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PubMed1979

Antigenic variation in visna virus.

Two antigenic variants of visna virus were isolated sequentially from a single sheep inoculated with a plaque-purified strain of virus designated 1514. The genetically stable variants, LV1-1 and LV1-4, are of two classes: LV1-1 is partially neutralized by antibody to the inoculum strain 1514, while LV1-4 is not neutralized by antibody to 1514. The genetic mechanism responsible for generating the antigenic variants was investigated by comparing the chymotryptic and tryptic maps of the envelope glycoprotein gp135 and core polypeptides (p30, p16, p14), and by comparing the pattern of large oligonucleotides produced by digestion of the RNAs by T1 ribonuclease. We show that only the peptide maps of gp135 differ among strains, that the number of peptide fragments altered is small and that gp135 is the polypeptide that elicits neutralizing antibody. The maps of the RNAs are identical. We conclude that mutation in the glycoprotein gene rather than recombination is more probably responsible for antigenic variation, and speculate on the special aspects of visna virus replication relevant to this phenomenon.

Amino Acid Sequence↗
PubMed1998

Molecular basis for antigenic variation of a protective strain-specific antigen of Ehrlichia risticii.

Ehrlichia risticii, the causative agent of Potomac horse fever, has recently been isolated from many vaccinated horses with typical clinical signs of the disease. The heterogeneity of the E. risticii isolates obtained from the vaccinated horses necessitates the identification of the molecular basis of strain variations to elucidate the vaccine failure and to aid in the development of an efficient vaccine against this disease. As an attempt, two major cross-reacting surface antigen genes of 50- and 85-kDa antigens, present separately in strains 25-D (isolated in 1984) and 90-12 (isolated in 1990 from a vaccinated horse), respectively, were cloned and sequenced. A comparative sequence analysis revealed differences and similarities between these two antigens with strain-specific sizes (SSA). The 2.5- and 1.6-kb genes coding for the 85- and 50-kDa proteins, respectively, contained many different tandem repeats. The identical repeat motifs were more frequent in the middle of both genes, but the numbers and positions of the repeats were altogether different in the genes. Many of these direct repeats of both genes had exact sequence homology and coded for the same amino acids. The homology of the 5'- and 3'-flanking regions of the two genes was greater than that of the regions in the central part of the genes. A comparative analysis of the deduced amino acid sequences of these two antigen genes indicated eight common domains, which were designated identical domains. Although the sequence homologies of these identical domains were the same, the positions of the domains in their respective strains were completely different. This finding might be one of the bases of antigenic variation between the strains. In addition, there were a few unique regions in both antigen genes where no sequence homology existed. These specific regions were designated unique domains. The 50-kDa protein had two such unique domains, and the 85-kDa protein had six such unique domains. The presence of such unique domains contributed to the large size variation of these SSA. The cross-reactivity of recombinant proteins confirmed the presence of conserved epitopes between these two antigens. The SSA have been determined to be apparent protective antigens of E. risticii.

Amino Acid Sequence↗
PubMed1997

Plasmodium falciparum: altered expressions of erythrocyte membrane-associated antigens during antigenic variation.

The O and R antigenic variants of the Plasmodium falciparum Palo Alto strain present differences in the morphology of the infected red blood cell membrane, in their adhesion properties, surface immunofluorescence, and agglutination specificities and importantly, induce a variant-specific protection after a primary infection in Saimiri sciureus monkeys. To identify potential targets of variant-specific immunity, we have compared the antigenic makeup of both variants by immunoblot. O-specific monkey sera generated similar profiles on both parasite types, while R-specific sera showed a consistent difference on a high-molecular-mass undefined antigen. Distinct antibody specificities were eluted from the surface of O- or R-infected erythrocytes, generating variant-specific agglutination, surface immunofluorescence, and immunoblot profiles. An antiserum raised to Pf60.1, predicted to cross-react with the cytoplasmic domain of PfEMP1, reacted with specific, SDS-soluble antigens in both variants. Antigens associated with the membrane of the infected red blood cells were further investigated using several specific antisera. The 85-kDa HRP1 gene product was more abundant in O than in R parasites, while the reverse was observed for the PfEMP3 protein. These data indicate that O and R parasites differ in the expression of several antigens associated with the membrane of the infected red blood cell.

Agglutination Tests↗
PubMed1999

Antigenic variation in Trypanosoma brucei infections: an holistic view.

