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Journal of Virology, December 1999, p. 10199-10207, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Characterization of Primary Isolate-Like Variants
of Simian-Human Immunodeficiency Virus
John M.
Crawford,1
Patricia L.
Earl,2
Bernard
Moss,2
Keith A.
Reimann,3
Michael S.
Wyand,4
Kelledy H.
Manson,4
Miroslawa
Bilska,1
Jin Tao
Zhou,1
C. David
Pauza,5
Paul W. H. I.
Parren,6
Dennis R.
Burton,6
Joseph G.
Sodroski,7
Norman L.
Letvin,3 and
David C.
Montefiori1,*
Department of Surgery, Duke University
Medical Center, Durham, North Carolina 277101;
Laboratory of Viral Diseases, National Institute of Allergy
and Infectious Diseases, Bethesda, Maryland
208922; Division of Viral
Pathogenesis, Beth Israel Deaconess Medical
Center,3 and Dana-Farber Cancer
Institute,7 Harvard Medical School, Boston,
Massachusetts 02215; Primedica Corporation, Worcester,
Massachusetts 016084; Department of
Pathology and Laboratory Medicine, University of Wisconsin,
Madison, Wisconsin 537065; and
Departments of Immunology and Molecular Biology, The
Scripps Research Institute, La Jolla, California
920376
Received 2 April 1999/Accepted 23 August 1999
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ABSTRACT |
Several different strains of simian-human immunodeficiency virus
(SHIV) that contain the envelope glycoproteins of either T-cell-line-adapted (TCLA) strains or primary isolates of human immunodeficiency virus type 1 (HIV-1) are now available. One of the
advantages of these chimeric viruses is their application to studies of
HIV-1-specific neutralizing antibodies in preclinical AIDS vaccine
studies in nonhuman primates. In this regard, an important
consideration is the spectrum of antigenic properties exhibited by the
different envelope glycoproteins used for SHIV construction. The
antigenic properties of six SHIV variants were characterized here in
neutralization assays with recombinant soluble CD4 (rsCD4), monoclonal
antibodies, and serum samples from SHIV-infected macaques and
HIV-1-infected individuals. Neutralization of SHIV variants HXBc2, KU2,
89.6, and 89.6P by autologous and heterologous sera from SHIV-infected
macaques was restricted to an extent that these viruses may be
considered heterologous to one another in their major neutralization
determinants. Little or no variation was seen in the neutralization
determinants on SHIV variants 89.6P, 89.6PD, and SHIV-KB9.
Neutralization of SHIV HXBc2 by sera from HXBc2-infected macaques could
be blocked with autologous V3-loop peptide; this was less true in the
case of SHIV 89.6 and sera from SHIV 89.6-infected macaques. The poorly
immunogenic but highly conserved epitope for monoclonal antibody
IgG1b12 was a target for neutralization on SHIV variants HXBc2, KU2,
and 89.6 but not on 89.6P and KB9. The 2G12 epitope was a target for
neutralization on all five SHIV variants. SHIV variants KU2, 89.6, 89.6P, 89.6PD, and KB9 exhibited antigenic properties characteristic of
primary isolates by being relatively insensitive to neutralization in peripheral blood mononuclear cells with serum samples from
HIV-1-infected individuals and 12-fold to 38-fold less sensitive to
inhibition with recombinant soluble CD4 than TCLA strains of HIV-1. The
utility of nonhuman primate models in AIDS vaccine development is
strengthened by the availability of SHIV variants that are heterologous
in their neutralization determinants and exhibit antigenic properties shared with primary isolates.
| |
INTRODUCTION |
Multiple simian-human
immunodeficiency virus (SHIV) variants have been constructed by
replacing env, tat, and rev of
molecularly cloned SIVmac239 with the corresponding genes of human
immunodeficiency virus type 1 (HIV-1). These variants broaden the scope
of studies to assess efficacy and correlates of immunity in preclinical
stages of vaccine development. SHIV is particularly advantageous for studies of HIV-1 envelope subunit vaccines in nonhuman primates. The
surface gp120 and transmembrane gp41 of HIV-1, both of which are
present on SHIV, are major targets for neutralizing antibodies (8). These envelope glycoproteins exhibit extensive genetic variability (26) and most likely exist as a trimolecular
complex of heterodimers in their native oligomeric form on the virus
surface (10, 14, 32, 71, 74). Genetic and structural
variability in gp120 and gp41 are potential obstacles for the
development of a broadly effective HIV-1 vaccine and add complexity to
the in vitro and in vivo assessment of neutralizing antibodies
(40).
Optimal use of the SHIV model requires knowledge of the antigenic
properties of the chimeric viruses. Assessments of the breadth of
antibody efficacy, for example, may require multiple virus variants
that are heterologous to one another in their neutralization determinants. It is also important to know whether the antigenicity of
the SHIV envelope glycoproteins resembles T-cell-line-adapted (TCLA)
variants or primary isolates of HIV-1. For example, as with other
lentiviruses (2, 11, 37), primary isolates of HIV-1 are less
sensitive to antibody-mediated neutralization in vitro than TCLA
strains (45, 60, 73). Primary isolates are also less
sensitive to inhibition by recombinant soluble CD4 (rsCD4) (12,
47). The sensitivity of HIV-1 to neutralization by antibody and
rsCD4 is strongly influenced by the structure of the native oligomeric
envelope glycoproteins. Specifically, some epitopes are exposed for
efficient antibody binding on TCLA strains more so than on primary
isolates (10, 46, 74). This is especially true for epitopes
residing in the V3 cysteine-cysteine loop of gp120 (6, 65,
70). A major emphasis is placed on achieving primary isolate
neutralization with candidate HIV-1 vaccines (8, 40, 46,
50).
Envelope glycoproteins of both TCLA strains and primary isolates of
HIV-1 have been used for SHIV construction. Some SHIV variants
replicate poorly and are relatively avirulent in macaques (5, 18,
21, 27, 30, 31, 33, 35, 54, 55, 64), whereas others replicate at
high levels persistently and induce AIDS (18, 20, 22-24, 34, 53,
55, 64, 66). Assessing vaccine efficacy with nonpathogenic SHIV
is limited to observations of sterilizing immunity (i.e., absence of
infection) and perhaps a reduction in transient virus loads, whereas
assessments made with pathogenic SHIV include protection from
immunologic suppression and AIDS. The validity of the SHIV model for
studies of antibody efficacy is supported by the observation that
passively administered antibodies can achieve both levels of protection
in macaques (16, 36, 40, 63).
Six SHIV variants were selected here for study. One SHIV contained the
envelope glycoproteins of the HXBc2 molecular clone of the IIIB TCLA
strain of HIV-1 (30, 31, 33). SHIV HXBc2 was later
engineered to contain the envelope glycoproteins of a primary isolate,
designated 89.6 (54). Both SHIV variants are relatively
avirulent in macaques and were subsequently passaged multiple times in
vivo to increase their virulence. A highly pathogenic variant of HXBc2
was termed SHIV KU2 (22), whereas highly pathogenic variants
of 89.6 were designated either 89.6P (53) or 89.6PD (34, 66). The latter two SHIV variants were isolated from the cells and plasma of the same infected animal, respectively, and
therefore are closely related. We also examined the KB9 molecular clone
of SHIV 89.6P, which exhibits many of the pathogenic properties of
89.6P (24). SHIV variants 89.6 and KB9 differ by 12 amino acids throughout the gp120 and gp41 sequences (24). The
pathogenicity of KB9 has been attributed to changes specific to the
ectodomain of the envelope glycoproteins (25).
The major neutralization determinants on SHIV variants HXBc2, 89.6, and
89.6P were shown previously to be different for each virus (15,
42). Most striking was the fact that 89.6P and its molecular
clone, KB9, no longer possessed at least some of the neutralization
determinants found on parental SHIV 89.6 and had actually acquired new
determinants not found on SHIV 89.6 (15, 42). One of the
goals of the present study was to determine whether a similar change in
neutralization determinants occurred when the nonpathogenic SHIV HXBc2
was passaged in macaques to obtain the pathogenic variant KU2. We also
assessed multiple SHIV variants to determine whether the antigenic
properties of their envelope glycoprotein resembled those of primary isolates.
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MATERIALS AND METHODS |
Viruses.
