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Journal of Virology, October 1998, p. 8437-8445, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Characterization of Simian-Human Immunodeficiency Virus Envelope Glycoprotein Epitopes Recognized by Neutralizing Antibodies from Infected Monkeys

Bijan Etemad-Moghadam,1 Gunilla B. Karlsson,1 Matilda Halloran,2 Ying Sun,1 Dominik Schenten,1 Mark Fernandes,1 Norman L. Letvin,2 and Joseph Sodroski1,3,*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,1 and Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center,2 Harvard Medical School, and Department of Immunology and Infectious Diseases, Harvard School of Public Health,3 Boston, Massachusetts

Received 26 March 1998/Accepted 15 June 1998

    ABSTRACT
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We characterized human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein epitopes recognized by neutralizing antibodies from monkeys recently infected by molecularly cloned simian-human immunodeficiency virus (SHIV) variants. The early neutralizing antibody response in each infected animal was directed mainly against a single epitope. This primary neutralizing epitope, however, differed among individual monkeys infected by identical viruses. Two such neutralization epitopes were determined by sequences in the V2 and V3 loops of the gp120 envelope glycoprotein, while a third neutralization epitope, apparently discontinuous, was determined by both V2 and V3 sequences. These results indicate that the early neutralizing antibody response in SHIV-infected monkeys is monospecific and directed against epitopes composed of the gp120 V2 and V3 variable loops.

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Human immunodeficiency viruses (HIV types 1 and 2 [HIV-1 and HIV-2]) and the related simian immunodeficiency viruses (SIV) cause AIDS in humans and monkeys, respectively (4, 11, 17, 25, 40). Since the beginning of the global AIDS epidemic, HIV-1 has infected over 30 million people. Despite extensive investigation, the development of a safe and effective HIV-1 vaccine remains elusive. Although the role of neutralizing antibodies in the control of HIV-1 infection is still poorly understood, several reports suggest that such antibodies can contribute to protective immunity. Chimpanzees have been shown to be protected against HIV-1 infection by immunization protocols that generate neutralizing antibodies (6, 26) or by passive immunization with an HIV-1-neutralizing monoclonal antibody (14, 20, 21). In monkeys infected with attenuated SIV, the temporal development of protective immunity against a superinfecting virus correlates with the generation of more broadly reactive neutralizing antibodies capable of inhibiting the challenge virus (13). Furthermore, the appearance of broadly neutralizing antibodies has been reported in long-term nonprogressors (52). Knowledge of the immunological correlates of a protective antiviral response would assist the design of vaccines and immunotherapeutics.

The HIV-1 envelope glycoproteins, gp120 and gp41, play an essential role in virus infectivity and pathogenesis (9, 38) and contain the antigenic determinants against which neutralizing antibodies are directed (56, 65). Infection of CD4+ T lymphocytes is initiated by binding of the gp120 envelope glycoprotein to the CD4 receptor on the cell surface (15), followed by binding of the gp120-CD4 complex to one member of the family of chemokine receptors (2, 10, 16, 18, 19, 22, 64, 67). The gp120 and gp41 glycoproteins are noncovalently bound to each other and form oligomers on the cell surface and on virions (8, 42, 66). Variable regions (V1 to V5) have been identified in the gp120 glycoproteins of different HIV and SIV. The major variable regions (V1 to V4) are organized into disulfide-linked loops that are exposed on the gp120 surface and that mask more-conserved gp120 structures (39). It is believed that the quaternary structure of the envelope glycoproteins also influences the exposure and, hence, the immunogenicity and antibody accessibility of these key viral proteins (23, 57, 58).

