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1 Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
2 Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
3 Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
4 Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
5 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
6 Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
Correspondence
Simon M. Barratt-Boyes
smbb{at}pitt.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Barouch et al., 2001; Casimiro et al., 2003; Davis et al., 2000; Patterson et al., 2004; Rose et al., 2001; Shiver et al., 2002). Adenovirus-based vaccines in particular are being tested in a number of other emerging infectious diseases, including Ebola virus infection and severe acute respiratory syndrome (Gao et al., 2003b; Sullivan et al., 2003). However, a major limitation of Ad5-based vectors is immunogenicity of the vector itself, which substantially limits boosting with the same strain (Juillard et al., 1995; Santra et al., 2005; Yang et al., 1995). A significant proportion of humans worldwide also have a pre-existing immunity to Ad5 (Kostense et al., 2004; Nwanegbo et al., 2004; Vogels et al., 2003), limiting the utility of this vector in the clinical setting.
To counter this problem we and others have developed adenoviral vectors based on uncommon viruses, including human serotypes Ad11, Ad24, Ad34 and Ad35, and chimpanzee serotypes AdC6, AdC7 and AdC68 (Barouch et al., 2004; Farina et al., 2001; Fitzgerald et al., 2003; Gao et al., 2003a; Mei et al., 2003; Pinto et al., 2003; Reyes-Sandoval et al., 2004; Seshidhar Reddy et al., 2003; Shiver & Emini, 2004; Vogels et al., 2003). A majority of humans do not have detectable neutralizing antibody (Ab) titres to Ad35 (Kostense et al., 2004; Nwanegbo et al., 2004; Seshidhar Reddy et al., 2003; Vogels et al., 2003), making this a promising vector for vaccine delivery and gene therapy. Ad35 is a group B virus that uses CD46 as a cellular receptor as opposed to the coxsackievirus and adenovirus receptor widely used by other adenoviruses including group C Ad5 (Gaggar et al., 2003). Moreover, Ad35 is not cross-neutralized by Ab to Ad5 (Barouch et al., 2004; Vogels et al., 2003), raising the possibility of combining Ad5 and Ad35 in a serial vaccine strategy. Murine studies support the use of Ad35-based vectors in HIV vaccine design (Barouch et al., 2004), and studies in the non-human primate suggest that a combination of heterologous adenoviral vectors is effective at inducing robust cellular and humoral immune responses to HIV Gag (Reyes-Sandoval et al., 2004). The immunogenicity of Ad35-based vectors has not yet been reported in non-human primates.
In the present study, we sought to test the immunogenicity of a prototype Ad35-based vaccine encoding the simian immunodeficiency virus (SIV) mac239 gag gene in Indian rhesus macaques. We took advantage of the fact that rhesus macaques do not have a pre-existing immunity to either Ad5 or Ad35 to evaluate a sequential vaccination strategy using recombinant vectors based on both serotypes. To determine the depth of T-cell immunity, we carried out detailed analyses of responses following vaccination and subsequent mucosal challenge with the pathogenic primary virus isolate SIV/DeltaB670. This uncloned virus contains multiple genotypes that are transmitted across the rectal mucosa (Amedee et al., 1995; Trichel et al., 1997), making it a highly relevant model of sexual exposure to HIV.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Gao et al., 2004). Expression of Gag protein in two parts allowed for potential presentation of subdominant epitopes that may otherwise be limited by competition from immunodominant epitopes (Palmowski et al., 2002). E3-deleted replication-competent Ad35-p17 and Ad35-p45 were constructed using the loxP recombination method as described previously (Gao et al., 2003a). Briefly, SalI–NotI fragments of codon-optimized gag p17 or gag p45 were cloned into the Ad35 shuttle plasmid pAd35E3. Plasmids were linearized with EcoRV and cotransfected with NotI-digested Ad35 helper virus Ad35E3/EYFP DNA into CRE8 cells. The resultant Ad35-based vectors were produced in HEK293 cells. Protein expression by Ad5- and Ad35-based vectors was confirmed by Western blot analysis of lysates of infected HEK293 cells using the SIV p17-specific and p27-specific monoclonal Abs KK59 and 2F12, respectively (Brown et al., 2003; and data not shown).
