT145 was included because of its strong reactivity
on the anti-HIV Ab test line and it displayed reactivity on
the specific test line down to a concentration of
0.125 mg/ml, but no reactivity was observed on the
control line at any concentration tested.
We investigated the reactivity of bNAbs on HIV
serological diagnostic tests approved by the FDA. The
laboratory-based BRC assay and three single-use rapid
tests (DC, Uni-Gold and DPP) were nonreactive with all
eight bNAbs evaluated. The tests selected represent
relevant assays for detecting HIV infection: the Combo,
Geenius and WB are all performed as part of a
recommended HIV diagnostic algorithm. Any one of
the rapid tests could be used for point-of-care testing or in
clinical trials for monitoring biomedical interventions.
The observed nonreactivity at 50 and 100 mg/ml and
1 mg/ml, are all clinically relevant concentrations within
the range or exceed the concentrations required for
protection as observed in macaque models [29]. These
data support the use of these assays to detect HIV-1
infection among persons who have received immuno-
prophylaxis with these bNAbs [18]. The availability of
specific serologic tests will simplify follow-up testing
among immunoprophylaxed persons and preclude the
need for more expensive laboratory-based nucleic acid

Table 2. Reactivity of six broadly neutralizing antibodies at different concentrations on SureCheck (gp41, gp120).

1.0 mg/ml 0.5 mg/ml 0.25 mg/ml 0.125 mg/ml 0.0625 mg/ml

CTL Test CTL Test CTL Test CTL Test CTL Test

3BNC117 R R NR NR – – – – – –
10-1074 R R R NR – – – – – –
N6 R R R R R NR – – – –
10E8 R R R R R R NR NR – –
10E8V4 R R R R NR NR – – – –
PGT145a NR SR NR SR NR SR NR SR NR NR

bNAbs were diluted in PBS pH 7.4. –, dilution below the detection limit was not tested. CTL, control line; NR, nonreactive; R, reactive; SR, strongly
reactive; Test, test line.
a
PGT145 tested as invalid at all concentrations up to 0.0625 mg/ml.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

 1564 AIDS 2021, Vol 35 No 10
tests (NAT). As such, these assays can be used at baseline
and following bNAb administration. In the AMP trial, in
clinical sites outside of the USA, screening for enrolment
is conducted with an HIV diagnostic algorithm involving
sequential testing using single-use rapid tests, wherein
discrepant results are confirmed with laboratory-based
immunoassays (G. Mboya, personal communication, 2
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March 2020). Our data show that VRC01 is nonreactive
in many rapid tests supporting the use of such assays in
follow up testing to identify new HIV infections during
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the trial. A limitation exists if HIV screening occurs soon
after administration, if bNAb titres reach greater than
1 mg/ml in the bloodstream. Most of the bNAbs utilized
in this study were supplied at maximum concentrations of
1 mg/ml, limiting our ability to test higher concentra-
tions, further evaluation would be needed.
We also noted that many bNAbs were nonreactive in both
the antibody and control lines of several assays, like
INSTI. Even though some of the bNAbs were diluted in
PBS and not in plasma, we interpreted the absence of
control line reactivity as an invalid result in accordance
with the package insert. The absence of bNAb reactivity
with protein A IgG-binding controls on INSTI was
unexpected as these antibodies are often purified by
protein A chromatography. As these assays are optimized
for performance with naturally occurring antibody levels,
the higher concentrations seen in our bNAb samples
could account for excess binding of detection reagents
prior to sample reaching the control or test portions of
assays. Nonetheless, dilutions in PBS permitted defining
reactivity specific to the bNAbs in these assays.
The reactivity with some bNAbs observed in our study
did not follow any predictable pattern, although those
targeting gp41 displayed slightly more reactivity among
the diagnostic tests evaluated than those that target gp120.
Indeterminate results on the WB were interpreted based
on strength of reactivity of the two major bands observed
in 10E8 and 10E8v4; gp41 displayed weak reactivity. As
bNAbs are often selected for their broadest and most
potent neutralization activity, often through binding to
single epitopes, our results suggest that such epitopes are
either missing in the antigens of the tests or, more likely,
that the antigens in the tests do not readily present these
epitopes in a conformation recognized by the bNAbs.
OQ reactivity against gp120 was unexpected, as the assay
is only designed to detect gp41, and was likely due to
nonspecific binding to a component in the assay’s
antigen construct.
Our titration of reactive bNAbs for SureCheck, the rapid
test that showed the most reactivity, revealed a limit of
detection as low as 0.0625 mg/ml. Defining limits of
detection for reactive assays will help define their clinical
utility. For instance, serum bNAb levels that consistently
fall below the detection limit will not impact the use of
these assays. Thus, serum bNAb levels achieved in
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
humans following immunoprophylaxis are an important
factor in selecting nonreactive assays. A limitation in this
study is only one laboratory-based Ag/Ab ELISA assay
was evaluated, as this was the only ELISA assay currently
in use in our laboratory.
Our findings on the limited tests available in our
laboratory provide evidence that bNAb reactivity in
FDA-approved serologic HIV tests is not always
predictable. This rational approach can identify HIV
diagnostic tests for which bNAbs of interest are
nonreactive and therefore appropriate for infection
monitoring when bNAbs are administered. Further
testing must occur on other assays and bNAbs to expand
on the data presented here.
Acknowledgements
Tara Smith was the main author of this manuscript,
performing a majority of the writing, testing and creation
of the tables. Silvina Masciotra, William M. Switzer,
Jeffrey A Johnson and Walid Heneine contributed as the
main reviewers and aided in study design and writing the
discussion. Vickie Sullivan performed the Western Blot
testing and reviewed the manuscript. Wei Luo aided in
testing inventory and reviewed the manuscript.
The following reagents were obtained through the NIH
AIDS Reagent Program, Division of AIDS, NIAID,
NIH: VRCO1 (12033) from Xueling Wu, Zhi-Yong
Yang, Yuxing Li, Gary Nabel, John Mascola; 10E8
(12294) from Jinghe Huang, Leo Laub, Mark Connors;
PGT121 (12343) and PGT145 (12703) from IAVI;
3BNC117 (12474) and 10–1074 (12477) from Michael
C. Nussenzweig; 10E8v4 (12865) from Peter Kwong; and
N6 (12968) from Mark Connors.
The views expressed in this article are those of the authors
and do not reflect the official position of the CDC. The
use of trade names is for information purposes only and
does not constitute endorsement by the CDC. This
research was supported in part by an appointment to the
Research Participation Program at the Centers for
Disease Control and Prevention administered by the
Oak Ridge Institute for Science and Education through
an interagency agreement between the U.S. Department
of Energy and CDC.
Data and abstract presented previously at the 2019 HIV
Diagnostic Conference in Atlanta, Georgia, USA, and
The International Workshop on HIV Transmission 2020.
Conflicts of interest
There are no conflicts of interest.

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