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Journal of Virology, October 2000, p. 9749-9754, Vol. 74, No. 20
Laboratory of Molecular Microbiology,
National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland 208921;
Department of Microbiology, Meharry Medical College,
Nashville, Tennessee 372082; and
Department of Surgery, Duke University Medical Center, Durham,
North Carolina 277103
Received 17 May 2000/Accepted 18 July 2000
We have previously reported that a chimpanzee infected with a
primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1DH12) developed an extremely potent
virus-neutralizing antibody. Immunoglobulin G purified from this animal
conferred sterilizing immunity following passive transfer to macaques
which were subsequently challenged with simian immunodeficiency
virus/HIV-1 chimeric virus strain DH12. In addition to being highly
strain specific, the chimpanzee antiserum did not bind to the V3 loop
peptide of HIV-1DH12, nor did it block the interaction of
gp120 with the CD4 receptor. When neutralization was examined in the
context of virus particles carrying chimeric envelope glycoproteins,
the presence of all five hypervariable regions (V1 to V5) was required
for optimal neutralization. Virions bearing chimeric gp120 containing
the V1-V2 and V4 regions of HIV-1DH12 could also be
neutralized, but larger quantities of the chimpanzee antiserum were
needed to block infection. These results indicate that the HIV-1 gp120
epitope(s) targeted by the chimpanzee antiserum is highly
conformational, involving surface elements contributed by all of the
hypervariable domains of the envelope glycoprotein.
Neutralizing antibodies (NAbs) have
been shown to be of critical importance for controlling infections and
preventing disease induced by viral pathogens; in many instances they
represent the first step of the adaptive immune response. For several
reasons, however, the role of NAbs in clearing acute human
immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus,
or simian immunodeficiency virus/HIV-1 chimeric virus (SHIV) infections remains unclear. First, the emergence of NAbs during primary lentiviral infections is not coincident with the decline of plasma viremia (28). Second, the potency of NAbs in the sera of
HIV-1-infected individuals is generally quite low and usually capable
of only partially reducing virus infectivity of primary isolates in in vitro assays (19, 27). In addition, sera containing
measurable neutralizing activity frequently fail to confer resistance
to a subsequent virus challenge in prophylactic-vaccine experiments conducted with nonhuman primates (2, 15). Other studies
indicate that vaccinated animals are able to control a virus inoculum
in the absence of detectable NAbs (3, 10, 35, 43). In no case has immunization elicited potent, broadly cross-reactive NAbs
against primary isolates (1, 8, 25, 38, 46, 47).
Although these results raise questions about the protective value of
NAbs, several recent reports have described resistance to lentivirus
challenge following the passive transfer of such antibodies to both
hu-PBL-SCID mice (14, 31, 37) and nonhuman primates
(12, 23, 24, 26, 34, 41). In one of these studies, the
administration of 10 to 100 times the amount of immunoglobulin G1b12
(IgG1b12) human monoclonal antibody needed to neutralize 90% of virus
infectivity in vitro completely protected SCID mice from an HIV-1
challenge (14). In other previously reported experiments, the transfer of high-titered IgG derived from a chimpanzee (number 1206) chronically infected with the dualtropic primary
HIV-1DH12 isolate resulted in sterilizing immunity of
macaques that were subsequently challenged with an SHIV bearing the
same envelope glycoprotein (41). In the latter
case, complete protection was observed when 100 times the amount of
polyclonal chimpanzee IgG needed to achieve 100% neutralization of
SHIVDH12, as measured in in vitro assays, was administered
to pig-tailed monkeys. These types of experiments clearly indicate that
the presence of preexisting NAbs can control a subsequent virus challenge.
It is worth mentioning that although several mechanisms have been
proposed for HIV-1 neutralization, the strong binding of antibody to
virus particles or to oligomeric gp120 expressed on the surfaces of
infected cells remains the best correlate of robust neutralizing
activity (13, 32, 36, 39, 41). This is in contrast to
the majority of antibodies detectable in the plasma of
HIV-1-infected individuals, which are directed against the gp160
precursor glycoprotein and intact or fragmented monomeric gp120 molecules released from either virus particles or the surfaces of
infected cells and not the virion-associated, oligomeric envelope glycoprotein complex (30).