Animals.
Eleven adult Indian rhesus macaques (Macaca mulatta) housed at the University of Pittsburgh Primate Facility for Infectious Disease Research were used in this study in compliance with institutional regulations. Molecular major histocompatibility complex (MHC) class I typing for the rhesus macaque alleles Mamu-A*01, A*02, A*08, A*11, B*01, B*03, B*04 and B*17 was carried out through a contract with the Wisconsin National Primate Research Center.
Immunization and SIV challenge.
Vaccine viruses were thawed and suspended in saline in separate syringes at a concentration of 1011 virus particles per 150 µl. Diluted viruses were kept cold and injected within 1 h of thawing. Viruses expressing p17 or p45 were given at separate sites by intramuscular injection in the lateral thigh or by intradermal injection in the inguinal region in sedated animals, respectively. Vaccinated and control monkeys were inoculated with an undiluted stock of the primary virus isolate SIV/DeltaB670 by atraumatic instillation into the rectum as described previously (Fuller et al., 2002).
ELISPOT assays.
Effector T-cell responses to SIV antigens were analysed in previously frozen peripheral blood mononuclear cells (PBMC) by IFN-
ELISPOT assay as described previously (Brown et al., 2003). Individual 15 mer peptides at >80 % purity representing Gag, Pol, Env and Nef sequences of SIVmac239 and overlapping by 11 aa (NIH AIDS Research & Reference Reagent Program) were dissolved in DMSO and used as antigens. Gag peptides were used in pools of eight peptides or 30–32 peptides (3·1–3·9 µg ml–1), or as individual peptides (5 µg ml–1) as described previously (Brown et al., 2003). Env and Nef peptides were used as single pools of 212 peptides (0·6 µg ml–1) and 64 peptides (1·6 µg ml–1), respectively. Pol peptides were split into two pools of 131 and 132 peptides (1 µg ml–1). Responses that were two times that of the background with a minimum number of spots of 10 per 200 000 cells were scored as positive.
Analysis of neutralizing Ab responses to adenoviral vectors.
Serum neutralizing Abs to Ad5 and Ad35 were measured using E1/E3-deleted Ad5 expressing enhanced green fluorescent protein and E3-deleted Ad35 expressing enhanced yellow fluorescent protein, respectively, as described previously (Nwanegbo et al., 2004). The end-point titre was calculated as the highest serum dilution that inhibited adenovirus infection of A549 cells by 
50 %.
Virus quantification and sequence analysis.
Quantification of virion-associated RNA in plasma was performed by real-time PCR as described previously (Fuller et al., 2002). For sequence determination, viral RNA was isolated from cell-free plasma of SIV-infected monkeys using viral RNA mini kit (Qiagen). To amplify the gag gene, first-strand cDNA synthesis was primed with random hexamers or the gag-specific primer BGAGR: 5'-GCGCTGCAGTGGGAGTTGCCCTGGTGTCAGT-3' and reverse transcribed using Superscript II reverse transcriptase (Invitrogen). PCR-amplified fragments containing 90 % of the gag gene were generated by using the primers BGAGF: 5'-GGCGAATTCATGGGCGTGAGAAACTCCGTCTTG-3' and BGAGR with the Expanded High Fidelity PCR system (Roche Applied Science), as per manufacturer's instructions, using an annealing temperature of 53 °C. For analysis of individual cloned viral cDNA sequences, amplicon DNA was purified from agarose gels and cloned into the pGEM-TA vector (Promega) prior to transformation into bacteria. Plasmid DNA was sequenced with a 3770 DNA analyser (Applied Biosystems). Sequence data were aligned with SIVmac239 (GenBank accession no. M33262
[GenBank]
) using CLUSTAL W.
Statistical analyses.
