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Journal of Virology, December 1998, p. 10270-10274, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Antibody Neutralization-Resistant Primary Isolates
of Human Immunodeficiency Virus Type 1
Paul W. H. I.
Parren,1,*
Meng
Wang,1
Alexandra
Trkola,2
James M.
Binley,2
Martin
Purtscher,3
Hermann
Katinger,3
John P.
Moore,2 and
Dennis R.
Burton1,*
Departments of Immunology and Molecular
Biology, The Scripps Research Institute, La Jolla, California
920371;
Aaron Diamond AIDS Research
Center, The Rockefeller University, New York, New York
100162; and
Institute of Applied
Microbiology, Vienna, Austria3
Received 3 February 1998/Accepted 12 August 1998
 |
ABSTRACT |
Although typical primary isolates of human immunodeficiency virus
type 1 (HIV-1) are relatively neutralization resistant, three human
monoclonal antibodies and a small number of HIV-1+ human
sera that neutralize the majority of isolates have been described. The
monoclonal antibodies (2G12, 2F5, and b12) represent specificities that
a putative vaccine should aim to elicit, since in vitro neutralization
has been correlated with protection against primary viruses in animal
models. Furthermore, a neutralization escape mutant to one of the
antibodies (b12) selected in vitro remains sensitive to neutralization
by the other two (2G12 and 2F5) (H. Mo, L. Stamatatos, J. E. Ip,
C. F. Barbas, P. W. H. I. Parren, D. R. Burton, J. P. Moore, and D. D. Ho, J. Virol.
71:6869-6874, 1997), supporting the notion that eliciting a
combination of such specificities would be particularly advantageous.
Here, however, we describe a small subset of viruses, mostly pediatric,
which show a high level of neutralization resistance to all three human monoclonal antibodies and to two broadly neutralizing sera. Such viruses threaten antibody-based antiviral strategies, and the basis for
their resistance should be explored.
| |
TEXT |
There is evidence to indicate that
antibody can protect or offer benefit against challenge with primary
isolates of human immunodeficiency virus type 1 (HIV-1) (3).
In passive-transfer experiments, the recombinant human antibody b12
completely protected against challenge with two primary isolates in the
hu-PBL-SCID mouse model when it was administered pre- or shortly
postexposure (11). The anti-gp41 antibody 2F5 did not
protect chimpanzees against challenge with a primary virus, but
seroconversion was delayed and the peak of measurable virus-specific
RNA in serum was either delayed or did not reach levels comparable to
those in the sera of control animals (7).
Protection in vivo appears to be directly related to neutralization in
vitro. For instance, it is considerably easier to protect against
challenge with readily neutralized T-cell-line-adapted (TCLA) strains
of HIV-1 than with the more refractory primary isolates (11,
20). Complete protection requires serum antibody concentrations
in vivo considerably in excess of the 90% neutralization titers
measured in typical in vitro assays. As a rough guide, in the
hu-PBL-SCID mouse model, antibody concentrations 1 to 2 orders of
magnitude higher than the 90% neutralization titers are needed. For
example, antibody b12 provided complete protection in the mouse model
at 50 mg/kg of body weight, which corresponds to a concentration in
serum of about 500 µg/ml, against two primary viruses for which the
90% neutralization titers were 15 and 5 µg/ml. A dose of 10 mg of
b12 per kg offered only partial protection.
Extrapolation from the mouse model to humans is uncertain, but it seems
likely that potent antibodies will be required to achieve protection.
In a recent comparative study, only three human monoclonal antibodies
(MAbs) were found to neutralize (90%) a range of clade B primary
isolates at concentrations equal to or less than 25 µg/ml
(9). These are MAb b12, which recognizes an epitope
overlapping the CD4 binding site of gp120 (4, 5); MAb 2G12,
which recognizes an epitope involving the base of the V3 loop and the
base of the V4 loop of gp120 (2, 27); and MAb 2F5, which
recognizes a linear sequence close to the transmembrane segment of gp41
(2, 8). Similar results were reported by Trkola et al.
(26). In that study, a tetrameric CD4 immunoglobulin G2
(IgG2) molecule was also found to be approximately as potent as the
three human MAbs. Furthermore, the antibodies and CD4 IgG2 were also
highly effective against viruses from clades other than B.