The derivation and biologic properties of SHIV
variants HXBc2 (30), KU2 (22), 89.6 (54), 89.6P (53), 89.6PD (34, 66), and
KB9 (24) are summarized in Table
1. Briefly, inoculation with either HXBc2
or 89.6 in macaques results in a relatively attenuated infection,
whereas inoculation with either KU2, 89.6P, 89.6PD, or KB9 results in
variable and sometimes rapid immune suppression and death from
AIDS-like illness. The IIIB and MN strains of HIV-1 were obtained from
Robert Gallo and have been described previously (17). HIV-1
strain SF-2 (29) was obtained from the NIH AIDS Research and
Reference Reagent Program (Bethesda, Md.) as donated by Jay Levy.
Cell-free stocks of SHIV variant HXBc2 and HIV-1 strains IIIB and MN
were produced in H9 cells as described previously (43).
Cell-free stocks of the remaining SHIV variants were produced in human
peripheral blood mononuclear cells (PBMC) as described previously for
primary HIV-1 isolates (41).
Cells.
H9 (17), MT-2 (19), and CEMx174
(59) are human CD4+ lymphoblastoid cell lines
that are highly permissive to infection with TCLA strains of HIV-1 and
many SHIV strains. These cells were maintained in growth medium
consisting of RPMI 1640 supplemented with 12% heat-inactivated fetal
bovine serum and 50 µg of gentamicin/ml. Human PBMC were prepared
from buffy coats of healthy, HIV-1-negative individuals obtained
through the Laboratory Services of the American Red Cross Carolina
Region in Charlotte, N.C. The PBMC were isolated by centrifugation over
lymphocyte separation medium (Organon-Teknika/Akzo, Durham, N.C.).
Cells at the interface were washed twice in growth medium containing
20% heat-inactivated fetal bovine serum and resuspended at a density
of 2.5 × 107 cells/ml and frozen in 1-ml portions in
liquid nitrogen with the aid of a Gordonier controlled-rate cryostat.
Prior to their use in neutralization assays and to grow virus stocks,
aliquots of PBMC were thawed in a room-temperature water bath and
incubated for 1 day at 37°C in 5% CO2-95% humidified
air in growth medium supplemented with phytohemagglutinin-P (5 µg/ml)
and 4% human interleukin-2 (IL-2). All human PBMC were prescreened for
an ability to support the replication of syncytium-inducing (SI) and
non-SI (NSI) primary isolates of HIV-1 to confirm the expression of
appropriate coreceptors for the virus, including CCR5. PBMC from rhesus
macaques (Macacca mulata) were similarly isolated from
heparinized peripheral blood.
Serum samples and other immunologic reagents.
Serum samples
were obtained from SHIV-infected macaques housed in primate facilities
maintained in accordance with guidelines set forth in Guide for
the Care and Use of Laboratory Animals (49). Additional
serum samples were obtained from patients who had been infected with
HIV-1 for at least 2 years and were attended by physicians at the Duke
University Medical Center. Due to either adverse reactions or personal
preference, these patients were not being treated with antiretroviral
drugs. All serum samples were heat inactivated for 1 h at 37°C
prior to use. Human monoclonal antibodies IgG1b12 and 2G12 have been
described previously (9, 57, 69); the latter antibody was
obtained from the NIH AIDS Research and Reference Reagent Program as
contributed by Hermann Katinger. Human rsCD4 was a generous gift from
Progenics Pharmaceuticals, Inc. (Tarrytown, N.Y.).
Peptides.
Peptides corresponding to the V3-loop of HIV-1
strains IIIB and 89.6 were synthesized and purified by the Laboratory
of Molecular Structure at the National Institute of Allergy and
Infectious Diseases, National Institutes of Health. The IIIB V3-loop
peptide consisted of the amino acid sequence
CTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA; the 89.6 V3-loop peptide had the
amino acid sequence CTRPNNNTRRRLSIGPGRAFYARRNIIGDIRQA.
Neutralizing antibody assays.
Two assays were used to assess
virus neutralization by antibody and rsCD4. One assay was performed in
either MT-2 or CEMx174 cells and used a reduction in virus-induced cell
killing as measured by neutral red uptake by viable cells as described
previously (43). HIV-1 strains IIIB and MN and all SHIV
variants used in these studies were highly infectious and cytopathic in
the MT-2 cells. Assays with SF2 were sometimes performed in CEMx174
cells because of a greater cytopathic effect relative to that of MT-2 cells with this virus. Briefly, 50 µl of cell-free virus containing 500 50% tissue culture infectious doses (TCID50) were
added to multiple dilutions of test serum, monoclonal antibodies, and
rsCD4 in 100 µl of growth medium in triplicate in 96-well culture
plates. The mixtures were incubated at 37°C for 1 h followed by
the addition of either MT-2 or CEMx174 cells (5 × 104
cells in 100 µl) to each well. Infection led to extensive syncytium formation and virus-induced cell killing in approximately 4 to 6 days
in the absence of antibodies. Neutralization was measured by staining
viable cells with Finter's neutral red in
poly-L-lysine-coated plates (43). Percent
protection was determined by calculating the difference in absorption
(A540) between test wells (cells plus serum
sample plus virus) and virus control wells (cells plus virus), dividing
this result by the difference in absorption between cell control wells
(cells only) and virus control wells, and multiplying by 100. Neutralization was measured at a time when virus-induced cell killing
in virus control wells was greater than 70% but less than 100%.
Neutralization titers are given as the reciprocal dilution required to
protect 50% of cells from virus-induced killing.
For assays in which V3-loop peptides were tested for their ability to
block neutralizing antibodies, serum samples were first diluted twofold
in growth medium and then incubated for 1 h at 37°C in the
presence and absence of peptide (50 µg/ml). The titer of neutralizing
antibodies was then determined in MT-2 cells as described above.
Assays were also performed in either human or macaque PBMC by using a
reduction in SHIV p27 Gag antigen synthesis as a measurement
of
neutralization as described previously (
42). Briefly,
diluted
serum samples or monoclonal antibodies were incubated with
virus
(500 TCID
50) in a total of 50 µl in triplicate for
1 h at 37°C
in 96-well U-bottom culture plates. Six wells
containing virus
only (no test sample) were included as controls.
Following a 1-h
incubation at 37°C, PBMC (4 × 10
5
cells in 150 µl of IL-2 growth medium) were added to each well
and
the mixtures were incubated for 24 h at 37°C. The cells were
then washed three times with 200 µl of growth medium to remove
the
virus inoculum and antibodies. Washed cells were resuspended
in 200 µl of IL-2 growth medium and incubated in fresh 96-well
U-bottom
plates until p27 production reached peak concentrations.
In some
experiments, 25 µl was removed after the final resuspension
and mixed
with 225 µl of 0.5% Triton X-100 spiked with a known
amount of p27
and incubated at 4°C overnight; the p27 content
of the mixture was
then measured to test for interference by residual
anti-p27 antibody in
the antigen detection enzyme-linked immunosorbent
assay (ELISA).
Culture supernatants (25 µl) were collected on
a daily basis
thereafter and mixed with 225 µl of 0.5% Triton
X-100 for the later
quantification of p27 produced by infection.
Viral p27 was quantified
with an antigen ELISA as described by
the supplier
(Organon-Teknika/Akzo). The 25-µl volume of culture
fluid removed
each day was replaced with 25 µl of fresh IL-2-containing
growth
medium. Measurements of p27 for the detection of neutralization
were
made on a harvest prior to the time when p27 production in
virus
control wells had reached peak concentrations, which is
when optimum
sensitivity is achieved in this assay (
75).
ELISA.
