1 Department of Infectious Disease and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
2 Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, W1144 Biomedical Science Tower, Pittsburgh, PA 15261, USA
3 Department of Veterinary Sciences, Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA
Correspondence
Ronald C. Montelaro
rmont{at}pitt.edu
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ABSTRACT |
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INTRODUCTION |
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Various studies have demonstrated that the control of EIAV replication and disease is directly related to host immune response, and not to attenuation of the infecting virus (Issel et al., 1982; Perryman et al., 1988
). For example, dexamethasone-induced immune suppression of inapparent carriers results in the recrudescence of disease associated with markedly increased virus replication (Craigo et al., 2002
; Kono et al., 1976
; Mealey et al., 2001
; Tumas et al., 1994
). The evolution of humoral and cellular immune responses during the progression from chronic disease to inapparent carrier status has been examined and characterized in detail (Hammond et al., 1997
; McGuire et al., 2002
; Mealey et al., 2003
; Rwambo et al., 1990a
; Tschetter et al., 1997
; Zhang et al., 1998
). The results of these studies have indicated that an 810 month time period post-infection is required for the development of a mature steady-state immunity that can mediate effective and enduring control of EIAV replication and disease. Interestingly, a similar length of time post-infection with attenuated EIAV is required for the development of maximum immune protection from virus exposure (Hammond et al., 1999
; Li et al., 2003
; Montelaro et al., 1996
, 1998
).
The role of specific humoral and cellular immune responses in mediating enduring protective immunity remains to be defined, but a combination of these immune factors is likely to function in a synergistic manner. In this regard, there is contradictory data on the potential role of neutralizing antibody responses in protective immunity. Virus-specific neutralizing antibody is typically not detected in experimentally infected equids until about 3 months post-infection, apparently precluding a role for neutralizing antibody in resolving acute viraemia and disease. However, neutralizing antibodies steadily increase in titre and breadth of neutralization specificity during the first year post-infection. Steady-state levels are reached concomitant with the achievement of sustained immune control of EIAV replication and disease observed in long-term inapparent carriers (Hammond et al., 1997; Howe et al., 2002
; Rwambo et al., 1990a
). Finally, the envelope variation observed during sequential disease episodes results in alterations in serum neutralization sensitivity, suggesting escape from critical antibody control (Howe et al., 2002
; Leroux et al., 1997
; Montelaro et al., 1984
; Payne et al., 1987
; Rwambo et al., 1990b
). These observations indicate a dynamic interaction between evolving virus populations and host immune responses in which neutralizing antibodies can be a determinant of control or escape.
Antigenic variation during persistent EIAV infection has been correlated with alterations in the surface (SU) gp90 and transmembrane (TM) gp45 envelope proteins, including amino acid substitutions and deletions, and frequent alterations in potential N-linked glycosylation sites (Hussain et al., 1987; Leroux et al., 2001
; Payne et al., 1987
; Rwambo et al., 1990b
; Zheng et al., 1997
). While variation may occur throughout the envelope sequence, variation is predominantly localized to the gp90 protein. Studies of EIAV envelope variation have identified eight conserved and eight variable regions within the heavy glycosylated gp90. In addition, a principal neutralizing domain (PND), located in the hypervariable V3 segment of the SU, has been suggested based on the presence of two adjacent neutralizing epitopes, Ent and Dnt. Another neutralizing epitope, Cnt, has been identified in the V5 region of gp90 (Ball et al., 1992
; Grund et al., 1996
; Hussain et al., 1987
, 1988
; Leroux et al., 1997
, 2001
). We recently reported on detailed neutralization epitope mapping studies using reciprocal domain substitutions between neutralization sensitive and resistant EIAV envelopes (Howe et al., 2002
). The results of these studies indicated the V3 and V4 domains as the predominant determinants of gp90 sensitivity or resistance to neutralization by immune serum from experimentally infected equids.