To enable comparison of Gag-specific T-cell responses following virus challenge between vaccinated and control animals, data for each animal were first averaged over predetermined intervals and the mean for all animals in a group was calculated. Mean values for the experimental versus the control animals were then compared over the sequential time points using the non-parametric binomial (sign) test (Day et al., 1999), which examines the consistency of binary differences (±) between the two groups across time (Fisher & van Belle, 1993). The same method was followed for comparison of virus loads over time in vaccinated and control groups.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). While a conventional replication-defective Ad5-based vector was used, we employed a replication-competent Ad35-based system, as E1-complementing cell lines necessary for the generation of E1-deleted vectors were still under development at the time the experiment was initiated.
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). The frequency of IFN--producing Gag-specific effector T cells in uncultured PBMC ranged from 1 : 1000 to 1 : 500 in a majority of animals after one to two vaccinations, confirming that vaccination with Ad5-based vectors is highly efficient in monkeys (Casimiro et al., 2003; Shiver et al., 2002). As expected, the initial series of vaccinations with Ad5-based vectors resulted in rapid induction of high titre Ad5-specific serum neutralizing Ab that did not cross-neutralize Ad35 (Fig. 1). Repeated boosting with Ad5-based vectors in this first series of four immunizations generally had limited effect. However, over time Ad5-specific neutralizing Ab titres waned in all animals, declining by a mean of 40-fold over the 27·3±2·8 weeks before the second series of immunizations (Fig. 1). This drop in titre likely facilitated the weak boosting of Gag-specific immune responses in M1501 at week 51 when Ad5-based vectors were used again, although no such boosting was noted in animal M1601 (Fig. 1). In contrast, vaccination with Ad35-based vectors resulted in a substantial boost of immunity to levels above that initially induced by Ad5-based vaccination in the six remaining animals (Fig. 1). Gag-specific effector T-cell frequencies in uncultured PBMC ranged from 1 : 500 to 1 : 250 in M7801, M1701 and M2301 after Ad35-based vaccination, demonstrating the potency of vaccination (Fig. 1). Generally, single vaccination with Ad35-based vectors induced minimal or no vector-specific neutralizing Ab responses, and in five of six animals the titre was undetectable at the time of the boost injection 9 weeks later, allowing significant boosting of Gag-specific responses (Fig. 1). Notably, in M2201 and M1701 the Ad35-specific neutralizing Ab titre dropped to undetectable levels by 10 weeks and 3 months after the second immunization with Ad35, respectively (Fig. 1 and data not shown).
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). Animal M1701 responded to peptides p35/p36 and p68/p69, each containing common 11 aa sequences, indicating that robust immune responses were directed towards two different regions of Gag. Boosting with Ad35-based vectors at weeks 64 and 73 did not alter the specificity and breadth of response primed by vaccination with Ad5-based vectors (Fig. 2a). Similarly, animal M7801 responded to two discrete regions of Gag following Ad5-based vaccination represented by peptides p14/p15 and p35/p36, with the same responses being boosted following Ad35-based boosts. Animal M2301 responded to eight peptides representing six different regions of Gag through vaccination (Fig. 2a). As expected, animals M2201 and M9700, which expressed the Mamu-A*01 allele, responded almost exclusively to peptides p45/p46 containing the immunodominant MHC class I-restricted CD8+ T-cell epitope CM9 (Gag181–189) (Miller et al., 1991) (Fig. 2a and data not shown). To determine whether the major peptide-specific responses noted in these animals were MHC class I- or class II-restricted, we depleted CD8+ or CD4+ T cells, respectively, from PBMC prior to ELISPOT analysis (Brown et al., 2003). IFN- release by PBMC from M1701 and M2301 to peptides p68 and p69, respectively, was completely abrogated when CD8+ but not CD4+ T cells were depleted, indicating that these responses were MHC class I-restricted. IFN- responses to peptide p35 by PBMC from M7801 were also CD8+ T-cell-dependent (Fig. 2b). In contrast, cytokine release by M7801 PBMC to peptide p15 was dependent upon CD4+ T cells and was therefore MHC class II-restricted (Fig. 2b). Collectively, these data indicate that adenovirus-based vaccination induces broad CD4+ and CD8+ T-cell immunity to Gag.