Nunc (Roskilde, Denmark) Immuno plates (MaxiSorb F96)
were coated with V3-loop peptides by adding 100 µl of a solution
containing peptide (1 µg/ml) in carbonate buffer (15 mM
Na2CO3, 35 mM NaHCO3 [pH 9.8])
overnight at 4°C. The solution was aspirated, and the wells were
washed once with 100 µl of phosphate-buffered saline (PBS; 0.14 M
NaCl, 2.7 mM KCl, 8 mM Na2HPO4, 1.7 mM
NaH2PO4 [pH 7.4]) and then filled with 100 µl of blocking buffer (95% [vol/vol] PBS, 5% [wt/vol] bovine
serum albumin, 5% [vol/vol] growth medium) and incubated for 2 h at 37°C. The plates were washed four times with PBS containing
0.05% [vol/vol] Tween 20. Serum samples were diluted 1:50 in borate
buffer (0.1 M boric acid, 47 mM sodium borate, 75 mM NaCl, 0.05%
[vol/vol] Tween 20) containing 2.5% fetal bovine serum, added to the
wells (each in duplicate), and incubated for 2 h at 37°C. The
wells were washed four times with PBS-Tween 20 and received 100 µl of
alkaline phosphatase-conjugated, goat anti-monkey immunoglobulin G
(IgG) (whole molecule; Sigma Chemical Co., St. Louis, Mo.) and
incubated for 2 h at 37°C. The wells were washed four times with
PBS-Tween 20 and incubated with 100 µl of
p-nitrophenylphosphate disodium hexahydrate (Sigma 104 phosphatase substrate) in diethanolamine buffer (0.9 M diethanolamine, 7 mM MgCl2 [pH 9.8] with concentrated HCl). Following
color development, the absorbance was read at 405 nm.
| |
RESULTS |
Neutralization of SHIV and TCLA strains of HIV-1 with sera from
SHIV-infected macaques.
One of our first goals was to assess the
relatedness of six SHIV variants by using sera from macaques infected
with either SHIV variant HXBc2, KU2, 89.6, or 89.6PD. Neutralization of
HXBc2, 89.6, and 89.6P was shown previously to be distinct, and
therefore these viruses were considered heterologous in their
neutralization determinants (15, 42). We confirmed and
extended those observations here by including SHIV variants KU2,
89.6PD, and KB9 in cross-sectional assessments. We also included HIV-1
strains MN and SF2 as representative TCLA viruses. The data are shown
in Table 2. For comparison, this table
contains titers reported previously for serum samples from long-term
SHIV 89.6-infected animals, 123-93 and 504-92, when assayed with SHIV
variants HXBc2, 89.6, and 89.6P and HIV-1 strains MN and SF2
(42).
As can be seen in Table
2, each SHIV was highly sensitive to
neutralization by autologous serum samples. Sera from SHIV-infected
animals also contained variable and sometimes potent neutralizing
activity against HIV-1 strains MN and SF2. Notably, however, sera
from
animals infected with either SHIV variant HXBc2 or 89.6 had
little or
no neutralizing activity against heterologous SHIV.
This was also true
for sera from animals infected with either
SHIV variant KU2 or 89.6PD,
with two exceptions: (i) serum from
KU2-infected animals often
neutralized HXBc2 better than KU2,
and (ii) serum from some
89.6PD-infected animals had nearly equivalent
neutralization potencies
against SHIV variants 89.6, 89.6P, 89.6PD,
and KB9. It was interesting
that sera from 89.6PD-infected animals
could neutralize 89.6 so well
when sera from 89.6-infected animals
had little neutralizing activity
against SHIV variants 89.6P,
89.6PD, and KB9. This unidirectional
cross-neutralizing activity
might be explained by either an enhanced
immunogenicity of the
89.6PD envelope glycoproteins or, alternatively,
by higher levels
of persistent SHIV 89.6PD replication relative to SHIV
89.6 replication
in
macaques.
Serum samples from SHIV 89.6PD-infected animals that cross-neutralized
SHIV 89.6 were obtained after 53 weeks of infection.
In contrast, serum
from a third animal (
R94056) infected with
89.6PD for only 31 weeks
failed to neutralize 89.6 despite having
potent neutralizing activity
against SHIV variants 89.6P, 89.6PD,
and KB9. This was also true for
serum samples obtained after 11
weeks of infection with 89.6PD in an
earlier study (
42). Due
to the heterologous nature of the
neutralization determinants
on these two viruses, antibodies that
neutralize 89.6 are not
generated until high titers of 89.6PD-specific
neutralizing antibodies
are detected in 89.6PD-infected macaques. This
is consistent with
the observation that potent neutralization of SHIV
89.6 was detected
after only 16 weeks of infection with SHIV 89.6 (Table
2).
Neutralization of SHIV with sera from HIV-1-infected
individuals.
We next examined the neutralization sensitivity of
each SHIV variant in cell lines and in human PBMC with serum samples
from HIV-1-infected individuals. Results of assays performed in cell lines are shown in Table 3. All serum
samples contained high titers of neutralizing antibodies against the
TCLA strains IIIB, MN, and SF2. SHIV variant KU2 was clearly the least
sensitive to neutralization by these serum samples, where positive
neutralization was low or undetectable with nine of nine samples
tested. By comparison, SHIV variants 89.6, 89.6P, 89.6PD, and KB9 were
more sensitive to neutralization in these assays, although the overall
sensitivity was moderate in comparison to that of MN and SF2 and more
closely resembled that of IIIB. Of note, 89.6P, 89.6PD, and KB9 had
approximately equal levels of neutralization sensitivity, again
indicating that the neutralization determinants of these three SHIV
variants are remarkably similar. Interestingly, SHIV HXBc2 was somewhat
less sensitive to neutralization than HIV-1 strain IIIB. It is possible in this case that the HXBc2 molecular clone of IIIB differs
antigenically from the dominant quasispecies present in the uncloned
IIIB stock.
We next examined the sensitivity of five SHIV variants in
neutralization assays performed with human PBMC with sera from seven
of
the HIV-1-infected individuals mentioned above. As shown in
Table
4, SHIV variants KU2, 89.6, 89.6P, and
89.6PD were relatively
insensitive to neutralization in these assays.
Specifically, each
variant was less sensitive than SHIV HXBc2. Three of
the serum
samples (
T00953,
W97464, and
P46471) had been assessed
previously with six primary HIV-1 isolates (
7). Serum
samples
that were most potent against those primary isolates were more
likely to neutralize SHIV variants KU2, 89.6, 89.6P, and 89.6PD.
These
latter SHIV variants were, overall, moderately more sensitive
to
neutralization than the primary HIV-1 isolates, perhaps because
they
consisted of less-complex quasispecies of genetic variants.
Also,
neutralization of 89.6, 89.6P, and 89.6PD was less potent
in human PBMC
than in MT-2 cells (Table
3). This discordant outcome
is unlikely to be
due to the different end points in the two assays,
since a 50%
reduction in cell viability in the MT-2 assay corresponds
consistently
to >80% reductions in p27 synthesis (unpublished
data). Differential
neutralization in these two cell types has
also been observed with the
HIV-1 89.6 primary isolate, where
the phenomenon was unrelated to
coreceptor usage (
39).
Sensitivity to inhibition by rsCD4.
Six SHIV variants were
compared to TCLA strains IIIB, MN, and SF2 in their sensitivity to
inhibition with rsCD4. As shown in Fig.
1, several SHIV variants were much less
sensitive to inhibition than TCLA strains in the MT-2 assay.
Specifically, the 50% inhibitory doses for SHIV variants 89.6, 89.6P,
89.6PD, KB9, and KU2 were 14-, 38-, 25-, 36- and 12-fold higher,
respectively, than the average dose required for 50% inhibition of
HIV-1 strains SF2 and IIIB and were even higher when compared to that
of MN. Of note, SHIV HXBc2 was approximately threefold less sensitive
to inhibition than uncloned HIV-1 IIIB, a result consistent with the
differential sensitivity to antibody-mediated neutralization exhibited
by these two viruses in the MT-2 assay (Table 3). It should also be
noted that variant KU2, which was the most resistant SHIV in
antibody-mediated neutralization assays, was not the most resistant to
inhibition by rsCD4. Nonetheless, it was at least 12-fold less
sensitive to inhibition with rsCD4 than the TCLA strains were. The
ability of rsCD4 inhibition to predict minor differences in
neutralization sensitivity between HIV-1 IIIB and SHIV HXBc2 but not
between KU2 and other SHIV variants might be explained by the fact that
the neutralization epitope(s) on HIV-1 IIIB and SHIV HXBc2 are similar,
whereas those on less-related viruses would be more divergent.
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FIG. 1.
Inhibition of HIV-1 and SHIV infection with rsCD4.
Viruses were incubated with various concentrations of rsCD4 ranging
from 0.002 to 5 µg/ml and then examined for infectivity in MT-2 cells
as described for antibody-mediated neutralization in Materials and
Methods. The height of each bar corresponds to the dose of rsCD4 that
was required to provide 50% protection from virus-induced cell
killing.