The present investigation expands on a previous study of the in vivo neutralization characteristics of an experimental infection-derived, in vitro neutralization-resistant virus isolate, EIAVPV564PND (Craigo et al., 2002
; Leroux et al., 1997
). To determine the effect of this PND deletion on envelope immunogenic properties and host immune control, two ponies were experimentally infected with an EIAV proviral construct containing the
PND envelope, EIAV
PND (Craigo et al., 2002
). Both experimentally infected ponies remained asymptomatic for EIA and experienced relatively low levels of plasma viral RNA during the 14-month observation period. In addition, both ponies produced high steady-state levels of EIAV envelope-specific antibodies, but developed only minimal neutralizing antibodies to the infecting EIAV
PND. Our initial interpretation of these data was that the PND domain gp90 was required for the production of neutralizing antibodies during persistent infection, indicating that the deletion in V3 affected envelope immunogenicity as well as antigenicity. To assess the role of host immune responses in control of virus replication, both ponies were transiently immune suppressed with a 10-day dexamethasone treatment that culminated with both animals developing EIA associated with a 4-log increase in virus loads. In characterizing the virus-specific host immunity in response to the dexamethasone treatment, we unexpectedly observed that high-titre, strain-specific, neutralizing antibodies against EIAV
PND developed post-immune suppression concomitant with a 100-fold reduction in steady-state plasma virus loads in the absence of significant gp90 amino acid variation. Post-immune suppression serum did not neutralize the parental EIAVPV, indicating highly type-specific serum neutralization. While differing markedly in antibody neutralization phenotypes, EIAV
PND and EIAVPV envelope amino acid sequences differ by only 1·8 %, including a 14 aa deletion in the V3 domain and a shift in an N-linked glycosylation site in the V4 domain the EIAV
PND gp90. Thus, these studies demonstrate that transient immune suppression and increased viraemia resulted in a modification of steady-state host immunity to the infecting virus and production of neutralizing antibody responses to a neutralization resistant
PND envelope.
This current study was designed to elucidate the mechanism behind the marked change in host immunity by differentiating between two possible routes to altering serum antibody neutralization properties. First, the transient immune suppression and increased viraemia may have induced antibodies to new envelope epitopes outside the previously defined V3 and V4 neutralization domains. Alternatively, the development of serum neutralization to the EIAVPND could be attributed to quantitative or qualitative changes in antibody responses to the defined V3 and V4 neutralization domains. In the current study, we have used the unique combination of EIAV
PND and EIAVPV envelopes that differ in neutralization sensitivity to post-immune suppression serum to distinguish between these alternative mechanisms of immune modulation.
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METHODS |
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Serum antibody neutralization assays.
The level of neutralization activity of the panel of reference immune serum from the experimentally infected ponies against the variant and chimeric envelope proviruses was determined using a standard viral infectious centre assay, as described previously (Hammond et al., 1997). Briefly, 105 FEK cells were added into a 24-well tissue culture plate and allowed to adhere overnight at 37 °C. All immune serum samples were heat inactivated before use in the assay. Twofold serial dilutions of each of the serum samples were incubated in the presence of 100 infectious units of the selected chimeric virus at 37 °C for 1 h. The serumvirus mixture was then added to the cells and incubated overnight at 37 °C. An overlay of 0·8 % carboxmethylcellulose was added to the infected cultures and incubated for a further 7 days at 37 °C. The cells were then fixed and permeabilized. Reference immune serum from an EIAV-infected horse (Lady) was used as a primary antibody, followed by an affinity-purified, horseradish peroxidase-conjugated, goat anti-horse immunoglobulin G (Sigma). The peroxidase substrate 3-amino-9-ethyl-carbazole (Sigma) in a sodium acetate buffer (pH 5·5) supplemented with H2O2, was used to visualize the EIAV infectious centres. The number of infectious centres was counted, and the 50 % reciprocal neutralization titre of each serum sample was determined by linear regression analysis. Titres below 1 : 20 are considered background as determined with uninfected control sera. Each neutralization assay was repeated at least twice to determine standard error values. Neutralization titres were compared using paired t-test analyses to determine statistical significance.
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RESULTS |
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Prior to immune suppression, both animals had developed a high EIAV envelope-specific antibody end-point titre averaging 1x106, which increased to a titre of 1x107 post-immune suppression (Fig. 1b, d). EIAV
PND-envelope-specific 50 % neutralizing antibody titres were around 1 : 50 in both animals prior to immune suppression. However, after immune suppression and resulting fever, envelope-specific neutralizing antibodies were detected against the infecting EIAV
PND strain with titres of 1 : 275 in pony #599 and 1 : 550 in pony #672. Sequence analysis pre- and post-immune suppression revealed 34 % variation within the gp90 consistent with previously observed evolution rates and the retention of the V3 deletion. Interestingly, at no time before or after dexamethasone treatment did either animal develop serum antibodies capable of neutralizing the parental EIAVPV strain (Fig. 1b, d
).