Several neutralization sites have been identified on gp120, including epitopes in the V3 loop (33, 36, 43), the V2 loop (24, 28, 31, 47), the CD4-binding site (60, 62), and CD4-induced (CD4i) structures (61). The gp41 glycoprotein has a single well-documented neutralization epitope recognized by the 2F5 antibody (49). The gp120 V3 loop contains many linear epitopes that elicit type-restricted antibody responses capable of neutralizing only genetically similar isolates (44, 51). In HIV-1-infected chimpanzees, the early-arising neutralizing antibodies are highly isolate specific and targeted to the V3 loop (50). A few, more broadly neutralizing monoclonal antibodies directed against V3 have also been recovered from humans infected with HIV-1 for long periods of time (27, 48). The epitopes for these antibodies map to either the conserved tip of the V3 loop (27) or to a complex but conserved epitope on both flanks of the V3 loop (48). In contrast to most antibodies against the V3 loop, antibodies directed against the CD4-binding site of gp120 recognize conserved, discontinuous epitopes and neutralize wider ranges of isolates (60, 63). These broadly neutralizing antibodies appear later in infection (5, 46). Antibodies against other conserved epitopes, the CD4i epitopes on gp120 and the 2F5 epitope on gp41, are more rarely elicited during natural HIV-1 infection (49, 61, 68).

Here, we evaluate the temporal generation and specificity of the neutralizing antibody response in monkeys infected with simian-human immunodeficiency viruses (SHIV). SHIV chimerae contain several HIV-1 genes, including that encoding the HIV-1 envelope glycoproteins, in an SIV background (41). Some SHIV variants replicate efficiently in monkeys and cause an AIDS-like disease (34, 54). There are several advantages to the use of this model for the study of the neutralizing antibody response to viral infection. First, the SHIV variants used in this study contain envelope glycoproteins from primary HIV-1 isolates, which are more clinically relevant than the envelope proteins from laboratory-adapted viruses previously studied. Second, the levels of viremia achieved in monkeys infected with the SHIV variants used herein are comparable to those observed in humans acutely infected with HIV-1 (55). Third, since the infecting SHIV isolates derive from molecular proviral clones (35), the precise sequence of the infecting viruses is known. The neutralizing activity elicited by two HIV-1 envelope glycoproteins that differ by only 12 amino acids in the ectodomain of the envelope glycoprotein was assessed. We found that homologous neutralizing antibodies appear within 30 to 40 days after infection and are directed against distinct epitopes on the gp120 V2 and V3 variable loops.

Temporal generation of homologous neutralizing antibodies. Previously, a chimeric SHIV, SHIV-89.6, was passaged in rhesus macaques and a pathogenic strain, SHIV-89.6P, was generated (54). A molecular proviral clone of SHIV-89.6P was used to generate an infectious virus, designated SHIV-KB9 (35). SHIV-KB9 has been shown to induce rapid depletion of CD4+ lymphocytes in rhesus monkeys (35, 35a). A sequence comparison between the original SHIV-89.6 and SHIV-KB9 indicated that the majority of the changes that occurred during serial animal passage are located in the env gene; 12 single amino acid substitutions encoded by this gene occurred in the gp120 and gp41 ectodomains, and a 140-bp deletion in the gene resulted in the ability to encode a gp41 glycoprotein with a carboxy-terminal cytoplasmic tail containing both HIV-1 and SIVmac239 sequences (35). In addition, two coding changes in the tat gene and single nucleotide changes in the U3 and R regions of the long terminal repeat (LTR) occurred during animal passage. To examine the neutralizing antibody responses to SHIV, a new virus, SHIV-KB9ct, was constructed (35b). SHIV-KB9ct is identical to SHIV-KB9, except that it does not contain the 12 amino acid changes in the gp120 and gp41 ectodomains (Fig. 1). Thus, SHIV-KB9 and SHIV-KB9ct differ subtly in envelope glycoprotein sequences that are potentially targeted by neutralizing antibodies. SHIV-KB9 and SHIV-KB9ct were produced in CEMx174 cells and inoculated into four rhesus monkeys each. In studies that will be reported elsewhere, the monkeys infected with SHIV-KB9 exhibited, on average, greater depletion of CD4+ lymphocytes than did animals infected with SHIV-KB9ct.