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). This raised the concern that the vaccine regimen may not have induced sustained memory responses. To test this directly, we challenged vaccinated and three control animals with the pathogenic uncloned isolate SIV/DeltaB670 via atraumatic intrarectal inoculation 11–12 weeks after the final boost (Table 1). This virus is related but distinct from SIVmac239 on which the vaccine was based (Amedee et al., 1995; Trichel et al., 1997). The two animals vaccinated with Ad5 alone had recall responses to Gag following infection, although the response in M1501 was minimal, despite the minor boost to Gag-specific T-cell responses generated by Ad5-based immunization in this animal. M1501 died of anaesthetic complications unrelated to SIV infection at week 15 post-infection (Fig. 3a). The six animals vaccinated with Ad5- and Ad35-based vectors generally had robust recall responses to Gag as a function of infection, although animal-to-animal variation was considerable (Fig. 3a). In contrast, the three control animals had poor Gag-specific responses following mucosal challenge with SIV/DeltaB670 (Fig. 3b). When the frequency of Gag-specific responses following infection was compared between animals receiving the Ad5- and Ad35-based vaccinations and control animals, the mean response was greater in vaccinated animals for at least 25 weeks post-infection (P<0·0175; Fig. 3c). This recall response was specific to the vaccine antigen, as cellular responses to Env, Pol and Nef were similar between the Ad5/Ad35 vaccine group and the control group post-challenge (Fig. 3d).
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). Animal M7801 had increased CD8+ T-cell responses to peptides p35/p36 following virus challenge but no boost in the CD4+ T-cell response to peptides p14/p15 (Fig. 4), despite complete sequence identity in this region between vaccine and challenge strains (data not shown). This animal had new responses to p1 and p67–p69 peptides as a result of infection. As expected, animal M2201 had marked increases post-challenge in the T-cell response to peptides p45/p46 containing the immunodominant and conserved Mamu-A*01-restricted CM9 epitope, approaching a frequency of 0·2 % in unseparated PBMC (Fig. 4). This is in noticeable contrast to the negligible responses of the two Mamu-A*01-expressing control animals M14301 and M15001 to Gag following challenge (Fig. 3b). Animal M3398, the single control animal for which a robust post-challenge Gag-specific response was detected, had responses directed exclusively to the p68/p69 region (Fig. 4). Collectively, these data indicate that vaccination induced robust memory responses to SIV Gag that were selectively recalled after virus challenge.
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a). Overall, monkeys in the Ad5/Ad35-vaccinated group had lower mean virus loads as compared with control animals at 11 of 12 time intervals, a finding that is statistically significant (P=0·003). However, the magnitude of the difference between groups exceeded 1 log only at two time intervals, being 9–12 weeks and 31–35 weeks post-infection, and was not significant over time (Fig. 5b). Control animals had a median time to death from AIDS of 41·0 weeks compared with 49·3 weeks for the Ad5/Ad35-vaccinated animals, a difference that did not reach significance (log rank test P=0·094) (Fig. 2c). Animal M2301 remains alive without AIDS at 70 weeks post-infection. These data demonstrate that vaccination had a measurable, albeit small, effect on virus load.