This lack of envelope-specific neutralizing antibody against EIAVPV and abundant neutralizing antibody against EIAVPND was unexpected due to the low level of gp90 variation observed between these two viruses (Fig. 2
). The few areas of sequence variation between the two viral envelopes were localized to the V3, V4 and C6 regions of the envelope gp90. The V3 region contained the most extensive variation between the two viral envelopes including the 14 aa deletion of the PND Ent epitope in the EIAV
PND. Other minor variations observed in the EIAV
PND compared to the EIAVPV envelope involved the shifting and addition of potential N-linked glycosylation sites in the V4 and C6 domains, respectively. These variations in EIAV
PND from its parent EIAVPV were retained after immune suppression and resolution of disease (Craigo et al., 2002
). Thus, these studies provided a novel panel of envelope variants and immune serum to examine the basis for the development of neutralizing antibodies to the EIAV
PND envelope after transient immune suppression of the inapparent carriers.
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The most dramatic increase in neutralization sensitivity occurred when both the V3 and V4 variable regions of the neutralization sensitive EIAVPND were substituted into the neutralization resistant EIAVPV backbone [gp90PV (V3V4)] (Fig. 4
). Immune serum from both ponies demonstrated a marked increase in their serum neutralizing antibody titres against the gp90PV (V3V4) to a mean of 1 : 8600, compared with the 1 : 10 neutralization titre observed with the parental envelope gp90PV, post-immune suppression. These data indicated a highly additive effect of the V3 and V4 domain substitutions in conferring serum neutralization sensitivity to the parental neutralization resistant EIAVPV.
As a complement to the preceding analyses, we next evaluated the neutralization sensitivity of the replication competent reciprocal chimeric envelope virus in which the V3 and V4 domains of the neutralization resistant EIAVPV envelope were substituted into the neutralization sensitive EIAVPND envelope backbone (Fig. 3a, b
). Neutralization analysis of this gp90
PND(V3V4) proviral construct demonstrated a 10-fold reduction in serum neutralization sensitivity compared with the parental gp90
PND envelope provirus. Thus, the 50 % neutralizing antibody titres for the post-immune suppression serum from the two ponies was calculated to be a mean titre of 1 : 20 against the gp90
PND(V3V4) envelope provirus, compared with a mean titre of about 1 : 400 against the parental envelope gp90
PND (Fig. 4
). These data demonstrate that the gp90 V3 and V4 domains are the predominant determinants of neutralization resistance to the post-immune suppression serum.
Taken together, the preceding combination of experiments evaluating changes in neutralization sensitivity and resistance, respectively, indicate that the V3 and V4 domains are the predominant determinants of neutralization sensitivity in post-immune suppression serum. These results suggest that the development of serum neutralizing antibodies by transient immune suppression was associated with changes in the qualitative or quantitative host antibody responses to the gp90 V3 and V4 domain and not to changes in the envelope determinants targeted by serum antibodies.
Evaluation of C6 glycosylation variation on neutralization sensitivity
The V4 region encompasses 7 aa that encode a single potential N-linked glycosylation site that is shifted only by two residues in the neutralization sensitive envelope gp90PND compared with the gp90PV (Fig. 2
). Since we observed a significant change in neutralization sensitivity based on this defined glycosylation variation, we next evaluated the effect of other variations in potential N-linked glycosylation sites within the gp90 on neutralization specificity. One of the few envelope variations observed outside the V3 and V4 regions was the introduction of a glycosylation site in the conserved C6 region of the EIAV
PND envelope that is not present in the C6 domain of the EIAVPV envelope (Fig. 2
). To address the effect of the additional glycosylation site within the C6 domain on serum neutralization phenotype, a panel of conserved C6 domain exchange chimeras was constructed (Fig. 5
a). The C6 region of the neutralization sensitive EIAV
PND was substituted into the parental neutralization resistant EIAVPV backbone [gp90PV(C6)] and into the highly neutralization sensitive gp90PV (V3V4) provirus construct [gp90PV(V3V4C6)]. Reciprocal C6 exchanges from the neutralization resistant EIAVPV were also substituted into the neutralization sensitive EIAV
PND backbone [gp90
PND(C6)] and into the engineered resistant gp90
PND(V3V4) construct [gp90
PND (V3V4C6)]. All of the new C6 exchange chimeras were replication competent (Fig. 5b
). In general, each of the chimeras had similar replication kinetics and similar RT levels by 30 days post-transfection.