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V3-loop-specific neutralization of SHIV variants HXBc2 and
89.6.
Serum samples from SHIV-infected macaques were assessed for
V3-loop-specific neutralizing antibodies. This was done by testing whether the addition of V3-loop peptides to serum samples reduced the
neutralization titer against the autologous SHIV. The results are shown
in Fig. 2. Autologous neutralization
titers of sera from three of three SHIV HXBc2-infected macaques were
reduced 68- to 94-fold by the addition of HXBc2 V3-loop peptide, in
comparison to when no peptide was added. As a relevant negative
control, addition of 89.6 V3-loop peptide had no significant effect on the neutralization titer of these serum samples. These outcomes roughly
corresponded to positive ELISA reactivity to an HXBc2 V3-loop peptide
and negative reactivity to an 89.6 V3-loop peptide, respectively (Fig.
3).
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FIG. 2.
Ability of V3-loop peptides to absorb neutralizing
antibodies in serum samples from SHIV-infected macaques. Serum samples
from macaques infected with either SHIV variant HXBc2 or 89.6 were
incubated in the presence and absence of V3-loop peptides (50 µg/ml)
and then examined for neutralizing antibody titer to the corresponding
homologous SHIV in MT-2 cells as described in Materials and Methods.
The height of each bar corresponds to the reciprocal serum dilution at
which 50% of cells were protected from virus-induced killing effects.
Values above each bar are the percent reductions in neutralization
titer relative to that of the corresponding serum sample that was
incubated with an equal volume of growth medium (GM) in place of
V3-loop peptide. Serum samples from animals 18001, 18024, and 18062 were obtained after 27 weeks of infection with HXBc2. Serum samples
from animals 123-93 and 504-92 were obtained after 124 weeks of
infection, and serum samples 259-94 and 305-94 were obtained after 16 weeks of infection with 89.6.
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FIG. 3.
V3-loop reactivity measured by peptide ELISA with serum
samples from SHIV-infected macaques. Serum samples were assessed at a
1:50 dilution for antibodies reactive with IIIB and 89.6 V3-loop
peptides in an ELISA as described in Materials and Methods. Serum
samples are the same as those described in the legend to Fig. 2. A
negative control serum sample was obtained from a healthy, noninfected
rhesus macaque. O.D., optical density.
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A different result was obtained with serum samples from animals
infected with SHIV 89.6. In this case, only one of four animals
had
neutralizing antibodies that could be blocked by the addition
of an
89.6 V3-loop peptide (animal 123-93). This same animal also
had the
strongest reactivity to the 89.6 V3-loop peptide by ELISA
(Fig.
3). A
moderate degree of SHIV 89.6 neutralizing activity
could also be
blocked by the addition of an HXBc2 V3-loop peptide,
a result in
agreement with the reactivity of this serum sample
with the HXBc2
V3-loop peptide by ELISA. Serum samples from three
remaining SHIV
89.6-infected animals showed no evidence of having
V3-loop-specific
antibodies as detected by neutralization-blocking
assays or peptide
ELISA.
Neutralization with IgG1b12 and 2G12.
Three human monoclonal
antibodies have been identified that recognize conserved epitopes in
either the CD4 binding domain of gp120 (IgG1b12) (8, 57),
the base of the V3/V4 region of gp120 (2G12) (69) or the
membrane-proximal ectodomain of gp41 (2F5) (48, 52), and are
capable of neutralizing TCLA strains and primary isolates broadly and
potently (13, 68). Two of these monoclonal antibodies,
IgG1b12 and 2G12, were tested for their ability to neutralize SHIV. As
shown in Table 5, 2G12 was capable of
neutralizing SHIV variants HXBc2, KU2, 89.6, 89.6P, and KB9 in MT-2
cells. Also, IgG1b12 was capable of neutralizing SHIV variants HXBc2,
KU2, and 89.6, but not 89.6P and KB9 in MT-2 cells. To determine
whether the inability of IgG1b12 to neutralize these latter two SHIV
variants was a property of the virus or the cells used for assay,
additional tests were performed in either rhesus or human PBMC. As
shown in Fig. 4, SHIV 89.6 remained
sensitive whereas 89.6P was highly resistant to IgG1b12 in rhesus PBMC. In addition, KB9 resisted neutralization by IgG1b12 at 18 µg/ml in
human PBMC (data not shown). These results indicate that the resistance
of 89.6P and KB9 to neutralization by IgG1b12 is independent of the
cells used for assay. In support of this conclusion, Karlsson et al.
obtained similar results when viruses bearing the 89.6 and KB9 envelope
glycoproteins were assessed with IgG1b12 in CEMx174 cells
(25).
View larger version (16K):
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|
FIG. 4.
Neutralization of SHIV variants 89.6 and 89.6P by
IgG1b12 in rhesus PBMC. Virus stocks were grown in human PBMC and
assayed in rhesus macaque PBMC. Virus (500 TCID50) was
incubated for 1 h at 37°C with various concentrations of IgG1b12
in 96-well U-bottom plates. Rhesus PBMC (stimulated with
phytohemagglutinin-P) in IL-2 growth medium were added (500,000 cells/well), and the plates were incubated overnight. The medium was
changed completely twice to remove the virus inoculum. Viral p27 was
quantified at a time when virus production in the absence of IgG1b12
was in a linear phase of increase and had yet to peak (2,133 ± 438 pg/ml for SHIV variant 89.6 and 2,319 ± 571 pg/ml for SHIV
variant 89.6P). Error bars are used to show the standard deviation for
average p27 values in triplicate wells. Values below the data points on
the 89.6 curve represent percent reductions in p27 synthesis relative
to infection in the absence of IgG1b12.
|
|
| |
DISCUSSION |
Several SHIV variants were shown here to represent a cross-section
of heterologous neutralization determinants and to resemble primary
isolates in terms of the antigenicity of their envelope glycoproteins.
These variants should prove useful when assessing breadth and potency
of antibody efficacy in preclinical HIV-1 vaccine studies in macaques.
Specifically, results obtained with serum samples from SHIV-infected
macaques indicated that SHIV variants HXBc2, KU2, 89.6, and 89.6P
(including 89.6PD and KB9) are heterologous to one another in their
major neutralization determinants. In addition, KU2, 89.6, 89.6P,
89.6PD, and KB9 exhibit antigenic properties characteristic of primary
isolates. Specifically, these SHIV variants were less sensitive to
rsCD4 and neutralizing sera than TCLA strains of HIV-1. As another
feature of primary isolates, neutralizing antibodies to SHIV 89.6 generated by SHIV 89.6 infection were not easily blocked by an 89.6 V3-loop peptide. This latter finding is in agreement with an earlier
study where 89.6 neutralization was affected mostly by changes in V2
and less commonly by changes in V3 (15).
The antigenic properties of SHIV variants 89.6P, 89.6PD, and KB9 were
nearly indistinguishable in assays with rsCD4 and sera from
SHIV-infected animals, suggesting that these viruses are homologous in
their neutralization determinants. In this regard, the fact that 89.6P
and 89.6PD were isolated from cells and plasma of the same animal,
respectively, and that KB9 is a molecular clone of a minor 89.6P
quasispecies seems to have had little impact on the determinants of
neutralization as detected by a variety of serologic reagents in vitro.
Our results also demonstrate that multiple passages in macaques can
have a profound influence on the neutralization determinants of SHIV.
One of the more striking examples of this was found with the
nonpathogenic SHIV HXBc2 and its animal-passaged pathogenic variant,
KU2. In particular, serum samples from HXBc2-infected animals had
little or no neutralizing activity against KU2 despite having potent
neutralizing activity against HXBc2. This outcome is unlikely to be
explained by a lack of shared epitopes between HXBc2 and KU2, since
infection with KU2 gave rise to antibodies that neutralized HXBc2. A
more likely explanation is that the neutralization epitopes on KU2 were
poorly exposed for efficient antibody binding relative to their
exposure on HXBc2. This would explain why sera from some KU2-infected
animals neutralized HXBc2 more potently than KU2. The envelope
glycoproteins of KU2 are likely to have adopted a structure resembling
primary isolate envelope glycoproteins as a consequence of in vivo
passage. Results of crystallographic and serologic studies suggest that
some neutralization epitopes on primary isolates are masked by the
V1/V2 loops (74) and the positioning of N-glycans (1,
56, 61, 62) on the native gp120 molecule. Other epitopes might be
occluded by subunit-subunit interactions in the quartenary structure of
the native oligomeric complex. It has been proposed that poorly exposed
epitopes on primary isolates are recognized by B cells in the context
of monomers and debris of envelope glycoproteins present during
infection to generate antibodies to epitopes exposed in a similar
fashion on TCLA strains (50, 51). Our results with SHIV
variants HXBc2 and KU2 are consistent with this hypothesis.