As noted earlier, the titers of NAbs in HIV-1-seropositive individuals
are usually quite low (19, 27), even in the case of
long-term nonprogressors who maintain low levels of circulating virus
(17, 33). The isolation of only three human monoclonal antibodies possessing broad, high-titered virus-neutralizing activities over the nearly two decades of the AIDS epidemic further testifies to
the rarity of this type of humoral response during natural infections
(4, 5, 29). We were therefore intrigued by the appearance of
extremely high-titered NAbs in chimpanzees following the inoculation of
the uncloned primary isolate HIV-1DH12 (40, 42,
44). The neutralizing activity in such persistently infected animals was initially measured in an assay in which duplicate, fourfold
dilutions of chimpanzee serum were incubated with virus for 1 h
prior to the addition of human peripheral blood mononuclear cells
(PBMC) previously activated for 2 days with antibodies to CD3 and CD28
in the presence of interleukin-2. The surviving virus fraction
(Vn/Vo = virus level in the presence of
neutralizing serum/control serum) in the culture supernatants at 7 to
10 days postinfection, measured by a reverse transcriptase (RT) assay, was plotted as a function of serum dilution; the HIV-1 neutralization titer was defined as the reciprocal of the serum dilution causing a
10-fold reduction in virus production (Vn/Vo = 0.1) (16). Neutralizing activity against
HIV-1DH12 became detectable in serum samples from one of
these chimpanzees (number 1206) at 6 weeks postchallenge (titer = 1:270), peaked at week 21 (titer = 1:25,000), and stabilized at a titer
of 1:10,000 at 1 year postinfection. When an assay that measures 100%
neutralization was used, the titer of NAbs in the serum collected from
the same animal at week 40 postinfection was approximately 1:2,800
(50). The virus-neutralizing activity of chimpanzee 1206 antiserum was
highly strain specific; no blocking activity (<1:20) against
HIV-1RF, HIV-1SF2, HIV-1IIIB, or
HIV-1MN was measured.
The availability of high-titered anti-HIV-1DH12 chimpanzee
antiserum possessing durable neutralizing activity has permitted us to
conduct passive-transfer experiments assessing different aspects of
primary lentiviral infections. It has been shown that HIV-1 NAbs
capable of blocking infections in vitro are also protective in vivo
(41) and that the administration of IgG from another chimpanzee chronically infected with HIV-1DH12 greatly
accelerated the physical and biological clearance of cell-free virus
particles from the blood (18). As a first step in
characterizing the neutralization epitope(s) recognized by chimpanzee
1206 serum, the entire env gene from the
HIV-1DH12 molecular clone DH125 (40) was
inserted into the genetic background of HIV-1AD8, a
molecular clone of the HIV-1Ada isolate, which is
refractory to neutralization by the antiserum. As previously reported,
the 100% neutralization titers directed against both
HIV-1DH12 and this chimeric virus, designated AD8/DHenv,
were nearly equivalent (approximately 1:2,000) (50),
indicating that the chimpanzee NAbs are primarily directed against the
HIV-1DH12 envelope glycoprotein.
The construction and characterization of additional chimeric viruses
have also been described in which gp120 or gp41 coding sequences, as
well as individual or multiple HIV-1DH12 gp120 variable regions, were transferred into HIV-1AD8 (7).
Stocks of these chimeric viruses were generated by transfecting
plasmids encoding full-length molecular clones into HeLa cells
(40). When the sensitivities to the chimpanzee antiserum of
the chimeric viruses bearing gp120 or gp41 coding sequences from
HIV-1DH12 were evaluated in anti-CD3 and -CD28
antibody-activated human PBMC as described above, only the AD8-DH120
virus, which carried the HIV-1DH12 gp120, was neutralized
(Fig. 1, right column). This result
clearly indicates that the neutralizing activity of the chimpanzee
antiserum is directed against the gp120, not the gp41, of
HIVDH12.
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Identification of gp120 Regions Targeted by a Highly Potent
Neutralizing Antiserum Elicited in a Chimpanzee Inoculated with a
Primary Human Immunodeficiency Virus Type 1 Isolate
ABSTRACT
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FIG. 1.
Schematic diagram of the parental and chimeric HIV-1
envelope glycoproteins and results of neutralization assay
with chimpanzee 1206 antiserum in human PBMC. The regions encoding the
signal peptide (SP), surface glycoprotein gp120,
transmembrane glycoprotein gp41, hypervariable regions (V1
to V5), and cleavage sites ( 
) are indicated. The individual vertical
lines represent amino acid residues that are different between
HIV-1DH12 and HIV-1AD8. Neutralization assays
were performed using anti-CD3 and -CD28 antibody-activated PBMC, as
previously described (16). Neutralization is reported as positive
(calculated Vn/Vo = 0.1, serum titers > 1:1,600) or negative (calculated Vn/Vo = 0.1, serum titers < 1:100). ND, neutralization could not be determined
using PBMC as target cells. HIV-1AD8 was previously
reported to be neutralization resistant (50).