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DISCUSSION |
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Montefiori and colleagues have reported a similar enhancement of serum neutralizing antibodies to HIV-1 in patients subjected to structured interrupted antiviral drug therapy regimens (Montefiori et al., 2001; Ortiz et al., 1999
, 2001
), suggesting a general role for transient waves of virus replication in boosting host immune control of persistent virus infection. However, the basis for the increase in serum neutralization to HIV-1 was undefined. While most lentivirus infections are associated with progressively degenerative diseases, the episodic nature and eventual immune control of EIAV replication and disease are unique among lentiviruses. Based on the observations presented here it is interesting to speculate that the enduring natural immunologic control of virus replication and disease achieved in horses infected with EIAV may in part be due to the discrete waves of viraemia characteristic of this persistent infection and their ability to boost host immunity.
The exact mechanisms by which transient waves of viraemia, naturally or experimentally induced, can markedly modify the specificity of host antibody responses to lentivirus infections remains to be elucidated. However, this immune modulation appears to be related to a boosting effect of the increased virus antigen presentation during the viraemia that cannot be accomplished by a steady-state virus-immune system status. Based on this model, one can postulate that the transient immune suppression and subsequent viraemia modify the existing viral envelope-specific antibody responses by boosting memory immune responses to critical viral envelope determinants. In the case of EIAV, the development of neutralizing antibody responses after transient immune suppression clearly correlates with changes in antibody targeted to the V3 and V4 domains of the gp90 envelope protein. It cannot be concluded from the current data whether this alteration is due only to quantitative increases in antibody levels to these principal neutralizing domains or also to qualitative changes in antibody population. Envelope-specific antibody titres increased only slightly in response to the dexamethasone treatment, while neutralizing antibody titres to the infecting EIAVPND increased from background levels (<1 : 20) to a mean of about 1 : 400. Thus, these data are consistent with the concept of substantial qualitative changes in envelope-specific antibodies in the absence of significant changes in the quantitative levels of envelope-specific antibodies.
The studies described here also elucidate further the antigenic architecture of the EIAV envelope glycoprotein and define in more detail envelope antibody neutralization determinants and the effects of natural variation on neutralization sensitivity. We previously identified the EIAV gp90 V3 domain as a principal neutralizing domain using synthetic peptide mapping of neutralizing monoclonal antibodies (Ball et al., 1992). These studies defined two adjacent neutralizing monoclonal antibody binding sites (Dnt and Ent) in the V3 domain loop of gp90 (Fig. 2
). Subsequent comparisons of natural variant EIAV envelopes differing in serum neutralization sensitivity confirmed the role of the V3 domain and identified the relatively small V4 domain as a second predominant neutralizing domain (Howe et al., 2002
). Despite the small number of animals presented here, the current studies reconfirm the role of the gp90 V3 and V4 domains as principal neutralization determinants of the EIAV envelope and their ability individually or in combination to confer neutralization sensitivity when substituted into a resistant envelope (e.g. EIAVPV). From the analyses of the EIAV
PND envelope neutralization determinants, it was demonstrated that the Dnt epitope of the V3 domain, in the absence of the adjacent Ent epitope, can serve as an effective target for serum neutralization. The characterization of the EIAV
PND envelope also highlighted the role of the potential N-linked glycosylation site in the 7-residue V4 domain in determining neutralization sensitivity, with absolute resistance or sensitivity being dictated by a shift in the glycosylation site by only 2 aa. While the V4 glycosylation site location was shown to be a major determinant of EIAV neutralization properties, the current data indicated that the differences in the number of N-linked glycosylation sites in the gp90 C6 domain in general did not affect envelope neutralization sensitivity. While all variations in envelope glycosylation may not be related to antigenic variation, the role of lentivirus envelope glycosylation variation in defining envelope antigenic and immunogenic properties is becoming increasingly evident (Back et al., 1994
; Cheng-Mayer et al., 1999
; Johnson & Desrosiers, 2002
; Lue et al., 2002
; Ly & Stamatatos, 2000
; Malenbaum et al., 2000
; Polzer et al., 2002
; Quinones-Kochs et al., 2002
). Our current working model to explain the interaction of the V3 and V4 domains as neutralization determinants is that the V3 domain is the actual target for neutralizing antibodies and that the V4 glycosylation site affects the accessibility of these V3 sequences to antibody neutralization.