Generally, comparative neutralization studies have shown that viruses
resistant to one of the three antibodies described above could still be
neutralized by other members of the panel. This finding is consistent
with observations that neutralization escape mutants selected by growth
of the primary isolate molecular clone HIV-1JR-CSF in the
presence of antibody b12 were still sensitive to neutralization by 2F5
and 2G12 (13). The escape mutants were shown to arise by
point mutations which reduced b12 binding to mature oligomeric envelope
on the virus (and gp120 monomer) but did not affect binding of the
other antibodies. However, we noted previously that certain isolates
with which we have worked appeared to be difficult to neutralize with
several antibodies. Such isolates may be important in considering
antiviral strategies, including vaccination, involving antibody. We
therefore determined to investigate the neutralization properties of a
number of isolates using the panel of MAbs described above and sera for
which we had preliminary evidence of unusually high neutralizing
titers. The viruses chosen included a panel of pediatric isolates
arising from mother-child transmission. This was because interruption
of mother-child transmission is a clear potential application of
prophylactic antibody (24) and because we had some evidence
of more neutralization-resistant viruses in this group.
Identification of two sera showing broad neutralization of primary
isolates.
A panel of sera was examined at The Scripps Research
Institute for neutralization of a diverse panel of isolates of
different clades (Table 1). To analyze
antibodies for neutralization activity against TCLA virus
HIV-1MN, we used an assay based on infection of HeLa cells
expressing human CD4 and the HIV-1 long terminal repeat fused to
lacZ as described previously (6, 21).
Neutralization of primary isolates was performed essentially as
described by Trkola et al. (26) except that we used a virus
inoculum of 100 rather than 10 50% tissue culture infective doses
(TCID50). Sera from 10 individuals, designated RW1 to RW10,
who had been infected for various periods from 3 to 10 years, and sera
from two donors, designated P and M, from whom antibody phage libraries
have been prepared (19), were used. We further included a
serum from a donor, designated FDA-2, which had been shown previously
to be relatively potent against a number of isolates (10, 15,
28). FDA-2 sera drawn at two different time points were tested.
One sample was a pool of four blood donations drawn between April 1990 and February 1991 and was obtained from the AIDS Research and
Reference Reagent Program (ARRRP), and the second sample was obtained in August of 1996. Table 1 shows that all of the sera effectively neutralized the TCLA strain HIV-1MN but that
neutralization of the primary isolates was much more restricted. The
best sera, RW-1, RW-3, and FDA-2, neutralized all the isolates. All the
other sera neutralized only some of the isolates. The two FDA-2 sera taken at different time points indicate an evolution of neutralizing antibody titers; both sera, however, are broadly neutralizing. Although
FDA-2 was one of the best-neutralizing sera observed in a previous
comparison of 15 different sera (15), Table 1 shows that at
least two RW sera had comparable or greater potency; both these sera
were from individuals who had been infected for 9 years or more. A
broadening of neutralizing antibody titers in long-term-infected
persons has been observed previously (14, 32). The sera RW-1
and FDA2 were chosen for detailed examination of neutralization of
pediatric isolates together with RW-7, a serum that is relatively
inefficient (Table 1).
Pediatric isolates resistant to neutralization by sera and
MAbs.
Table 2 shows a comparison of
neutralization titers of the above-described sera and three potent
human MAbs against 14 pediatric isolates. The panel of isolates was
obtained from the ARRRP and included isolates transmitted in utero as
well as isolates transmitted intra- and postpartum. The majority of
isolates were neutralized by the sera RW-1 and FDA2 but not by the
serum RW-7. About half of the isolates were neutralized by each of the
MAbs. This is a lower figure than has been generally observed for clade
B isolates (see, e.g., reference 26) and may suggest
that the pediatric panel is more resistant to antibody neutralization
than a more general selection of viruses (i.e., adult based). Three
viruses in particular, i.e., 92US076, 92US077, and 93US143, were not
neutralized by any of the sera at a 1:32 dilution or any of the three
MAbs at concentrations up to 50 µg/ml. These three isolates were also resistant to a cocktail of the three MAbs, each at 17 µg/ml. It appears that they have a general enhanced resistance to antibody neutralization. Of note is that all three are syncytium-inducing viruses.
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TABLE 2.
Neutralization titers of potent neutralizing sera and
MAbs against pediatric primary isolates and an
adult isolatea
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Selected resistant viruses were also tested in a second set of
experiments performed at the Aaron Diamond AIDS Research Center
(ADARC)
(Table
3); neutralization assays were
performed as described
previously (
26). Here also 92US077
and 93US143 were highly resistant
to the three test MAbs and also to
the potently neutralizing tetrameric
CD4 IgG2 molecule. CD4 IgG2 has
been shown to be highly effective
in neutralizing primary isolates from
diverse clades (
26). 92US076
was sensitive to MAb 2G12,
which may possibly be explained by
the 10-fold lower viral inoculum
used in the ADARC neutralization
assay. Apart from 92US076's
sensitivity to MAb 2G12, however,
the results were very consistent
between the two laboratories.