In view of the strain-specific nature of the chimpanzee NAbs, an enzyme-linked immunosorbent assay assessing the reactivity of chimpanzee antiserum with a 25-amino-acid peptide encompassing most of the V3 region of HIV-1DH12 gp120 was carried out. As has been reported for other primary HIV-1 isolates (45, 48), no binding of serum samples, collected at 10 different times during the course of the chimpanzee infection, to the V3 peptide was detected (data not shown). To determine whether the antiserum from animal 1206 targeted the CD4 binding site, soluble HIV-1DH12 gp120 released from recombinant baculovirus-infected insect cells was incubated with chimpanzee serum, and its reactivity with CD4 was monitored. No reduction in CD4 binding was observed with any of the samples of chimpanzee antiserum tested (data not shown).
To further evaluate potential HIV-1DH12 gp120 neutralization epitopes, the sensitivities of six of the nine intra-gp120 chimeric viruses capable of replicating in human PBMC to chimpanzee 1206 antiserum were assessed. Chimeric viruses AD8-DH120A, -G, and -H do not replicate to detectable levels in PBMC (6). As indicated in the right column of Fig. 1, the only intra-gp120 chimeric virus neutralized by chimpanzee 1206 serum was AD-DH120I, which contains all five variable regions of the HIV-1DH12 gp120 in the genetic background of HIV-1AD8. Taken at face value, all of these results indicate that the gp120 epitope targeted by NAbs in the serum from animal 1206 is conformational, involving surfaces contributed by hypervariable domains V1 to V5 of the envelope glycoprotein.
Although, as noted in the preceding paragraph, the chimeric viruses
AD8-DH120A, -G, and -H are essentially replication incompetent in human
PBMC, it was previously reported that they are able to infect primary
monocyte-derived macrophages and a human osteosarcoma (HOS) cell line
expressing both CD4 and the CCR5 chemokine receptor (6).
Using HOS-CD4.CCR5 (9) target cells, we examined the sensitivities of the two parental HIV-1 strains and the full ensemble of chimeric viruses to neutralization by the chimpanzee antiserum. In
these neutralization assays, cell-free virus was incubated with the
chimpanzee serum at room temperature for 30 min, and the mixture was
then added to the adherent HOS-CD4.CCR5 cells, using the previously
described tissue culture conditions (6). As shown in Fig.
2a, serum from chimpanzee 1206 readily
neutralized both the parental HIV-1DH12 and the chimeric
virus containing HIV-1DH12 gp120 (DH120), but not the
parental HIV-1AD8. Also consistent with the neutralization
results with human PBMC (Fig.1), the chimpanzee antiserum neutralized
the AD8-DH120I chimeric virus, which carries all five variable regions
of HIV-1DH12 gp120. Surprisingly, one other intra-gp120
chimeric virus, AD8-DH120G, which contains the V1-V2 and the V4
regions of HIV-1DH12 gp120, was partially neutralized. To
better assess the neutralization sensitivities of the two intra-gp120 chimeric viruses relative to the parental HIV-1DH12, the
three virus preparations were incubated with serially diluted serum and
their infectivities were measured by RT production in the HOS-CD4.CCR5
cells (Fig. 2b). In this HOS cell system, the titers of chimpanzee
antiserum which neutralized 50% of the infectivity of
HIV-1DH12 and the chimeric viruses AD8-DH120I and -G were
approximately 1:8,000, 1:3,000, and 1:800, respectively. Thus, although
AD8-DH120G could be neutralized by the chimpanzee 1206 serum, it was
far less sensitive than the parental HIV-1DH12.
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Although it is now generally appreciated that neutralization of HIV-1
is correlated with the binding of antibodies to oligomeric gp120 on
virus particles, we still wished to identify and characterize epitopes
associated with monomeric wild-type and chimeric gp120 molecules that
are recognized by the chimpanzee antiserum. To this end, HeLa cells
were infected with recombinant vaccinia viruses expressing either the
parental or chimeric envelope glycoproteins (21), and the gp120 released into the culture supernatant
was immunoprecipitated with chimpanzee 1206 serum and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by Western blot analysis using rabbit anti-gp160
antiserum (22, 49). The gp120s analyzed were derived from
HIV-1IIIB(vPE-16) (11), the parental strains
HIV-1AD8 and HIV-1DH12 (vvADenv and vvDHenv, respectively), and the chimeric envelope AD8-DH120A to -I
(vv120Aenv to -Ienv) (6, 21, 22). As shown in Fig.