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  		FIG. 1.   Structure of the SHIV-KB9 and -KB9ct chimeras. The top part of the figure shows the genetic composition of the chimeric SHIV used in this study. The SIVmac239-derived elements of the genome are represented by the shaded rectangles, and the HIV-1-specific components are represented by white rectangles. The circles and triangle mark the coding changes that occurred during animal passage. The white circles represent the nucleotide changes in the LTR; the change in the R region is present in both the 3' and 5' LTR, and the substitution in U3 is present only in the 3' LTR. The triangle marks the 140-bp deletion affecting the HIV-1 gp41 tail. The encoded amino acid substitutions in Tat and the gp41 cytoplasmic tail are present in both KB9 and KB9ct, whereas the env ectodomain changes are present only in KB9. The lower portion of the figure indicates the differences in amino acid composition between KB9 and KB9ct. The sequence of KB9ct in this portion of the envelope glycoproteins is identical to that of 89.6.

To analyze the temporal generation of antibodies against the SHIV-KB9 and SHIV-KB9ct envelope glycoproteins, plasma samples obtained at different times after infection were used to precipitate 35S-labelled HIV-1 envelope glycoproteins from lysates of COS-1-transfected cells (data not shown). Table 1 shows the time points at which antibodies capable of precipitating either the gp120 or gp160 glycoproteins of the homologous infecting virus were first detected. All four monkeys infected with SHIV-KB9ct seroconverted after 2 weeks. There was more variability in the serologic responses to the envelope glycoproteins in the SHIV-KB9-infected animals; monkeys 13921 and 13930 seroconverted after 2 weeks, whereas monkey 13876 seroconverted at day 17 and monkey 13970 never seroconverted. It is interesting to note that the only monkey that did not seroconvert, animal 13970, also exhibited the lowest CD4+-lymphocyte counts (Table 1). There may exist a threshold level of CD4+ lymphocytes beneath which seroconversion is inefficient.

                              
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  		TABLE 1.   CD4+-lymphocyte counts and antibody response

To determine if SHIV infection resulted in elicitation of HIV-1-specific neutralizing antibodies, we used a single-round env complementation assay. Recombinant HIV-1 were produced by cotransfection of COS-1 cells with two plasmids, pHXBH10Delta env-CAT and pSVIIIenv (30). The pHXBH10Delta env-CAT plasmid contains an HIV-1 provirus with a deletion in the envelope gene, and the nef gene is replaced with a gene encoding chloramphenicol acetyltransferase (CAT). Different pSVIIIenv plasmids encoding either the KB9 or the KB9ct envelope glycoproteins were used. Recombinant virions were used for infection of CEMx174 cells in the presence of a 1:50 dilution of plasma derived from the infected monkeys. Plasma samples from infected monkeys were evaluated for the presence of neutralizing antibodies at various time points after infection (Fig. 2). Table 1 indicates the earliest time at which plasma samples exhibited the ability to neutralize 50% of the recombinant virions containing the homologous envelope. In four animals, 50% neutralizing activity appeared after 4 weeks, and by 7 weeks, all the animals that had seroconverted displayed neutralizing activity for viruses with the homologous envelopes. By day 71, maximal homologous neutralizing activity was detected in the plasma of all the monkeys that had seroconverted (Fig. 2).


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  		FIG. 2.   Temporal emergence of neutralizing antibodies against viruses with homologous envelope glycoproteins. The presence of antibodies able to neutralize recombinant CAT viruses with homologous envelope glycoproteins was assessed by using plasma from infected monkeys at various time points after infection. The horizontal axes designate days postinfection, and the vertical axes show the level of neutralization normalized to the value observed in the presence of preimmune plasma. CEMx174 cells were infected with the respective homologous recombinant viruses in the presence of a 1:50 dilution of plasma from SHIV-KB9ct-infected monkeys (A) or SHIV-KB9-infected monkeys (B). Symbols represent the monkeys designated as shown.