Trypanosoma brucei parasites undergo clonal phenotypic (antigenic) variation to promote their transmission between mammals and tsetse-fly vectors. This process is classically considered to be a mechanism for evading humoral immune responses, but such an explanation cannot account for the high rate of switching between variable antigens or for their hierarchical (i.e. non-random) expression. I suggest that these anomalies can be explained by a new model: that antigenic variation has evolved as a bifunctional, rather than as a unifunctional, strategy that not only evades humoral immune responses but also enables competition between parasite strains in concomitantly infected hosts. This competition causes a depression of cellular responses. My proposal gives rise to a number of testable predictions. First, low numbers of trypanosomes should express some variable antigen types (VATs) in infections several weeks before these VATs are detectable. Second, as an infection progresses, the number of VATs expressed simultaneously in the population should decrease. Third, immunisation to generate a T helper 1 response against those VATs that are expressed most frequently should lower parasitaemias and reduce virulence.

Animals↗
PubMed1997

Antigenic variation among bovine viral diarrhea virus (BVDV) strains and the role of different cell fixation methods in immunoassays.

Antigenic variation among 13 Quebec isolates of bovine viral diarrhea virus (BVDV), 4 reference strains and 2 American isolates were studied by peroxidase-linked antibody assay (PLA assay) and neutralization test (NT). The Quebec strains consisted of 3 isolates before 1993 and 10 isolates from 1993. In the PLA assay, we compared 2 different fixatives, acetone and formalin. Acetone-fixation allowed us to identify 6 groups from amongst the viruses tested. All the Quebec isolates were different from the reference strains. In addition, antigenic variation was detected between Quebec isolates obtained before and during 1993. However, PLA assays performed after formalin fixation did not detect these antigenic variations. Neutralization tests were carried out with 2 polyclonal antibodies (PAb) and 6 monoclonal antibodies (MAb). They were used to classify BVDV strains and isolates into 4 groups and 7 subgroups respectively. In conclusion, we demonstrated that the BVDV isolates from the 1993 outbreak in Quebec are antigenically different from reference strains and from isolates existing in Quebec before 1993. In addition, we have shown that 2 internationally used fixation-methods in PLA assay give different results. The usefulness of each method is discussed.

Animals↗
PubMed1997

Mechanisms of antigenic variation in African trypanosomes.

African trypanosomes can escape destruction by the immune system of their mammalian host by antigenic variation of the trypanosome surface coat. This coat is mainly composed of a single protein species, the Variant Surface Glycoprotein or VSG. The genes for VSGs are expressed in a polycistronic telomeric expression site together with at least eight expression site-associated genes (ESAGs). Trypanosomes may switch coat either by replacing the VSG gene in the active expression site by a different one, or by activating another expression site with concomitant silencing of the previously active one. Here we review our present knowledge of antigenic variation in Trypanosome brucei. We focus on four questions: How do trypanosomes switch from one VSG gene expression site to another one? What is the role of the novel base J in silencing expression sites? What is the functional significance of the antigenic variation of the heterodimeric transferrin receptor encoded by two ESAG genes? Why do trypanosomes have multiple expression sites at all?

Africa↗
PubMed1999

Antigenic variation in malaria: a 3' genomic alteration associated with the expression of a P. knowlesi variant antigen.

Antigenic variation of malaria parasites was discovered in P. knowlesi, using a schizont-infected cell agglutination (SICA) assay to detect variant antigens expressed at the surface of infected erythrocytes. Later studies utilizing stable clones, Pk1(A+) and its direct derivative, Pk1(B+)1+, showed that SICA[+] clones express distinct parasite-encoded antigens of approximately 200 kDa. Here we identify a P. knowlesi variant antigen gene and cDNA and demonstrate that it encodes the 205 kDa variant antigen expressed by B+ parasites. This gene belongs to a multigene family, which we term SICAvar. Its ten-exon structure with seven cysteine-rich coding modules is unique compared to P. falciparum var genes. Further, we highlight a 3' genomic alteration that we predict is related to SICAvar gene switching.

Amino Acid Sequence↗
PubMed1997

Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes.

We have identified and characterized an elaborate genetic system in the Lyme disease spirochete Borrelia burgdorferi that promotes extensive antigenic variation of a surface-exposed lipoprotein, VlsE. A 28 kb linear plasmid of B. burgdorferi B31 (lp28-1) was found to contain a vmp-like sequence (vls) locus that closely resembles the variable major protein (vmp) system for antigenic variation of relapsing fever organisms. Portions of several of the 15 nonexpressed (silent) vls cassette sequences located upstream of vlsE recombined into the central vlsE cassette region during infection of C3H/HeN mice, resulting in antigenic variation of the expressed lipoprotein. This combinatorial variation could potentially produce millions of antigenic variants in the mammalian host.