3a, the chimpanzee antiserum exhibited
high specificity for and readily immunoprecipitated the gp120 from
HIV-1DH12 but not the gp120 from HIV-1AD8 or
HIV-1IIIB. In a control experiment for this and other gp120
immunoprecipitations, the direct analysis of the two parental and nine
chimeric gp120s produced in HeLa cells following infection with
recombinant vaccinia viruses revealed similar reactivities with the
polyclonal anti-gp160 rabbit antibody (Fig. 3b). When the chimeric
gp120s were subjected to immunoprecipitation using the chimpanzee
antiserum, only two (AD8-DH120A [V1-V2] and AD8-DH120I [V1 to V5])
were efficiently immunoprecipitated (Fig. 3c). Like the parental
HIV-1AD8 gp120, only small amounts of the other chimeric gp120s were immunoprecipitated and recognized by the rabbit anti-gp160 polyclonal antibody in this overexposed Western blot (Fig. 3c). Thus,
the HIV-1DH12 V1-V2 region, when present alone in a
chimeric gp120, was readily immunoprecipitated by the chimpamzee 1206 serum but was nonreactive when it was associated with the
HIV-1DH12 V3, V4, and V5 regions in other chimeric
envelopes.
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In this study, we have characterized the immune serum from a chimpanzee previously inoculated with the uncloned primary isolate HIV-1DH12. Both the neutralizing and gp120-immunoprecipitating antibodies in the chimpanzee antiserum exhibited high specificity for HIV-1DH12. No reactivity was observed with a peptide spanning the V3 loop of the HIV-1DH12 gp120, and a monomeric chimeric gp120 carrying this variable region was not immunoprecipitated. Unlike some HIV-1 NAbs, the chimpanzee antiserum did not block binding to the CD4 receptor. When analyzed in the context of virions bearing a chimeric envelope glycoprotein, all of the highly variable regions were required for optimal neutralization, implying that the HIV-1DH12 neutralization epitopes are conformational. Although neutralization required at minimum the presence of the V1-V2 and V4 regions of the HIV-1DH12 gp120, the high sensitivity of AD8-DH120I (V1 to V5) compared to that of AD8-DH120G (V1-V2 and V4) to neutralization by the chimpanzee antiserum suggested that the structure of the AD8-DH120I gp120 is more similar to that of the parental HIV-1DH12 gp120 than is the structure of the AD8-DH120G gp120.
The highly conformational nature of the HIV-1DH12 epitope(s) recognized by the chimpanzee serum resulted in the paradoxical results obtained in immunoprecipitation and neutralization experiments conducted with chimeric envelope glycoproteins. For example, although the chimeric virus AD8-DH120G, which contains the V1-V2 and V4 regions of HIV-1DH12, was neutralized by the chimpanzee antiserum, the same chimeric gp120 released from recombinant vaccinia virus-infected HeLa cells could not be immunoprecipitated. Conversely, the chimeric gp120 monomer containing the V1-V2 region of HIV-1DH12 (AD8-DH120A) was immunoprecipitated as efficiently as the parental HIV-1DH12 gp120 expressed in HeLa cells (Fig. 3b), yet virus bearing the same chimeric envelope was neutralization resistant. Perhaps the antibodies that immunoprecipitate this monomeric gp120 are unable to bind this antigen when it is particle associated. Nonetheless, it is highly likely that in the context of the virus particle, the V1-V2 and V4 regions contain binding sites for the NAb and the seemingly discordant results in various assays may reflect vastly different levels of neutralizing and immunoprecipitating antibody activities in the chimpanzee antiserum. It is worth noting that although the precise location of the V1-V2 and V4 regions in the proposed structure of the HIV-1 gp120 have not been determined (because the V1-V2 region was deleted from the crystallized protein and the V4 domain was disordered in the crystal lattice), these two variable domains have been positioned on opposite sides of monomeric gp120 (20). This raises the interesting possibility that the neutralizing epitopes we have identified are formed from V1-V2 and V4 regions of two adjacent gp120 molecules within the trimeric complex rather than from an individual gp120 molecule. Additional experiments will be needed to confirm this hypothesis.
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FOOTNOTES |
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* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, NIH, NIAID, 9000 Rockville Pike, Bldg. 4, Rm. 339, Bethesda, MD 20892-0460. Phone: (301) 496-0576. Fax: (301) 402-0226. E-mail: mcho{at}nih.gov.
Present address: Protein Engineering Laboratory, Korea Research
Institute of Bioscience and Biotechnology, Yusong, Taejon 305-600, Republic of Korea.
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Journal of Virology, October 2000, p. 9749-9754, Vol. 74, No. 20
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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