Taken together, this series of studies indicates that the V3 and V4 domains are predominant targets for neutralizing antibody responses, but that the ability of the immune system to respond to these targets is apparently influenced by the overall context of antigen presentation, particularly the V3V4 domain interactions. For example, neutralizing antibodies are routinely produced in equids experimentally infected with EIAVPV, but these neutralizing antibodies fail to inactivate the EIAVPND envelope (Howe et al., 2002
; Leroux et al., 1997
). Conversely, the neutralizing antibodies elicited by transient immune suppression of ponies experimentally infected with EIAV
PND failed to inactivate the EIAVPV envelope (Craigo et al., 2002
). These observations suggest that the initial exposure of the EIAV envelope to the host immune system may restrict the specificity of neutralizing antibody responses to the highly variable envelope domains, similar to the original antigenic sin described for other virus and bacterial infections (Fazekas & Webster, 1966
; Good et al., 1993
; Klenerman & Zinkernagel, 1998
; Mongkolsapaya et al., 2003
; Tsuchiya et al., 2000
). Studies in HIV have suggested that the initial antibody response to the immunodominant epitopes of the hypervariable V3 region may impede the future responses to emerging variants, thus provided the virus with a window of opportunity to escape immune surveillance (Kohler et al., 1994
; Locher et al., 1999
). Overcoming original antigenic sin for vaccine development is not a new problem and several other viral vaccines, such as dengue haemorrhagic fever, influenza, malaria and Lymphocytic choriomeningitis virus have been impeded by this immune restriction (Fazekas & Webster, 1966
; Good et al., 1993
; Klenerman & Zinkernagel, 1998
; Mongkolsapaya et al., 2003
; Tsuchiya et al., 2000
) and continue to be an ongoing question for HIV vaccines (Kundu et al., 1998
; Nara & Garrity, 1998
; Singh et al., 2002
; Verschoor et al., 1999
).
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ACKNOWLEDGEMENTS |
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REFERENCES |
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Ball, J. M., Rushlow, K. E., Issel, C. J. & Montelaro, R. C. (1992). Detailed mapping of the antigenicity of the surface unit glycoprotein of equine infectious anemia virus by using synthetic peptide strategies. J Virol 66, 732742.[Abstract]
Chen, M., Shi, C., Kalia, V., Tencza, S. B., Montelaro, R. C. & Gupta, P. (2001). HIV gp120 V1/V2 and C2-V3 domains glycoprotein compatibility is required for viral replication. Virus Res 79, 91101.[CrossRef][Medline]
Cheng-Mayer, C., Brown, A., Harouse, J., Luciw, P. A. & Mayer, A. J. (1999). Selection for neutralization resistance of the simian/human immunodeficiency virus SHIVSF33A variant in vivo by virtue of sequence changes in the extracellular envelope glycoprotein that modify N-linked glycosylation. J Virol 73, 52945300.
Craigo, J. K., Leroux, C., Howe, L., Steckbeck, J. D., Cook, S. J., Issel, C. J. & Montelaro, R. C. (2002). Transient immune suppression of inapparent carriers infected with a principal neutralizing domain-deficient equine infectious anaemia virus induces neutralizing antibodies and lowers steady-state virus replication. J Gen Virol 83, 13531359.
Fazekas de, St. Groth S. & Webster, R. G. (1966). Disquisitions of original antigenic sin. I. Evidence in man. J Exp Med 124, 331345.