Amino Acid Sequence↗
PubMed1980

Antigenic variation of influenza A virus nucleoprotein detected with monoclonal antibodies.

Monoclonal antibodies were used to study antigenic variation in the nucleoprotein of influenza A viruses. We found that the nucleoprotein molecule of the WSN/33 strain possesses at least five different determinants. Viruses of other influenza A virus subtypes showed antigenic variation in these nucleoprotein determinants, although changes in only one determinant were detected in H0N1 and animal strains. The nucleoprotein of human strains isolated from 1933 through 1979 could be divided into six groups, based on their reactivities with monoclonal antibodies; these groups did not correlate with any particular hemagglutinin or neuraminidase subtype. Our results indicate that antigenic variation in the nucleoproteins of influenza A viruses proceeds independently of changes in the viral surface antigens and suggest that point mutations and genetic reassortment may account for nucleoprotein variability.

Antibodies, Viral↗
PubMed1993

New observations on antigenic diversification of RNA viruses. Antigenic variation is not dependent on immune selection.

Recent results have revealed novel features in the process of antigenic diversification of FMDV. (i) Antigenic variation is not necessarily the result of immune selection. (ii) Single, critical amino acid replacements may either have a minor effect on antigenic specificity or cause a drastic antigenic change affecting many epitopes on an antigenic site. (iii) The effect of such a critical replacement may be suppressed by additional substitutions at neighbouring sites. (iv) Antigenic diversification does not necessarily involve net accumulation of amino acid substitutions over time. We review evidence that some of these features apply also to other riboviruses and retroviruses. A model is proposed to relate antigenic variation without immune selection to the quasispecies structure of RNA virus populations.

Antigenic Variation↗
PubMed2001

Antigenic variation at the infected red cell surface in malaria.

Many pathogens that either rely on an insect vector to complete their life cycle (e.g., Trypanosoma spp. and Borrelia spp.) or exist in a unique ecological niche where transmission from host to host is sporadic (e.g., Neisseria spp.) have evolved strategies to maintain infection of their mammalian hosts for long periods of time in order to ensure their survival. Because they have to survive in the face of a fully functional immune system, a common feature of many of these organisms is their development of sophisticated strategies for immune evasion. For the above organisms and for malaria parasites of the genus Plasmodium, a common theme is the ability to undergo clonal antigenic variation. In all cases, surface molecules that are important targets of the humoral immune response are encoded in the genome as multicopy, nonallelic gene families. Antigenic variation is accomplished by the successive expression of members of these gene families that show little or no immunological cross-reactivity. In the case of malaria parasites, however, some of the molecules that undergo antigenic variation are also major virulence factors, adding an additional level of complication to the host-parasite interaction. In this review, we cover the history of antigenic variation in malaria and then summarize the more recent data with particular emphasis on Plasmodium falciparum, the etiological agent of the most severe form of human malaria.

Animals↗
PubMed2004

DNA binding by the meningococcal RdgC protein, associated with pilin antigenic variation.

The RdgC protein of Neisseria gonorrhoeae is required for efficient pilin antigenic variation, although its precise role has yet to be established. We demonstrate that the nearly identical RdgC from Neisseria meningitidis binds DNA with little specificity for sequence or structure, like the Escherichia coli protein. We also show that neither protein is able to constrain torsional tension in relaxed DNA. These data exclude several possible roles for RdgC in pilin antigenic variation and suggest that RdgC performs a similar function in both E. coli and the Neisseria spp.

Amino Acid Sequence↗
PubMedDate not supplied

Telomeric reciprocal recombination as a possible mechanism for antigenic variation in trypanosomes.

In African trypanosomes, antigenic variation is achieved through differential gene activation, with one antigen gene being expressed at a time among a large collection of antigen-specific sequences. Transcription of the antigen gene always takes place in a telomere, but different telomeres can alternatively act as the expression site. Telomeric antigen genes can be expressed without apparent DNA rearrangement, but they can also, like non-telomeric genes, have access to the telomeric expression site through a duplicative transposition mechanism resembling gene conversion. We report here that, as previously suggested, telomeric genes may use another route to be activated. This mechanism of gene activation is by reciprocal crossing-over upstream from the gene, in the so-called 'barren' region. This allows the antigen gene to be placed in the previously activated telomere, while inactivating the formerly expressed gene by recombination into a silent environment. At least for the telomeric antigen gene described here, three possible activation mechanisms coexist.

Animals↗
PubMed1996

Antigenic variation and the within-host dynamics of parasites.