To determine if SHIV-infected monkey plasma was capable of neutralizing viruses with heterologous envelope glycoproteins, recombinant viruses containing the KB9 and KB9ct envelope glycoproteins were incubated with plasma from animals infected with the heterologous virus and infectivity was assessed. Figure 3 shows the results of the cross-neutralization analysis. Although the KB9 and KB9ct envelope glycoproteins differ by only 12 amino acids in their respective ectodomains, cross neutralization with plasma from the infected monkeys was either extremely weak or not detectable. Thus, the early neutralizing antibody response in SHIV-infected monkeys appears to be restricted to the infecting virus strain.


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  		FIG. 3.   Cross-neutralizing activity in plasma from day 71 postinfection. Preimmune plasma and plasma from day 71 postinfection were used in a 1:50 dilution to assess neutralization of viruses with KB9 and KB9ct envelope glycoproteins. Entry of the recombinant CAT viruses with KB9 envelope glycoproteins (top panel) and with KB9ct envelope glycoproteins (bottom panel) is shown. The animal number and the specific SHIV with which it was infected are indicated at the bottom of the figure. P, samples incubated with preimmune plasma; 71, samples incubated with plasma from day 71.

Genetic mapping of the neutralization epitopes. Previous studies of plasma from animals or humans infected by primate immunodeficiency viruses have mostly utilized synthetic peptides to map neutralization epitopes on the envelope glycoproteins (32, 45, 50). Here, we used a panel of recombinant viruses with defined envelope glycoproteins to characterize the dominant neutralization epitopes recognized by the antibodies in the infected monkey plasma. We constructed a collection of recombinant KB9 envelope glycoproteins in which the single amino acid changes that occurred during animal passage were reverted, individually or in combination, to the original amino acids present in the parental 89.6 and KB9ct envelope glycoproteins. The coding changes were introduced into the KB9 env gene by using the Quickchange site-directed mutagenesis kit (Stratagene). All 10 amino acid changes in the KB9 gp120 envelope glycoprotein were reverted individually, and each new envelope glycoprotein was designated KB9 (-amino acid [aa] number). For example, in KB9(-143), the leucine 143 in the KB9 envelope glycoprotein was converted back to the proline found in the 89.6 and KB9ct envelope glycoproteins at this position. An additional envelope glycoprotein, designated wtKBs9, was created. The wtKBs9 envelope glycoprotein is identical to the KB9 protein except that, in the former, gp41 changes were reverted back to amino acids originally present in the 89.6 and KB9ct envelope glycoproteins. The wtKBs9 envelope glycoprotein allows an examination of the role of the gp41 changes in specifying the epitopes associated with the observed type-specific neutralization activity. We also created a few selected envelope glycoproteins in which the amino acid changes found in the KB9 envelope glycoproteins were introduced into the KB9ct protein. These envelope glycoproteins were designated KB9ct(+aa number). For example, in KB9ct(+308), the arginine located at position 308 in the KB9 envelope glycoprotein was introduced into the KB9ct envelope protein.

Figure 4 shows the results of our analysis in which neutralization epitopes were genetically mapped for the plasma of each SHIV-infected animal. A plasma sample from KB9ct-infected monkey 15865 was assessed for the ability to neutralize recombinant viruses containing the different envelope glycoproteins (Fig. 4A). Viruses with the KB9ct envelope glycoproteins were neutralized efficiently by plasma from monkey 15865 at day 71 after infection, whereas infection by the virus with the KB9 envelope glycoproteins was unaffected. The wtKBs9-enveloped virus was not neutralized, suggesting that the two amino acids in gp41 are not sufficient to create the KB9ct-specific neutralization epitope. All of the viruses with the KB9(-aa) series of envelope glycoproteins behaved like the viruses with KB9 envelope glycoproteins, with one notable exception. The KB9(-308)-enveloped viruses were neutralized in the same way as viruses with the KB9ct envelope glycoproteins. Viruses containing the KB9ct(+308) envelope glycoproteins were resistant to neutralization by plasma from monkey 15865, indicating that the majority of the neutralizing activity in this plasma is directed against epitopes determined by the specific amino acid residue at position 308. These results suggest that the differential neutralization of viruses with KB9 and KB9ct envelope glycoproteins by plasma from monkey 15865 is determined by a single amino acid (aa 308) in the gp120 V3 loop.