Good, M. F., Zevering, Y., Currier, J. & Bilsborough, J. (1993). Original antigenic sin, T cell memory, and malaria sporozoite immunity: an hypothesis for immune evasion. Parasite Immunol 15, 187193.[Medline]
Grund, C. H., Lechman, E. R., Pezzuolo, N. A., Issel, C. J. & Montelaro, R. C. (1996). Fine specificity of equine infectious anaemia virus gp90-specific antibodies associated with protective and enhancing immune responses in experimentally infected and immunized ponies. J Gen Virol 77, 435442.[Abstract]
Hammond, S. A., Cook, S. J., Lichtenstein, D. L., Issel, C. J. & Montelaro, R. C. (1997). Maturation of the cellular and humoral immune responses to persistent infection in horses by equine infectious anemia virus is a complex and lengthy process. J Virol 71, 38403852.[Abstract]
Hammond, S. A., Raabe, M. L., Issel, C. J. & Montelaro, R. C. (1999). Evaluation of antibody parameters as potential correlates of protection or enhancement by experimental vaccines to equine infectious anemia virus. Virology 262, 416430.[CrossRef][Medline]
Hammond, S. A., Li, F., McKeon, B. M., Sr Cook, S. J., Issel, C. J. & Montelaro, R. C. (2000). Immune responses and viral replication in long-term inapparent carrier ponies inoculated with equine infectious anemia virus. J Virol 74, 59685981.
Harrold, S. M., Cook, S. J., Cook, R. F., Rushlow, K. E., Issel, C. J. & Montelaro, R. C. (2000). Tissue sites of persistent infection and active replication of equine infectious anemia virus during acute disease and asymptomatic infection in experimentally infected equids. J Virol 74, 31123121.
Howe, L., Leroux, C., Issel, C. J. & Montelaro, R. C. (2002). Equine infectious anemia virus envelope evolution in vivo during persistent infection progressively increases resistance to in vitro serum antibody neutralization as a dominant phenotype. J Virol 76, 1058810597.
Hussain, K. A., Issel, C. J., Schnorr, K. L., Rwambo, P. M. & Montelaro, R. C. (1987). Antigenic analysis of equine infectious anemia virus (EIAV) variants by using monoclonal antibodies: epitopes of glycoprotein gp90 of EIAV stimulate neutralizing antibodies. J Virol 61, 29562961.[Medline]
Hussain, K. A., Issel, C. J., Schnorr, K. L., Rwambo, P. M., West, M. & Montelaro, R. C. (1988). Antigenic mapping of the envelope proteins of equine infectious anemia virus: identification of a neutralization domain and a conserved region on glycoprotein 90. Arch Virol 98, 213224.[Medline]
Issel, C. J., Adams, W. V., Jr, Meek, L. & Ochoa, R. (1982). Transmission of equine infectious anemia virus from horses without clinical signs of disease. J Am Vet Med Assoc 180, 272275.[Medline]
Johnson, W. E. & Desrosiers, R. C. (2002). Viral persistance: HIV's strategies of immune system evasion. Annu Rev Med 53, 499518.[CrossRef][Medline]
Klenerman, P. & Zinkernagel, R. M. (1998). Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394, 482485.[CrossRef][Medline]
Kohler, H., Muller, S. & Nara, P. L. (1994). Deceptive imprinting in the immune response against HIV-1. Immunol Today 15, 475478.[CrossRef][Medline]
Kono, Y., Hirasawa, K., Fukunaga, Y. & Taniguchi, T. (1976). Recrudescence of equine infectious anemia by treatment with immunosuppressive drugs. Natl Inst Anim Health Q (Tokyo) 16, 815.[Medline]
Kundu, S. K., Dupuis, M., Sette, A., Celis, E., Dorner, F., Eibl, M. & Merigan, T. C. (1998). Role of preimmunization virus sequences in cellular immunity in HIV-infected patients during HIV type 1 MN recombinant gp160 immunization. AIDS Res Hum Retrovir 14, 16691678.[Medline]
Leroux, C., Issel, C. J. & Montelaro, R. C. (1997). Novel and dynamic evolution of equine infectious anemia virus genomic quasispecies associated with sequential disease cycles in an experimentally infected pony. J Virol 71, 96279639.[Abstract]
Leroux, C., Craigo, J. K., Issel, C. J. & Montelaro, R. C. (2001). Equine infectious anemia virus genomic evolution in progressor and nonprogressor ponies. J Virol 75, 45704583.