One of the pediatric isolates (93US143)
has previously been described
by Mascola et al. (
12) as
being relatively resistant to neutralization
by 2G12 and 2F5
antibodies. That study also identified another
relatively resistant
nonpediatric isolate, 92US714, which was
obtained from a Baltimore
intravenous drug user. Since another
comparative study showed
neutralization of 92US714 in some assay
formats (
9), we
included this isolate in our analysis. Compared
to other primary
isolates, 92US714 was resistant. In contrast
to the other two resistant
isolates (92US077 and 93US143), however,
both 92US076 and 92US714 were
sensitive to CD4 IgG2 (Table
3).
To make certain that the resistant phenotypes were not a result of
unusually fast growth kinetics of these viruses, we performed
a kinetic
study in which p24 antigen production was measured every
day between
day 1 and day 7 and on day 10. 92US143 replicated
rapidly, peaking
between days 2 and 3. 92US076 and 92US077 replicated
more slowly,
however, peaking between days 5 and 7, with a profile
similar to that
of HIV-1
JR-CSF, a virus which is sensitive to
neutralization by b12 (
13). There was therefore no
correlation
between a resistant phenotype and growth kinetics in the
absence
of neutralizing antibody. To control for the different growth
kinetics of these isolates, we harvested virus from each individual
neutralization assay over several days (day 4 to day 6 postinfection).
The day on which the first peak virus production was detected
was
chosen to calculate neutralization titers. We consistently
found a
general resistance of the isolates indicated above to
neutralization by
potent neutralizing
antibody.
Mascola et al. reported that hyperimmune anti-HIV Ig (HIVIG) was able
to synergize with 2F5 and 2G12 in neutralization assays
of the panel of
primary isolates they examined (
12). Accordingly,
we
assessed the ability of HIVIG or control human IgG at a high
concentration (2.5 mg/ml) alone and in combination with the three
MAbs
(each at 17 µg/ml) to neutralize the resistant pediatric
viruses. We
observed some reduction in infectivity, but in no
case was 90%
neutralization achieved. The more neutralization-sensitive
isolate,
92US072, was readily neutralized by HIVIG and HIVIG-antibody
combinations (data not
shown).
Finally, the ability of autologous sera to neutralize the pediatric
viruses was measured (Table
4). The
autologous sera also
had little effect on the resistant isolates,
although the autologous
serum taken 6 months after virus isolation did
reach 90% neutralization
of 92US143 at a dilution of 1:32. The more
sensitive control viruses
were neutralized by these sera at dilutions
comparable to those
shown in Table
2.
Reactivities of soluble gp120 and gp41 from resistant viruses with
MAbs.
Neutralization resistance seems to be possible through at
least two mechanisms. First, local changes through point mutations which reduce the affinity of the neutralizing antibody to the virion
may occur, as has been described for the V2 (31) or V3 (18) loop and in vitro escape mutants of MAb b12
(13). Second, more-global conformational changes which make
viruses more refractory to neutralization by subtle alterations of the
envelope antigenic makeup may occur through mutations in distal sites.
One such mutation in the gp41 subunit (A-T at position 582) which made
the mutant virus (a variant of TCLA virus IIIB) less sensitive to
neutralization by several antisera and anti-CD4 binding site antibodies
has been described (22, 23, 25, 30). By the second
mechanism, certain difficult-to-neutralize viruses may acquire
resistance to neutralizing antibodies to multiple antigenic sites.
Resistance by the first mechanism is therefore due to a loss of the
relevant epitope through primary structural variation, whereas
resistance by the second mechanism is mediated through changes in
tertiary and quaternary structures, such as sequestering of the epitope
from the antibody-accessible surface area.
Although there is a poor correlation between the presence of an epitope
on monomeric gp120 and its accessibility to antibody
on oligomeric
gp120 (
16), the absence of an epitope on monomeric
gp120, at
least for the epitopes studied here, does predict its
absence from the
oligomer. To investigate this possibility for
the resistant isolates
identified, we studied the binding of MAbs
IgG1 b12 and 2G12 with
detergent-solubilized primary isolate gp120
captured with a sheep
antibody against the gp120 C terminus immobilized
on an enzyme-linked
immunosorbent assay (ELISA) plate as described
previously
(
17). The results showed that loss of binding to
gp120 is
not a general explanation for the resistant phenotype
of these
isolates. Captured solubilized gp120 from all four resistant
isolates
(92US076, 92US077, 93US143, and 93US714) bound MAb 2G12,
whereas IgG1
b12 bound well to gp120 from 92US077 and 93US714
but not from 92US076
and 92US143 (Fig.