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  		FIG. 4.   Comparative neutralization of recombinant envelope glycoproteins. A panel of recombinant envelope glycoproteins containing amino acids shared with either KB9 or KB9ct was tested for neutralization with plasma samples from the infected monkeys. Plasma samples from day 71 were used in this analysis, and CAT activity was normalized to the value observed in the presence of preimmune plasma for each virus; thus, a value of 1 designates no neutralization. The results of the neutralization assays are shown here for the following animals: KB9ct-infected animals 15865 (A), 11796 (B), 13939 (C), and 13898 (D) and KB9-infected animals 13930 (E), 13921 (F), and 13876 (G). The horizontal axes indicate the various recombinant envelope glycoproteins, and the vertical axes show the level of neutralization normalized to the value observed in the presence of preimmune plasma.

Plasma from other animals infected with SHIV-KB9ct were also examined. The predominant KB9ct-specific neutralizing activity in plasma from monkey 11796 was determined by an amino acid at position 190 in the gp120 V2 loop (Fig. 4B). An asparagine in the KB9ct envelope glycoproteins was replaced by a serine in the KB9 envelope glycoproteins, resulting in the loss of an N-linked glycosylation site. Neutralization by plasma from another SHIV-KB9ct-infected monkey, 13939, was also largely determined by the amino acid at position 190 (Fig. 4C). Thus, in three monkeys infected by an identical virus, one animal raised neutralizing antibodies against epitopes determined by the gp120 V3 loop whereas the other two generated neutralizing antibodies against epitopes specified by the gp120 V2 loop.

Analysis of plasma from monkey 13898 presented a more complicated picture (Fig. 4D). Plasma from monkey 13898 at day 71 enhanced the entry of viruses with the KB9 envelope glycoproteins approximately twofold. This enhancement activity appeared to require the presence of most of the SHIV-KB9 gp120 changes associated with in vivo passage, since entry of the viruses with the KB9(-aa) series of envelope glycoproteins was not enhanced to the same degree as that of the KB9 virus. The neutralization potency of plasma from monkey 13898 was influenced by changes in residue 190 in the V2 loop. However, the degree of the effect of changes in residue 190 was not as great as that found for plasma samples from animals 11796 and 13939. This could reflect the greater complexity of a dominant neutralizing epitope or the presence of more than one neutralizing epitope recognized by this plasma.

Epitope mapping analysis with plasma from KB9-infected monkeys indicated that the early neutralization epitopes on the KB9 envelope glycoproteins are more complex than those identified on the SHIV-KB9ct envelope glycoproteins. Figure 4E displays the neutralization of a panel of viruses with different envelope glycoproteins by using plasma from animal 13930. Viruses with the wtKBs9 and most of the KB9(-aa) envelope glycoproteins were neutralized as well as viruses with the KB9 envelope glycoproteins. However, viruses with the KB9(-187), KB9(-190), and KB9(-308) envelope glycoproteins exhibited an intermediate degree of neutralization, suggesting that these three residues may influence or contribute to the neutralization epitope. The sensitivity of viruses with KB9ct(+187/190/308) envelope glycoproteins to neutralization by this plasma sample implies that these three amino acid changes are sufficient to specify the neutralization epitope on the KB9 envelope glycoproteins. Interestingly, viruses with envelope glycoproteins containing only some of the changes [KB9ct(+190), KB9ct(+308), and KB9ct(+187/190)] were not neutralized by plasma from monkey 13930. Thus, lysine 187, serine 190, and glutamic acid 308 apparently cooperate to specify a major early neutralizing epitope on the SHIV-KB9 envelope glycoproteins. The neutralizing antibodies elicited in another SHIV-KB9-infected monkey, 13921, are also apparently directed against a similar epitope (Fig. 4F).