Li, F., Craigo, J. K., Howe, L., Steckbeck, J. D., Cook, S., Issel, C. & Montelaro, R. C. (2003). A live attenuated equine infectious anemia virus proviral vaccine with a modified S2 gene provides protection from detectable infection by intravenous virulent virus challenge of experimentally inoculated horses. J Virol 77, 72447253.
Lichtenstein, D. L., Issel, C. J. & Montelaro, R. C. (1996). Genomic quasispecies associated with the initiation of infection and disease in ponies experimentally infected with equine infectious anemia virus. J Virol 70, 33463354.[Abstract]
Locher, C. P., Grant, R. M., Collisson, E. A., Reyes-Teran, G., Elbeik, T., Kahn, J. O. & Levy, J. A. (1999). Antibody and cellular immune responses in breakthrough infection subjects after HIV type 1 glycoprotein 120 vaccination. AIDS Res Hum Retroviruses 15, 16851689.[CrossRef][Medline]
Lue, J., Hsu, M., Yang, D., Marx, P., Chen, Z. & Cheng-Mayer, C. (2002). Addition of a single gp120 glycan confers increased binding to dendritic cell-specific ICAM-3-grabbing nonintegrin and neutralization escape to human immunodeficiency virus type 1. J Virol 76, 1029910306.
Ly, A. & Stamatatos, L. (2000). V2 loop glycosylation of the human immunodeficiency virus type 1 SF162 envelope facilitates interaction of this protein with CD4 and CCR5 receptors and protects the virus from neutralization by anti-V3 loop and anti-CD4 binding site antibodies. J Virol 74, 67696776.
Malenbaum, S. E., Yang, D., Cavacini, L., Posner, M., Robinson, J. & Cheng-Mayer, C. (2000). The N-terminal V3 loop glycan modulates the interaction of clade A and B human immunodeficiency virus type 1 envelopes with CD4 and chemokine receptors. J Virol 74, 1100811016.
McGuire, T. C., Fraser, D. G. & Mealey, R. H. (2002). Cytotoxic T lymphocytes and neutralizing antibody in the control of equine infectious anemia virus. Viral Immunol 15, 521531.[CrossRef][Medline]
Mealey, R. H., Fraser, D. G., Oaks, J. L., Cantor, G. H. & McGuire, T. C. (2001). Immune reconstitution prevents continuous equine infectious anemia virus replication in an Arabian foal with severe combined immunodeficiency: lessons for control of lentiviruses. Clin Immunol 101, 237247.[CrossRef][Medline]
Mealey, R. H., Zhang, B., Leib, S. R., Littke, M. H. & McGuire, T. C. (2003). Epitope specificity is critical for high and moderate avidity cytotoxic T lymphocytes associated with control of viral load and clinical disease in horses with equine infectious anemia virus. Virology 313, 537552.[CrossRef][Medline]
Mongkolsapaya, J., Dejnirattisai, W., Xu, X. N. & 11 other authors (2003). Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med 9, 921927.[CrossRef][Medline]
Montefiori, D. C., Hill, T. S., Vo, H. T., Walker, B. D. & Rosenberg, E. S. (2001). Neutralizing antibodies associated with viremia control in a subset of individuals after treatment of acute human immunodeficiency virus type 1 infection. J Virol 75, 1020010207.
Montelaro, R. C., Parekh, B., Orrego, A. & Issel, C. J. (1984). Antigenic variation during persistent infection by equine infectious anemia virus, a retrovirus. J Biol Chem 259, 1053910544.
Montelaro, R., Ball, J. M. & Rushlow, K. (1993). Equine Retroviruses. In The Retroviridae, pp. 257360. Edited by J. A. Levy. New York: Plenum.