Many parasites exhibit antigenic variation within their hosts. We use mathematical models to investigate the dynamical interaction between an antigenically varying parasite and the host's immune system. The models incorporate antigenic variation in the parasite population and the generation of immune responses directed against (i) antigens specific to individual parasite variants and (ii) antigens common to all the parasite variants. Analysis of the models allows us to evaluate the relative importance of variant-specific and cross-reactive immune responses in controlling the parasite. Early in the course of infection within the host, when parasite diversity is below a defined threshold value (the value is determined by the biological properties of the parasite and of the host's immune response), the variant-specific immune responses are predominant. Later, when the parasite diversity is high, the cross-reactive immune response is largely responsible for controlling the parasitemia. It is argued that increasing antigenic diversity leads to a switch from variant-specific to cross-reactive immune responses. These simple models mimic various features of observed infections recorded in the experimental literature, including an initial peak in parasitemia, a long and variable duration of infection with fluctuating parasitemia that ends with either the clearance of the parasite or persistent infection.

Animals↗
PubMed2004

Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.

The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.

Age Distribution↗
PubMed1994

Molecular basis of antigenic variation in infectious bursal disease virus.

Four antigenically different strains of infectious bursal disease virus (IBDV), characterized by their reactivities with a panel of neutralizing monoclonal antibodies (MAbs), were selected to determine the molecular basis of antigenic variation. The large genome segment A, encoding the structural proteins of the U.S. variants GLS, DS326, E/Del and the vaccine strain D78, was cloned and sequenced. Comparison of the deduced amino acid sequences of the U.S. variants with other IBDV strains showed that most of the amino acid substitutions occur in the central region between residues 212 to 332, especially in the two hydrophilic regions between residues 212 to 223 and residues 314 to 324 of VP2 protein. By comparing the amino acid sequences of these variant viruses and their reactivities with IBDV specific MAbs, the putative amino acids involved in the formation of virus-neutralizing epitopes were identified. Comparison of the D78 versus PBG98 sequence showed that Gln at position 249 (Gln249) appears to be critical in binding with MAb B69. Similarly, comparison of the U.S. variant sequences with other serotype 1 sequences showed unique substitution(s) at residue Glu321 in GLS, residues Ile286, Asp318, Glu323 in E/Del, and residues Glu311 and Gln320 in DS326, which could be potential residue(s) involved in the recognition of MAb57, MAb67, and MAb179 epitopes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Antigenic variation in trypanosomes: secrets surface slowly.

Among pathogenic micro-organisms that evade the mammalian immune responses. Trypanosoma brucei has developed the most elaborate capacity for antigenic variation. Trypanosomes branched early during eukaryotic evolution. They are characterized by many aberrations, ranging from the unusual compartmentation of metabolic pathways to the heresy of RNA editing. The ubiquitous phenomenon of glycosylphosphatidylinositol-anchoring of eukaryotic plasma membrane proteins and RNA trans-splicing (trypanosome genes contain no introns), which adds an identical leader sequence to all trypanosome mRNAs, were first defined during studies of antigenic variation. Genetic transformation of trypanosomes and the high efficiency of gene targeting provide new opportunities to investigate the regulation of antigenic variation. There is every reason to expect trypanosomes to provide further surprises and insights into the evolution of genetic regulatory mechanisms.

Animals↗
PubMedDate not supplied

Sequences homologous to variant antigen mRNA spliced leader in Trypanosomatidae which do not undergo antigenic variation.

Trypanosomes which parasitize mammals have evolved mechanisms to evade immune attack, such as the occupation of 'safe' intracellular sites (for example, Trypanosoma cruzi), or antigenic variation, exemplified by the salivarian trypanosomes (for example, Trypanosoma brucei). Antigenic variation is mediated by sequential expression of single variant surface glycoprotein (VSG) genes, and often involves transposition of the active gene. Every VSG transcript examined shares the same 5' terminal 35-nucleotide leader sequence. In T. brucei, this leader is encoded within a 1.4-kilobase unit tandemly reiterated to form a large array. It is hypothesized that this array is distantly linked to the expressed VSG gene and functions as a multiple promoter of VSG gene transcription, restricting transcription to that gene which, through genomic rearrangement, is placed downstream from the array. Leader and structural gene sequences are presumably juxtaposed by RNA splicing. Here we show that several trypanosomatids, both those which undergo antigenic variation (Trypanosoma congolense and Trypanosoma vivax) and those which do not (T. cruzi and Leptomonas collosoma), contain reiterated sequences homologous to the T. brucei spliced leader (SL). These results suggest that the SL, although utilized in VSG gene expression, is an ancestral sequence also used in the expression of other trypanosomatid genes.

Animals↗