In the third SHIV-KB9-infected animal analyzed, monkey 13876, only the two V2 amino acid residues at positions 187 and 190 determine the KB9-specific neutralization epitope (Fig. 4G). The loss of the glycosylation site resulting from the serine 190 substitution was insufficient to reconstitute the epitope. Instead, residues 187 and 190 were apparently both important for the phenotype.

Generation of more broadly neutralizing antibodies. The antibody response against HIV-1, including the fraction of antibodies with virus-neutralizing activity, matures in months or even years after initial infection. To examine the breadth of the neutralizing antibody response in SHIV-infected monkeys, animal plasma samples obtained later in the course of infection were characterized. Figure 5 shows the results of assays that examined the ability of plasma obtained at later time points in infection to neutralize viruses with both KB9 and KB9ct envelope glycoproteins. Antibodies capable of neutralizing viruses with both envelope glycoproteins evolved in the plasma of SHIV-KB9-infected animals at various time points (Fig. 5E to G). This heterologous neutralizing activity was evident by day 92 in monkey 13930, by day 153 in monkey 13876, and by day 253 in monkey 13921. 


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  		FIG. 5.   Cross-neutralization of viruses with heterologous envelope glycoproteins by plasma from late time points after infection. Plasma samples from time points subsequent to day 71 were tested for neutralization of viruses with both KB9 () and KB9ct (oplus ) envelopes. The horizontal axes indicate days postinfection. CAT activity was normalized to the value observed in the presence of preimmune plasma and is shown for the following infected animals: KB9ct-infected monkeys 15865 (A), 11796 (B), 13898 (C), and 13939 (D) and KB9-infected animals 13930 (E), 13921 (F), and 13876 (G).

Our study of the evolution of neutralizing activity in SHIV-KB9ct-infected monkeys was limited by the fact that all four rhesus macaques were sacrificed on day 162. However, by this time after infection, little or no neutralizing activity against viruses with the KB9 envelope glycoproteins was evident in the plasma from SHIV-KB9ct-infected monkeys (Fig. 5A to D).

Plasma samples from SHIV-KB9- and SHIV-KB9ct-infected monkeys were tested for the ability to neutralize envelope glycoproteins from a heterologous laboratory-adapted HIV-1 strain, HXBc2 (53), and two primary isolates, ELI (1) and MN (29). Figure 6 shows that none of the plasma samples from the infected monkeys exhibited neutralizing activity against viruses with the HXBc2 or ELI envelope glycoproteins. Because the KB9 and KB9ct envelope glycoproteins differ by only 12 amino acids, the heterologous neutralizing activity seen in plasma samples obtained later in infection from SHIV-KB9-infected animals is probably directed against variable envelope glycoprotein epitopes that are shared by both KB9 and KB9ct but not HXBc2 or ELI. On the other hand, plasma samples from all infected animals, except monkey 13898, showed strong neutralizing activity against viruses with MN envelope glycoproteins. The temporal pattern of plasma neutralization of viruses with the MN envelope glycoproteins was similar to that seen for viruses with homologous envelope glycoproteins.


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  		FIG. 6.   Neutralization of viruses with the divergent envelope glycoproteins. Entry of recombinant CAT virus with divergent envelope glycoproteins was tested in the presence of plasma from all infected monkeys at day 71, as well as the latest available time points. Results of neutralization assays using viruses with HXBc2 envelope glycoproteins (A and B), with ELI envelope glycoproteins (C and D), and with MN envelope glycoproteins (E and F) are shown. Horizontal axes designate days postinfection, and vertical axes show the level of neutralization normalized to the value observed in the presence of preimmune plasma. Symbols represent the monkeys designated, as shown.