At least one neutralization epitope on KU2 must have been adequately
exposed to permit potent neutralization of this SHIV by sera from some
KU2-infected animals. This result is consistent with the antigenic
properties of primary isolates. For example, some epitopes on primary
isolates are potent targets for autologous neutralizing antibodies
generated by infection; such epitopes are relatively strain specific,
and it may take many months for the antibodies to be generated
(44, 51, 72). The fact that sera from KU2-infected animals
had little or no neutralizing activity against SHIV variants 89.6, 89.6P, 89.6PD, and KB9 is consistent with the notion that the
neutralization epitope(s) detected on KU2 is relatively strain specific.
Similar to our observations with SHIV KU2, multiple animal passage had
a profound effect on the neutralization determinants of SHIV 89.6 when
deriving 89.6P and 89.6PD. In contrast to KU2 infection, however, serum
from one 89.6PD-infected animal failed to neutralize parental 89.6 despite the serum's ability to neutralize 89.6PD potently. Such
strain-specific neutralization by serum from 89.6PD-infected animals
has been observed previously and seems to be associated with earlier
stages of infection (42). This outcome is consistent with
the SHIV 89.6 envelope glycoproteins originating from a primary isolate
and having at least some of its neutralization epitopes masked. An
unusual feature of both viruses, however, was their increased
sensitivity to neutralization in MT-2 cells relative to human PBMC,
which was also observed for 89.6P. Although unusual for primary
isolates, this property has also been observed with primary HIV-1 89.6 (39). The exact nature of this phenomenon is uncertain and
did not appear to be related to coreceptor usage in the case of HIV-1
89.6 (39). Along these same lines, the titers of autologous
neutralizing antibodies generated by infection with SHIV variants 89.6 and 89.6PD were higher than would be expected for a primary isolate when measured in MT-2 cells. Titers were much lower, however, when
measured previously in PBMC (42), where they more closely approximated the titers expected for primary isolate neutralization (44, 51, 72). These observations suggest that SHIV 89.6 and
its derivatives are somewhat atypical for primary isolates in terms of
their high sensitivity to neutralization in MT-2 cells, although they
resemble primary isolates in other important features.
Finally, the broadly cross-neutralizing human monoclonal antibodies
2G12 and IgG1b12 were used to examine the presence of conserved
neutralization epitopes on SHIV. Our assessments showed that SHIV
variants HXBc2, KU2, 89.6, 89.6P, and KB9 were sensitive to
neutralization by 2G12, whereas only SHIV variants HXBc2, KU2, and 89.6 were sensitive to neutralization by IgG1b12. Thus, as reported
previously (25), we confirm that the IgG1b12 determinant present on SHIV 89.6 was lost upon in vivo passage of this virus when
deriving 89.6P and KB9. The 89.6 and KB9 envelope glycoproteins differ
by 12 amino acids (24). Three of these changes in gp120, including I186V, E187K, and N190S (this latter mutation resulted in the
acquisition of a potential site of N-glycan addition in KB9) are
located in a region identified as important for in vitro escape from
IgG1b12 in the case of the JR-FL strain as reported previously
(38).
The differential neutralization of nonpathogenic SHIV 89.6 relative to
pathogenic variants 89.6P and KB9 with IgG1b12 suggest that resistance
to this monoclonal antibody is somehow related to in vivo virulence. In
support of this notion, nonpathogenic SHIV HXBc2 was approximately 10 times more sensitive to IgG1b12 than its pathogenic counterpart, KU2.
The determinants of KB9 pathogenicity have been shown to reside in the
ectodomain of the envelope glycoproteins (25), which is
where the IgG1b12 epitope resides (8). It is doubtful that
virulence was related to escape from neutralizing antibodies equivalent
to IgG1b12, since sera from SHIV-infected animals did not exhibit
IgG1b12-like potency. Thus, the amino acid changes affecting IgG1b12
resistance and SHIV virulence are similar in location but would appear
to arise independently. These SHIV variants will be useful when
assessing the efficacy of IgG1b12 and 2G12 in passive immunization
experiments. They also will be useful in testing the efficacy of
vaccines that are capable of generating antibodies equivalent to
IgG1b12 and 2G12. Unfortunately, the poor immunogenicity of the
epitopes recognized by IgG1b12 and 2G12 has so far precluded their
successful addition as a component of current HIV-1 vaccine candidates.
In summary, the utility of nonhuman primate models for HIV-1 vaccine
development is strengthened by the availability of heterologous SHIV
challenge stocks, some of which exhibit antigenic properties of primary
isolates. It may be argued that one remaining obstacle to overcome when
optimizing this model for studies of neutralizing antibodies is to
develop a similar repertoire of SHIV variants that exhibit an NSI
biologic phenotype and utilize CCR5 as their sole coreceptor. CCR5 and
CXCR4 chemokine receptors are the major coreceptors used for HIV-1
entry (3, 58). Strains that use CXCR4 alone (X4 viruses) or
in addition to CCR5 (X4R5 viruses) have an SI phenotype in MT-2 cells,
whereas those that use CCR5 exclusively (R5 viruses) have an NSI
phenotype in MT-2 cells (4). All of the SHIV variants
described here are either X4 or X4R5 viruses. Given that most strains
of HIV-1 isolated soon after infection are R5 viruses (3, 4,
58), one might question the relevance of using X4 or X4R5 viruses
to assess the efficacy of antibodies generated by candidate HIV-1
vaccines. As a counterargument, however, antibody-mediated
neutralization of HIV-1 has not been shown to be influenced by the
differential use of CXCR4 and CCR5 coreceptors (28, 39, 67).
In fact, no evidence exists to support the notion that neutralizing
antibodies broadly effective against X4 or X4R5 viruses will not be
equally effective against R5 viruses. We believe that the repertoire of
SHIV variants described here are appropriate for studies of antibody
efficacy in macaques as they relate to HIV-1 vaccine development.
| |
ACKNOWLEDGMENTS |
We thank Yichen Lu for SHIV 89.6PD, Opendra Narayan for SHIV KU2,
Paul Maddon for rsCD4, and James Blanchard for serum samples from a
subset of KU2-infected macaques.
This work was supported by grants from the NIH, including AI-85343
(D.C.M. and N.L.L.), AI65303 (M.S.W.), AI36643 (C.D.P.), AI33292
(D.R.B.), and AI40377 (P.W.H.I.P.).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Surgery, Box 2926, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-5278. Fax: (919) 684-4288. E-mail:
monte005{at}mc.duke.edu.
| |
REFERENCES |
| 1.
|
Back, N. K. T.,
L. Smit,
J.-J. de Jong,
W. Keulen,
M. Schutten,
J. Goudsmit, and M. Tersmette.
1994.
An N-glycan within the human immunodeficiency virus type 1 gp120 V3 loop affects virus neutralization.
Virology
199:431-438[Medline].
|
| 2.
|
Baldinotti, F.,
D. Matteucci,
P. Mazzetti,
L. Gianelli,
P. Bandecchi,
F. Tozzini, and M. Bendinelli.
1994.
Serum neutralization of feline immunodeficiency virus is markedly dependent on passage history of the virus and host system.
J. Virol.
68:4572-4579[Abstract/Free Full Text].
|
| 3.
|
Berger, E. A.
1997.
HIV entry and tropism: the chemokine receptor connection.
AIDS
11(Suppl. A):S3-S16.
|
| 4.
|
Berger, E. A.,
R. W. Doms,
E. M. Fenyö,
B. T. M. Korber,
D. R. Littman,
J. P. Moore,
Q. J. Sattentau,
H. Schuitemaker,
J. Sodroski, and R. A. Weiss.
1998.
HIV-1 phenotypes classified by coreceptor usage.
Nature
391:240[Medline].
|
| 5.
|
Bogers, W. M. J. M.,
R. Dubbes,
P. T. Haaft,
H. Niphuis,
C. Cheng-Mayer,
C. Stahl-Hennig,
G. Hunsmann,
T. Kuwata,
M. Hayami,
S. Jones,
S. Ranjbar,
N. Almond,
J. Stott,
B. Rosenwirth, and J. L. Heeney.
1997.