1). The resistant
isolate
92US077 even retains the binding sites on gp120 of both MAb b12
and MAb 2G12. Similarly, there was no correlation between binding
of
MAb 2F5 to captured gp41 and neutralization resistance, since
ELISA
signals two to five times greater than background signals
and
comparable to those of controls were found for all viruses,
except
93US143, for which binding was unclear (data not shown).
From these
results, it therefore seems that in some cases resistance
may simply be
due to the absence of epitope expression on subunits
constituting the
oligomeric envelope spikes but that in other
cases resistance is a more
complicated phenomenon, possibly reflecting
a more global perturbation
of the oligomeric envelope on the virion
surface.
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FIG. 1.
Reactivity of soluble gp120 from resistant viruses with
MAbs. Infectious culture supernatants were treated with detergent, and
gp120 was captured in the well of an ELISA plate coated with sheep
anti-gp120 antibody D7324. The reactivities of MAb IgG1 b12 (circles),
MAb 2G12 (squares), and control antibody PA-53 (triangles) against
HIV-2 envelope protein are shown. As a positive control for the amount
of primary gp120 captured, the reactivity of a single 1:5,000 dilution
of pooled seropositive human plasma (QC256; diamonds) is plotted on the
y axis.
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To date only three MAbs, b12, 2F5, and 2G12, that efficiently
neutralize a broad range of primary isolates of HIV-1 have been
identified (
2,
4,
5,
8,
9,
26,
27). These antibodies
are
being used as molecular templates and aids in antibody-based
vaccine
design (
3) and have potential for passive immunoprophylaxis
of HIV-1 infection (
11). In addition, a tetrameric CD4 IgG2
molecule which is highly effective in neutralizing diverse isolates
of
HIV-1 in vitro has been described (
1,
26). Previous
neutralization
studies of panels of primary isolates indicated the
majority of
primary isolates to be sensitive to neutralization by at
least
of one the three potent MAbs (
5,
9,
26), suggesting
that
a cocktail of these antibodies, passively transferred or elicited
by a vaccine, may be effective in protecting against HIV-1 infection.
In these previous studies, we identified only one (clade D) isolate
which resisted all three MAbs (
9,
26). Significantly, we
now
identify four resistant clade B primary isolates, three of
which are
pediatric. In addition, these four isolates resist neutralization
by
two potently neutralizing sera. The high frequency of
neutralization-resistant
viruses in the panel of pediatric primary
isolates studied is
noteworthy. This may result from the circumstance
that perinatal
HIV-1 infection is established in the presence of
maternal anti-HIV-1
antibody.
In conclusion, some viruses have a general resistance to antibody
neutralization. In some cases, resistance can be simply
explained as
loss of the relevant epitope on envelope subunits.
In others, more
complex phenomena involving the conformation or
arrangement of
oligomeric envelope spikes is probably involved.
Highly resistant
viruses threaten antibody-based vaccine efforts,
and the basis for
their resistance is being
explored.
| |
ACKNOWLEDGMENTS |
We are grateful to Robert Walker for providing a panel of sera from
HIV-1+ donors. We thank John Sullivan and Merlin Robb for
providing sera from pediatric donors, James Robinson for providing the
control MAb PA-53, and Gerald Quinnan and Harvey Alter for FDA-2 serum. HIVIG was obtained from Albert Prince via the ARRRP. Virus isolates were collected from various geographical regions of the world by the
World Health Organization and the National Institute of Allergy and
Infectious Diseases. All viruses were obtained via the ARRRP. Pediatric
isolates were deposited by Merlin Robb, David Ho, John Sullivan, and
Cecelia Hutto. Isolate 92US714 was from Kenrad Nelson.
This study was supported by NIH grants AI33292 (D.R.B.), AI40377 and
AI42653 (P.W.H.I.P.), and AI36082 and HL59735 (J.P.M.) and by the
Elisabeth Glaser Pediatric AIDS Foundation, of which J.P.M. is an
Elisabeth Glaser Scientist and of which P.W.H.I.P. is a scholar
(PFR-77348). A.T. acknowledges a fellowship from the Fonds zur
Förderung der wissenschaftlicher Forschung (J01165-MED) and the
Austrian Program for Advanced Research and Technology.
| |
FOOTNOTES |
*
Corresponding author. Mailing address for Paul W. H. I. Parren: The Scripps Research Institute, Department of Immunology, IMM2,
10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 784-9298. Fax: (619) 784-8360. E-mail: parren{at}scripps.edu. Mailing address for
Dennis R. Burton: The Scripps Research Institute, Department of
Immunology, IMM2, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone:
(619) 784-9298. Fax: (619) 784-8360. E-mail: burton{at}scripps.edu.
| |
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Journal of Virology, December 1998, p. 10270-10274, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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