Montelaro, R. C., Grund, C., Raabe, M., Woodson, B., Cook, R. F., Cook, S. & Issel, C. J. (1996). Characterization of protective and enhancing immune responses to equine infectious anemia virus resulting from experimental vaccines. AIDS Res Hum Retroviruses 12, 413415.[Medline]
Montelaro, R. C., Cole, K. S. & Hammond, S. A. (1998). Maturation of immune responses to lentivirus infection: implications for AIDS vaccine development. AIDS Res Hum Retroviruses 14, S255S259.[Medline]
Nara, P. L. & Garrity, R. (1998). Deceptive imprinting: a cosmopolitan strategy for complicating vaccination. Vaccine 16, 17801787.[CrossRef][Medline]
Ortiz, G. M., Nixon, D. F., Trkola, A. & 16 other authors (1999). HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 104, R1318.[Medline]
Ortiz, G. M., Wellons, M., Brancato, J. & 9 other authors (2001). Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. Proc Natl Acad Sci U S A 98, 1328813293.
Payne, S. L., Fang, F. D., Liu, C. P., Dhruva, B. R., Rwambo, P., Issel, C. J. & Montelaro, R. C. (1987). Antigenic variation and lentivirus persistence: variations in envelope gene sequences during EIAV infection resemble changes reported for sequential isolates of HIV. Virology 161, 321331.[Medline]
Perryman, L. E., O'Rourke, K. I. & McGuire, T. C. (1988). Immune responses are required to terminate viremia in equine infectious anemia lentivirus infection. J Virol 62, 30733076.[Medline]
Polzer, S., Dittmar, M. T., Schmitz, H. & Schreiber, M. (2002). The N-linked glycan g15 within the V3 loop of the HIV-1 external glycoprotein gp120 affects coreceptor usage, cellular tropism, and neutralization. Virology 304, 7080.[CrossRef][Medline]
Quinones-Kochs, M. I., Buonocore, L. & Rose, J. K. (2002). Role of N-linked glycans in a human immunodeficiency virus envelope glycoprotein: effects on protein function and the neutralizing antibody response. J Virol 76, 41994211.
Rwambo, P. M., Issel, C. J., Adams, W. V., Jr, Hussain, K. A., Miller, M. & Montelaro, R. C. (1990a). Equine infectious anemia virus (EIAV) humoral responses of recipient ponies and antigenic variation during persistent infection. Arch Virol 111, 199212.[Medline]
Rwambo, P. M., Issel, C. J., Hussain, K. A. & Montelaro, R. C. (1990b). In vitro isolation of a neutralization escape mutant of equine infectious anemia virus (EIAV). Arch Virol 111, 275280.[Medline]
Singh, R. A., Rodgers, J. R. & Barry, M. A. (2002). The role of T cell antagonism and original antigenic sin in genetic immunization. J Immunol 169, 67796786.
Tschetter, J. R., Byrne, K. M., Perryman, L. E. & McGuire, T. C. (1997). Control of equine infectious anemia virus is not dependent on ADCC mediating antibodies. Virology 230, 275280.[CrossRef][Medline]
Tsuchiya, H., Furukawa, M., Matsui, M., Katsuki, K. & Inouye, S. (2000). Original antigenic sin phenomenon in neutralizing antibody responses in children with enterovirus meningitis. J Clin Virol 19, 205207.[CrossRef][Medline]
Tumas, D. B., Hines, M. T., Perryman, L. E., Davis, W. C. & McGuire, T. C. (1994). Corticosteroid immunosuppression and monoclonal antibody-mediated CD5+ T lymphocyte depletion in normal and equine infectious anaemia virus-carrier horses. J Gen Virol 75, 959968.[Abstract]
Verschoor, E. J., Davis, D., van Gils, M. & 9 other authors (1999). Efforts to broaden HIV-1-specific immunity by boosting with heterologous peptides or envelope protein and the influence of prior exposure to virus. J Med Primatol 28, 224232.[Medline]
Zhang, W., Lonning, S. M. & McGuire, T. C. (1998). Gag protein epitopes recognized by ELA-A-restricted cytotoxic T lymphocytes from horses with long-term equine infectious anemia virus infection. J Virol 72, 96129620.
Zheng, Y. H., Nakaya, T., Sentsui, H., Kameoka, M., Kishi, M., Hagiwara, K., Takahashi, H., Kono, Y. & Ikuta, K. (1997). Insertions, duplications and substitutions in restricted gp90 regions of equine infectious anaemia virus during febrile episodes in an experimentally infected horse. J Gen Virol 78, 807820.[Abstract]
Received 16 June 2004;
accepted 25 September 2004.
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