Comparison of in vitro and in vivo infectivity of different clade B HIV-1 envelope chimeric simian/human immunodeficiency viruses in Macaca mulatta.
Virology
236:110-117[Medline].
|
| 6.
|
Bou-Habib, D. C.,
G. Roderiquez,
T. Oravecz,
P. W. Berman,
P. Lusso, and M. A. Norcross.
1994.
Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization.
J. Virol.
68:6006-6013[Abstract/Free Full Text].
|
| 7.
|
Bradney, A. P.,
S. Scheer,
J. M. Crawford,
S. P. Buchbinder, and D. C. Montefiori.
1999.
Neutralization escape in human immunodeficiency virus type 1-infected long-term nonprogressors.
J. Infect. Dis.
179:1264-1267[Medline].
|
| 8.
|
Burton, D. R., and D. C. Montefiori.
1997.
The antibody response in HIV-1 infection.
AIDS
11(Suppl. A):S87-S98.
|
| 9.
|
Burton, D. R.,
J. Pyati,
R. Koduri,
S. J. Sharp,
G. B. Thornton,
P. W. H. I. Parren,
L. S. W. Sawyer,
R. M. Hendry,
N. Dunlop,
P. L. Nara,
M. Lamacchia,
E. Garratty,
E. R. Stiehm,
Y. J. Bryson,
Y. Cao,
J. P. Moore,
D. D. Ho, and C. F. Barbas, III.
1994.
Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody.
Science
266:1024-1027[Abstract/Free Full Text].
|
| 10.
|
Chan, D. C., and P. S. Kim.
1998.
HIV entry and its inhibition.
Cell
93:681-684[Medline].
|
| 11.
|
Cook, R. F.,
S. L. Berger,
K. E. Rushlow,
J. M. McMannus,
S. J. Cook,
S. Harrold,
M. L. Raabe,
R. C. Montelaro, and C. J. Issel.
1995.
Enhanced sensitivity to neutralizing antibodies in a variant of equine infectious anemia virus is linked to amino acid substitutions in the surface unit envelope glycoprotein.
J. Virol.
69:1493-1499[Abstract].
|
| 12.
|
Daar, E. S.,
X. L. Li,
T. Moudgil, and D. D. Ho.
1990.
High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency type 1 isolates.
Proc. Natl. Acad. Sci. USA
87:6574-6578[Abstract/Free Full Text].
|
| 13.
|
D'Souza, P. M.,
D. Livnat,
J. A. Bradac,
S. H. Bridges, and the AIDS Clinical Trials Group Antibody Selection Working Group, and Collaborating Investigators.
1997.
Evaluation of monoclonal antibodies to human immunodeficiency virus type 1 primary isolates by neutralization assays: performance criteria for selecting candidate antibodies for clinical trials.
J. Infect. Dis.
175:1056-1062[Medline].
|
| 14.
|
Earl, P. L.,
R. W. Doms, and B. Moss.
1990.
Oligomeric structure of the human immunodeficiency virus type 1 envelope glycoprotein.
Proc. Natl. Acad. Sci. USA
87:648-652[Abstract/Free Full Text].
|
| 15.
|
Etemad-Moghadam, B.,
G. B. Karlsson,
M. Halloran,
Y. Sun,
D. Schenten,
M. Fernandes,
N. L. Letvin, and J. Sodroski.
1998.
Characterization of simian-human immunodeficiency virus envelope glycoprotein epitopes recognized by neutralizing antibodies from infected macaques.
J. Virol.
72:8437-8445[Abstract/Free Full Text].
|
| 16.
|
Foresman, L.,
F. Jia,
Z. Li,
C. Wang,
E. B. Stephens,
M. Sahni,
O. Narayan, and S. V. Joag.
1998.
Neutralizing antibodies administered before, but not after, virulent SHIV prevent infection in macaques.
AIDS Res. Hum. Retroviruses
14:1035-1043[Medline].
|
| 17.
|
Gallo, R. C.,
S. Z. Salahuddin,
M. Popovic,
G. M. Shearer,
M. Kaplan,
B. F. Haynes,
T. J. Palker,
R. Redfield,
J. Oleske,
B. Safai,
G. White,
P. Foster, and P. D. Markham.
1984.
Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.
Science
224:500-503[Abstract/Free Full Text].
|
| 18.
|
Haaft, P. T.,
B. Verstrepen,
K. Überla,
B. Rosenwirth, and J. Heeney.
1998.
A pathogenic threshold of virus load defined in simian immunodeficiency virus- or simian-human immunodeficiency virus-infected macaques.
J. Virol.
72:10281-10285[Abstract/Free Full Text].
|
| 19.
|
Harada, S.,
Y. Koyanagi, and N. Yamamoto.
1985.
Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay.
Science
229:563-566[Abstract/Free Full Text].
|
| 20.
|
Harouse, J. M.,
R. C. H. Tan,
A. Gettie,
P. Dailey,
P. A. Marx,
P. A. Luciw, and C. Cheng-Mayer.
1998.
Mucosal transmission of pathogenic CXCR4-utilizing SHIV-SF33A variants in rhesus macaques.
Virology
248:95-107[Medline].
|
| 21.
|
Igarashi, T.,
R. Shibata,
F. Hasebe,
Y. Ami,
K. Shinohara,
T. Komatsu,
C. Stahl-Henning,
H. Petry,
G. Hunsmann,
T. Kuwata,
M. Jin,
A. Adachi,
T. Kurimura,
M. Okada,
T. Miura, and M. Hayami.
1994.
Persistent infection with SIVmac chimeric virus having tat, rev, vpu, env and nef of HIV type 1 in macaque monkeys.
AIDS Res. Hum. Retroviruses
10:1021-1029[Medline].
|
| 22.
|
Joag, S. V.,
Z. Li,
L. Foresman,
D. M. Pinson,
R. Raghavan,
W. Zhuge,
I. Adany,
C. Wang,
F. Jia,
D. Sheffer,
J. Ranchalis,
A. Watson, and O. Narayan.
1997.
Characterization of the pathogenic KU-SHIV model of acquired immunodeficiency syndrome in macaques.
AIDS Res. Hum. Retroviruses
13:635-645[Medline].
|
| 23.
|
Joag, S. V.,
Z. Li,
L. Foresman,
E. B. Stephens,
L. J. Zhao,
I. Adany,
D. M. Pinson,
H. M. McClure, and O. Narayan.
1996.
Chimeric simian human immunodeficiency virus that causes progressive loss of CD4+ T cells and AIDS in pig-tailed macaques.
J. Virol.
70:3189-3197[Abstract].
|
| 24.
|
Karlsson, G. B.,
M. Halloran,
J. Li,
I.-W. Park,
R. Gomila,
K. A. Reimann,
M. K. Axthelm,
S. A. Iliff,
N. L. Letvin, and J. Sodroski.
1997.
Characterization of molecularly cloned simian-human immunodeficiency viruses causing rapid CD4+ lymphocyte depletion in rhesus monkeys.
J. Virol.
71:4218-4225[Abstract].
|
| 25.
|
Karlsson, G. B.,
M. Halloran,
D. Schenten,
J. Lee,
P. Racz,
K. Tenner-Racz,
J. Manola,
R. Gelman,
B. Etemad-Moghadam,
E. Desjardins,
R. Wyatt,
N. P. Gerard,
L. Marcon,
D. Margolin,
J. Fanton,
M. K. Axthelm,
N. L. Letvin, and J. Sodroski.
1998.
The envelope glycoprotein ectodomains determine the efficacy of CD4+ T lymphocyte depletion in simian-human immunodeficiency virus-infected macaques.
J. Exp. Med.
188:1159-1171[Abstract/Free Full Text].
|
| 26.
|
Korber, B. T. M.,
E. E. Allen,
A. D. Farmer, and G. L. Myers.
1995.
Heterogeneity of HIV-1 and HIV-2.
AIDS
9:S5-S18.
|
| 27.
|
Kuwata, T.,
T. Igarashi,
E. Ido,
M. Jin,
A. Mizuno,
J. Chen, and M. Hayami.
1995.