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) despite having a potent T-cell response to the Mamu-A*01-restricted CM9 epitope (Fig. 4), suggesting that T-cell activity directed towards this epitope was no longer effective. To test for virus escape from cytotoxic T cells, we sequenced the virus inoculum and viruses isolated from plasma after infection of the four animals expressing Mamu-A*01 (Table 1) and compared the CM9 coding sequence and the surrounding region with the SIVmac239 vaccine sequence. All species of the SIV/DeltaB670 inoculum expressed the CM9 epitope, but there were multiple variations in the flanking sequence when compared with SIVmac239 (Fig. 6a). Escape mutations in the CM9 epitope were found in viruses isolated from three of four Mamu-A*01-expressing animals, with 63 and 100 % of virus clones from animal M2201 harbouring escape mutations by weeks 15 and 23 post-infection, respectively, coincident with the increase in virus load (Fig. 6a). The control-vaccinated animal M15001 had epitope escape mutations in 100 % of virus clones present at week 19 despite minimal Gag-specific T-cell responses to virus (Figs 3b and 6a). Notably, different mutations within the CM9-coding sequence were found in viruses isolated at several time points from the non-Mamu-A*01-expressing animal M1701, with 40 and 75 % of clones isolated at weeks 45 and 62, respectively, expressing mutations (Fig. 6b). Peptides spanning this sequence and flanking regions did not elicit IFN- responses during acute and chronic stages of infection in this animal, indicating that mutation did not accompany a detectable T-cell response to an epitope overlapping the CM9 region (Fig. 6c). No consistent extraepitopic mutations temporally associated with CM9 mutations could be identified.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Mei et al., 2003; Shiver & Emini, 2004; Vanniasinkam & Ertl, 2005). Ad35 has been the focus of considerable research based on its low seroprevalence in the global human population and its distinction as a group B virus that is not cross-neutralized by Abs to Ad5 (Gao et al., 2003a; Kostense et al., 2004; Nwanegbo et al., 2004; Seshidhar Reddy et al., 2003; Vogels et al., 2003). Murine studies have demonstrated that Ad35-based vaccines are immunogenic in the face of immunity to Ad5 (Barouch et al., 2004), and we now extend those findings to the preclinical non-human primate model. Our study utilized a first-generation, replication-competent Ad35 vector. Preliminary studies showed that Ad35 infection was subclinical in monkeys and that the virus was not readily transmitted, as infectious Ad35 could not be recovered from saliva, serum or urine following intramuscular injection with Ad35-expressing enhanced yellow fluorescence protein (data not shown). However, replicating Ad35 is not ideal for vaccine development, particularly as the virus can cause disease in elderly and immunosuppressed individuals (Sanchez et al., 1997). With the development of E1-deleted Ad35 packaging cell lines we now have the capacity to generate replication-defective Ad35-based vectors that will be used in future studies (Gao et al., 2003a).
Ad35-based vaccination boosted but did not expand the T-cell repertoire primed by Ad5-based vaccination, which included both CD4+ and CD8+ T-cell responses. Similarly, other studies have demonstrated the induction of broad T-cell responses to virus in monkeys following adenovirus- and attenuated poxvirus-based vaccination (Casimiro et al., 2003; Hel et al., 2002; Reyes-Sandoval et al., 2004; Santra et al., 2005). While the responses following Ad35-based vaccination in our study were greater than those induced by repetitive Ad5-based vaccination, in general the extent of the increase was not as great as anticipated given the heterologous nature of the vectors. Neutralizing Ab responses to Ad35 were not elicited following Ad5-based vaccination; hence there is no evidence that virus was cleared prior to infection of target cells. It is possible that cross-reactive T-cell immunity to Ad35 was induced through priming immunizations with Ad5, resulting in premature elimination of Ad35-infected cells by adenovirus-specific cytotoxic T cells. A direct comparison of Ad5- and Ad35-based vectors as priming vaccines is needed to determine the relative immunogenicity of the two vector systems. It is interesting to note that serotype-specific neutralizing Abs to both Ad5 and Ad35 waned over time and in the case of Ad35 were undetectable in two animals after two immunizations, suggesting that additional immunizations with the same vector may have been efficacious. Similarly, a boosting response was noted by Casimiro et al. (2003) when two immunizations of 1010 virus particles of Ad5-based vectors were administered 24 weeks apart to rhesus macaques, even in Ad5-experienced monkeys. In contrast, findings by others indicate that two administrations of 1012 virus particles of Ad5-based vaccines produced sustained neutralizing Ab titres for over 130 weeks that substantially limited T-cell responses to transgenes upon subsequent Ad5 administration (Santra et al., 2005). Taken together these findings suggest that the specific vector dose may significantly influence the durability of vector-specific neutralizing Ab titre and the capacity of subsequent injections with the same vector to boost T-cell immunity.