In this study, by using two molecularly defined, related SHIV, the neutralizing responses to the HIV-1 envelope glycoproteins in outbred primate hosts were characterized. As has been observed in other systems (46), the neutralizing antibodies that arise in the first few months of infection are strain restricted. Remarkably, the neutralizing antibodies within each infected animal appear to be directed towards a very limited number of epitopes. Even in animals initially infected with identical viruses, different epitopes predominate as the major neutralization determinant. A common feature of all the neutralization epitopes characterized in this study is the contribution of either gp120 V2 or V3 components, or both, to the integrity or recognition of the epitope. This result is consistent with the previous identification of V2- or V3-directed neutralizing monoclonal antibodies derived from HIV-1-infected individuals (27, 28, 48). The restriction of early-arising neutralizing antibodies to the V2 and V3 loops may reflect the limited number of exposed neutralization epitopes available on the HIV-1 envelope glycoprotein complex. Recent evidence suggests that the V2 and V3 loops occupy regions of the envelope glycoproteins facing the target cell membrane, once CD4 binding has occurred (38a). This is consistent with the probable role of the V3 loop in interactions with the chemokine receptors (10, 12) and with the role of the V2 loop in masking neutralization epitopes related to the chemokine receptor-binding surface of gp120 (7, 59, 68). If potent virus neutralization requires interference with receptor binding, there may be a limited number of neutralization targets exposed on the HIV-1 envelope glycoproteins. Of the potential neutralization sites, the variable loops may exhibit greater surface exposure and thus be more immunogenic than more-conserved elements. The apparent limitation of the neutralizing antibody response within an individual infected animal may simply reflect the spatial proximity of all the variable, well-exposed neutralizing epitopes. In such a case, the antibodies against V2 or V3 epitopes that arise initially will mask overlapping epitopes and dominate the strain-restricted neutralizing antibody response.

Although the number of infected animals is small, there appear to be some differences in the specific V2 and V3 structures to which neutralizing antibodies are generated in animals infected with SHIV-KB9 and SHIV-KB9ct. The major neutralization epitopes in two of the three SHIV-KB9-infected monkeys were specified by residues in both the V2 and V3 loops, suggesting that these epitopes may be discontinuous structures contributed to by both V2 and V3 segments. This is consistent with previous work suggesting the structural proximity of and functional interactions between these loops (3, 37). In other studies, we have demonstrated that viruses with the KB9 envelope glycoproteins are more resistant to neutralization by a number of monoclonal antibodies than are viruses with the KB9ct envelope glycoproteins (35a). Neutralization resistance of HIV-1 has been proposed to result from a more "closed" envelope glycoprotein conformation, in which the major gp120 variable loops assume positions that minimize the accessibility of gp120 epitopes to antibodies. Such a closed conformation of the KB9 envelope glycoproteins might involve the movement of the V2 and V3 loops into adjacent positions, increasing the likelihood that antibodies recognizing discontinuous epitopes with both V2 and V3 elements are elicited. In this respect, it is interesting that glutamic acid 187 and arginine 308 in the KB9ct envelope glycoproteins undergo reciprocal charge changes in the KB9 envelope glycoproteins, retaining the potential to form a salt bridge. The conversion to lysine at position 187 and glutamic acid at position 308 would probably decrease the distance of the salt bridge, consistent with a closer relationship of the V2 and V3 loops. The loss of the N-linked glycosylation site at position 190 in the KB9 envelope glycoproteins might help in accommodating a more-proximal V3 structure. While further work will be needed to clarify these details, the results do suggest that the identified segments of the V2 and V3 loops are proximal on the KB9 envelope glycoproteins.

Even when antibodies that neutralize more than the infecting virus are generated in the SHIV-infected animal, this neutralization extends only to a limited number of virus variants. Strain restriction of neutralization is a serious obstacle to the development of an HIV-1 vaccine. It is hoped that the SHIV model system and the study of the ability of different envelope glycoprotein variants to elicit antibody responses in vivo will contribute to approaches to improve the immunogenic properties of this key viral antigen.

    ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health, the G. Harold and Leila Mathers Foundation, the Friends 10, and Douglas and Judith Krupp.

    FOOTNOTES

* Corresponding author. Mailing address: JFB 824, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3371. Fax: (617) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.

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Journal of Virology, October 1998, p. 8437-8445, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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