Construction of human immunodeficiency virus 1/simian immunodeficiency virus strain mac chimeric viruses having vpr and/or nef of different parental origins and their in vitro and in vivo replication.
J. Gen. Virol.
76:2181-2191[Abstract/Free Full Text].
|
| 28.
|
LaCasse, R. A.,
K. E. Follis,
T. Moudgil,
M. Trahey,
J. M. Binley,
V. Planelles,
S. Zolla-Pazner, and J. H. Nunberg.
1998.
Coreceptor utilization by human immunodeficiency virus type 1 is not a primary determinant of neutralization sensitivity.
J. Virol.
72:2491-2495[Abstract/Free Full Text].
|
| 29.
|
Levy, J. A.,
A. D. Hoffman,
S. M. Kramer,
J. A. Landis,
J. M. Shimabukuro, and L. S. Oshiro.
1984.
Isolation of lymphocytopathic retrovirus from San Francisco patients with AIDS.
Science
225:840-842[Abstract/Free Full Text].
|
| 30.
|
Li, J. T.,
M. Halloran,
C. I. Lord,
A. Watson,
J. Ranchalis,
M. Fung,
N. L. Letvin, and J. G. Sodroski.
1995.
Persistent infection of macaques with simian-human immunodeficiency viruses.
J. Virol.
69:7061-7071[Abstract].
|
| 31.
|
Li, J.,
C. I. Lord,
W. Haseltine,
N. L. Letvin, and J. Sodroski.
1993.
Infection of cynomolgus monkeys with a chimeric HIV-1/SIVmac virus that expresses the HIV-1 envelope glycoproteins.
J. AIDS
5:639-646.
|
| 32.
|
Lu, M.,
S. C. Blacklow, and P. S. Kim.
1995.
A trimeric structural domain of the HIV-1 transmembrane glycoprotein.
Nat. Struct. Biol.
2:1075-1082[Medline].
|
| 33.
|
Lu, Y.,
M. S. Salvato,
C. D. Pauza,
J. Li,
J. Sodroski,
K. Manson,
M. Wyand,
N. Letvin,
S. Jenkins,
N. Touzjian,
C. Chutkowski,
N. Kushner,
M. LeFaile,
L. G. Payne, and B. Roberts.
1996.
Utility of SHIV for testing HIV-1 vaccine candidates in macaques.
J. Acquir. Immun. Defic. Syndr. Hum. Retrovirol.
12:99-106[Medline].
|
| 34.
|
Lu, Y. C.,
C. D. Pauza,
X. S. Lu,
D. C. Montefiori, and C. J. Miller.
1998.
Rhesus macaques that become systemically infected with pathogenic SHIV 89.6-PD after intravenous, rectal, or vaginal inoculation and fail to make an antiviral antibody response rapidly develop AIDS.
J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.
19:6-18[Medline].
|
| 35.
|
Luciw, P. A.,
E. Pratt-Lowe,
K. E. S. Shaw,
J. A. Levy, and C. Cheng-Mayer.
1995.
Persistent infection of rhesus macaques with T-cell line-tropic and macrophage-tropic clones of simian/human immunodeficiency viruses (SHIV).
Proc. Natl. Acad. Sci. USA
92:7490-7494[Abstract/Free Full Text].
|
| 36.
|
Mascola, J. R.,
M. G. Lewis,
G. Stiegler,
D. Harris,
T. C. VanCott,
D. Hayes,
M. K. Louder,
C. R. Brown,
C. V. Sapan,
S. S. Frankel,
Y. Lu,
M. L. Robb,
H. Katinger, and D. L. Birx.
1999.
Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies.
J. Virol.
73:4009-4018[Abstract/Free Full Text].
|
| 37.
|
Means, R. E.,
T. Greenough, and R. C. Desrosiers.
1997.
Neutralization sensitivity of cell culture-passaged simian immunodeficiency virus.
J. Virol.
71:7895-7902[Abstract].
|
| 38.
|
Mo, H.,
L. Stamatatos,
J. E. Ip,
C. F. Barbas,
P. W. H. I. Parren,
D. R. Burton,
J. P. Moore, and D. D. Ho.
1997.
Human immunodeficiency virus type 1 mutants that escape neutralization by human monoclonal antibody IgG1b12.
J. Virol.
71:6869-6874[Abstract].
|
| 39.
|
Montefiori, D. C.,
R. G. Collman,
T. R. Fouts,
J. Y. Zhou,
M. Bilska,
J. A. Hoxie,
J. P. Moore, and D. P. Bolognesi.
1998.
Evidence that antibody-mediated neutralization of human immunodeficiency virus type 1 is independent of coreceptor usage.
J. Virol.
72:1886-1893[Abstract/Free Full Text].
|
| 40.
|
Montefiori, D. C., and T. G. Evans.
1999.
Toward an HIV-1 vaccine that generates potent, broadly cross-reactive neutralizing antibodies.
AIDS Res. Hum. Retroviruses
15:689-698[Medline].
|
| 41.
|
Montefiori, D. C.,
G. Pantaleo,
L. M. Fink,
J. T. Zhou,
J. Y. Zhou,
M. Bilska,
G. D. Miralles, and A. S. Fauci.
1996.
Neutralizing and infection-enhancing antibody responses to human immunodeficiency virus type 1 in long-term nonprogressors.
J. Infect. Dis.
173:60-67[Medline].
|
| 42.
|
Montefiori, D. C.,
K. A. Reimann,
M. S. Wyand,
K. Manson,
M. G. Lewis,
R. G. Collman,
J. G. Sodroski,
D. P. Bolognesi, and N. L. Letvin.
1998.
Neutralizing antibodies in sera from macaques infected with chimeric simian-human immunodeficiency virus containing the envelope glycoproteins of either a laboratory-adapted variant or a primary isolate of human immunodeficiency virus type 1.
J. Virol.
72:3427-3431[Abstract/Free Full Text].
|
| 43.
|
Montefiori, D. C.,
W. E. Robinson, Jr.,
S. S. Schuffman, and W. M. Mitchell.
1988.
Evaluation of antiviral drugs and neutralizing antibodies to human immunodeficiency virus by a rapid and sensitive microtiter infection assay.
J. Clin. Microbiol.
26:231-235[Abstract/Free Full Text].
|
| 44.
|
Moog, C.,
H. J. A. Fleury,
I. Pellegrin,
A. Kirn, and A. M. Aubertin.
1997.
Autologous and heterologous neutralizing antibody responses following initial seroconversion in human immunodeficiency virus type 1-infected individuals.
J. Virol.
71:3734-3741[Abstract].
|
| 45.
|
Moore, J. P.,
Y. Cao,
L. Qing,
Q. J. Sattentau,
J. Pyati,
R. Koduri,
J. Robinson,
C. F. Barbas,
D. R. Burton, and D. D. Ho.
1995.
Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120.
J. Virol.
69:101-109[Abstract].
|
| 46.
|
Moore, J. P., and D. D. Ho.
1995.
HIV-1 neutralization: the consequences of viral adaptation to growth on transformed T cells.
AIDS
9(Suppl. A):S117-S136.
|
| 47.
|
Moore, J. P.,
J. A. McKeating,
Y. X. Huang,
A. Ashkenazi, and D. D. Ho.
1992.
Virions of primary human immunodeficiency virus type 1 isolates resistant to soluble CD4 (sCD4) neutralization differ in sCD4 binding and glycoprotein gp120 retention from sCD4-sensitive isolates.
J. Virol.
66:235-243[Abstract/Free Full Text].
|
| 48.
|
Muster, T.,
R. Guinea,
A. Trkola,
M. Purtscher,
A. Klima,
F. Steindl,
P. Palese, and H. Katinger.
1994.
Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS.
J. Virol.
68:4031-4034[Abstract/Free Full Text].
|
| 49.
|
National Institutes of Health.
1985.
Guide for the care and use of laboratory animals.
National Research Council, National Academic Press, Washington, D.C.
|
| 50.
|
Parren, P. W. H. I.,
D. R. Burton, and Q. J. Sattentau.
1997.
HIV-1 antibody debris or virion?
Nat. Med.
3:366-367[Medline].
|
| 51.
|
Pilgrim, A. K.,
G. Pantaleo,
O. J. Cohen,
L. M. Fink,
J. Y. Zhou,
J. T. Zhou,
D. P. Bolognesi,
A. S. Fauci, and D. C. Montefiori.
1997.
Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term nonprogressive infection.
J. Infect. Dis.
176:924-932[Medline].
|
| 52.
|
Purtschur, M.,
A. Trkola,
A. Grassauer,
P. M. Schultz,
A. Klima,
S. Dopper,
G. Gruber,
A. Buchacher,
T. Muster, and H. Katinger.
1996.
Restricted antigenic variability of the epitope recognized by the neutralizing gp41 antibody 2F5.
AIDS
10:587-593[Medline].
|
| 53.
|
Reimann, K. A.,
J. T. Li,
R. Veazey,
M. Halloran,
I.-W. Park,
G. B. Karlsson,
J. Sodroski, and N. L. Letvin.
1996.
A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vivo passage in rhesus monkeys.
J. Virol.
70:6922-6928[Abstract/Free Full Text].
|
| 54.
|
Reimann, K. A.,
J. T. Li,
G. Voss,
C. Lekutis,
K. Tenner-Racz,
P. Racz,
W. Lin,
D. C. Montefiori,
D. E. Lee-Parritz,
Y. C. Lu,
R. G. Collman,
J. Sodroski, and N. L. Letvin.
1996.
An env gene derived from a primary HIV-1 isolate confers high in vivo replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys.
J. Virol.
70:3198-3206[Abstract].
|
| 55.
|
Reimann, K. A.,
A. Watson,
P. J. Dailey,
W. Lin,
C. I. Lord,
T. D. Steenbeke,
R. A. Parker,
M. K. Axthelm, and G. B. Karlsson.
1999.
Viral burden and disease progression in rhesus monkeys infected with chimeric simian human immunodeficiency viruses.
Virology
256:15-21[Medline].
|
| 56.
|
Reitter, J. N.,
R. E. Means, and R. C. Desrosiers.
1998.
A role for carbohydrates in immune evasion in AIDS.
Nat. Med.
4:679-684[Medline].
|
| 57.
|
Roben, P.,
J. P. Moore,
M. Thali,
J. Sodroski,
C. F. Barbas III, and D. R. Burton.
1994.
Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1.
J. Virol.
68:4821-4828[Abstract/Free Full Text].
|
| 58.
|
Rucker, J., and R. W. Doms.
1998.
Chemokine receptors as HIV coreceptors: implications and interactions.
AIDS Res. Hum. Retroviruses
14(Suppl. 3):S241-S246.
|
| 59.
|
Salter, R. D.,
D. N. Howell, and P. Cresswell.
1985.
Gene regulating HLA class I antigen expression in T-B lymphoblast hybrids.
Immunogenetics
21:235-246[Medline].
|
| 60.
|
Sawyer, L. S. W.,
M. T. Wrin,
L. Crawford-Miksza,
B. Potts,
Y. Wu,
P. A. Weber,
R. D. Alfonso, and C. V. Hanson.
1994.
Neutralization sensitivity of human immunodeficiency virus type 1 is determined in part by the cell in which the virus is propagated.
J. Virol.
68:1342-1349[Abstract/Free Full Text].
|
| 61.
|
Schønning, K.,
B. Jansson,
S. Olofsson, and J.-E. S. Hansen.
1996.
Rapid selection for an N-linked oligosaccharide by monoclonal antibodies directed against the V3 loop of human immunodeficiency virus type 1.
J. Gen. Virol.
77:753-758[Abstract/Free Full Text].
|
| 62.
|
Schønning, K.,
B. Jansson,
S. Olofsson,
J. O. Neilsen, and J.-E. S. Hansen.
1996.
Resistance to V3-directed neutralization caused by an N-linked oligosaccharide depends on the quaternary structure of the HIV-1 envelope oligomer.
Virology
218:134-140[Medline].
|
| 63.
|
Shibata, R.,
T. Igarashi,
N. Haigwood,
A. Buckler-White,
R. Ogert,
W. Ross,
R. Willey,
M. W. Cho, and M. A. Martin.
1999.
Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys.
Nat. Med.
5:204-210[Medline].
|
| 64.
|
Shibata, R.,
F. Maldarelli,
C. Siemon,
T. Matano,
M. Parta,
G. Miller,
T. Fredrickson, and M. A. Martin.
1997.
Infection and pathogenicity of chimeric simian-human immunodeficiency viruses in macaques: determinants of high virus loads and CD4 cell killing.
J. Infect. Dis.
176:362-373[Medline].
|
| 65.
|
Spenlehauer, C.,
S. Saragosti,
H. J. A. Fleury,
A. Kirn,
A.-M. Aubertin, and C. Moog.
1998.
Study of the V3 loop as a target epitope for antibodies involved in the neutralization of primary isolates versus T-cell-line-adapted strains of human immunodeficiency virus type 1.
J. Virol.
72:9855-9864[Abstract/Free Full Text].
|
| 66.
|
Steger, K. K.,
M. Dykhuizen,
J. L. Mitchen,
P. W. Hinds,
B. L. Preuninger,
M. Wallace,
J. Thomson,
D. C. Montefiori,
Y. Lu, and C. D. Pauza.
1998.
CD4+-T-cell and CD20+-B-cell changes predict rapid disease progression after simian-human immunodeficiency virus infection in macaques.
J. Virol.
72:1600-1605[Abstract/Free Full Text].
|
| 67.
|
Trkola, A.,
T. Ketas,
V. N. KewalRamani,
F. Endorf,
J. M. Binley,
H. Katinger,
J. Robinson,
D. R. Littman, and J. P. Moore.
1998.
Neutralization sensitivity of human immunodeficiency virus type 1 primary isolates to antibodies and CD4-based reagents is independent of their coreceptor usage.
J. Virol.
72:1876-1885[Abstract/Free Full Text].
|
| 68.
|
Trkola, A.,
A. B. Pomales,
H. Yuan,
B. Korber,
P. J. Maddon,
G. P. Allaway,
H. Katinger,
C. F. Barbas III,
D. R. Burton,
D. D. Ho, and J. P. Moore.
1995.
Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG.
J. Virol.
69:6609-6617[Abstract].
|
| 69.
|
Trkola, A.,
M. Purtscher,
T. Muster,
C. Ballaun,
A. Buchacher,
N. Sullivan,
K. Srinivasa,
J. Sodroski,
J. P. Moore, and H. Katinger.
1996.
Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1.
J. Virol.
70:1100-1108[Abstract].
|
| 70.
|
Vancott, T. C.,
V. R. Polonis,
L. D. Loomis,
N. L. Michael,
P. L. Nara, and D. L. Birx.
1995.
Differential role of V3-specific antibodies in neutralization assays involving primary and laboratory-adapted isolates of HIV type 1.
AIDS Res. Hum. Retroviruses
11:1379-1390[Medline].
|
| 71.
|
Weissenhorn, W.,
S. A. Wharton,
L. J. Calder,
P. L. Earl,
B. Moss,
E. Alirandis,
J. J. Skehel, and D. C. Wiley.
1996.
The ectodomain of HIV-1 env subunit gp41 forms a soluble, alpha-helical, rod-like oligomer in the ansence of gp120 and the N-terminal fusion peptide.
EMBO J.
15:1507-1514[Medline].
|
| 72.
|
Wrin, T.,
L. Crawford,
L. Sawyer,
P. Weber,
H. W. Sheppard, and C. V. Hanson.
1994.
Neutralizing antibody responses to autologous and heterologous isolates of human immunodeficiency virus.
J. Acquir. Immune Defic. Syndr.
7:211-219.
|
| 73.
|
Wrin, T.,
T. P. Loh,
J. C. Vennari,
H. Schuitemaker, and J. H. Nunberg.
1995.
Adaptation to persistent growth in the H9 cell line renders a primary isolate of human immunodeficiency virus type 1 sensitive to neutralization by vaccine sera.
J. Virol.
69:39-48[Abstract].
|
| 74.
|
Wyatt, R., and J. Sodroski.
1998.
The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.
Science
280:1884-1888[Abstract/Free Full Text].
|
| 75.
|
Zhou, J. Y., and D. C. Montefiori.
1997.
Antibody-mediated neutralization of primary isolates of human immunodeficiency virus type 1 in peripheral blood mononuclear cells is not affected by the initial activation state of the cells.
J. Virol.
71:2512-2517[Abstract].
|
Journal of Virology, December 1999, p. 10199-10207, Vol. 73, No. 12
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