A key goal of vaccination is to induce sustained memory responses that produce enhanced immunity following virus infection. While our serial adenovirus-based regimen induced potent T-cell responses, the duration of these responses prior to challenge was limited. Other similar studies have emphasized the durability of the vaccine response induced through Ad5-based vaccination, although as discussed above these workers used 10-fold higher doses of vector, which may have had an impact on T-cell responses (Santra et al., 2005). Despite the rapid decline of Gag-specific T-cell frequencies after the Ad35-based boosts in our study, the anamnestic T-cell response to Gag following infection with SIV was strong and durable, with increased T-cell frequencies being present as a function of vaccination for 25 weeks. Of note is the prominent response of a number of animals to the region of capsid represented by peptides p67–p70, which has not previously been defined as immunogenic. We were not able to determine the MHC restriction of these responses; however, epitope mapping using purified 9 mer peptides identified at least two distinct epitopes within this region recognized by PBMC from animal M7801 post-challenge (data not shown). Overall, the immune response post-challenge in our cohort of animals had a detectable, albeit minor, effect on virus load, a finding that is not unexpected given the clear role of other viral antigens in vaccine-induced protection from disease, notably Env (Letvin et al., 2004). Future studies will need to focus on using replication-defective Ad35-based vectors expressing a range of viral antigens in a priming regimen to test the efficacy of this vaccine system rigorously.
An unexpected finding of our study was the identification of a novel mechanism of virus escape from T-cell recognition. The immunodominant Mamu-A*01-restricted CM9 epitope is highly conserved amongst SIV strains and other lentiviruses, including SIV/DeltaB670 as we now show, and virus escape within the epitope is generally uncommon and slow to evolve in infected macaques (Barouch et al., 2002, 2003; Friedrich et al., 2004a; Peyerl et al., 2003, 2004). Virus escape from T-cell recognition in monkeys infected with SIVmac239 or SHIV-89.6P is associated with flanking mutations that are necessary to maintain in vitro replicative fitness (Friedrich et al., 2004a; Peyerl et al., 2003, 2004), although mutated viruses are stable and do not revert to wild-type sequence upon subsequent infection (Friedrich et al., 2004b). While only a small number of Mamu-A*01-expressing animals were followed, our findings are notable in that virus escape from this immunodominant epitope occurred relatively early in the course of infection with SIV/DeltaB670 without any consistent temporal association with flanking mutations. Indeed, the three individual mutations present in viruses from these monkeys are common in CM9 escape mutants following SIV infection and each produce a 100-fold reduction in epitope binding affinity for Mamu-A*01 compared with the wild-type epitope (Barouch et al., 2003). Interestingly, the broader sequence of SIV/DeltaB670 flanking CM9 is hypervariable when compared with SIVmac239 with a dissimilarity of 12 %. This includes a valine residue at position 161, which in SIVmac239 isolates is frequently mutated from isoleucine at the time of CM9 epitope escape (Friedrich et al., 2004a). It is conceivable that the stable pre-existing sequence differences in SIV/DeltaB670 impart the capacity for CM9 mutation to occur without incurring fitness costs, thus enabling virus escape relatively early during infection. Consistent with this hypothesis is the discovery that the mutation in the CM9 coding sequence was found in an animal that did not express Mamu-A*01 and which lacked detectable cellular responses to the region. Whether this translates into a lack of a survival advantage in Mamu-A*01-expressing monkeys when infected with SIV/DeltaB670, in contrast to infection with SIVmac251 (Muhl et al., 2002; Palmowski et al., 2002), SIVmac239 (Mothe et al., 2003) and SHIV-89.6P (Zhang et al., 2002), remains to be definitively determined.
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ACKNOWLEDGEMENTS |
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Received 18 August 2005;
accepted 11 October 2005.
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