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Title: Isolation and Characterization of Adenoviruses Persistently Shed from the Gastrointestinal Tract of Non-Human Primates}
Article:
Abstract:
Adenoviruses are important human pathogens that have been developed as vectors for gene therapies and genetic vaccines. Previous studies indicated that human infections with adenoviruses are self-limiting in immunocompetent hosts with evidence of some persistence in adenoid tissue. We sought to better understand the natural history of adenovirus infections in various non-human primates and discovered that healthy populations of great apes( chimpanzees, bonobos, gorillas, and orangutans) and macaques shed substantial quantities of infectious adenoviruses in stool. Shedding in stools from asymptomatic humans was found to be much less frequent, comparable to frequencies reported before. We purified and fully sequenced 30 novel adenoviruses from apes and 3 novel adenoviruses from macaques. Analyses of the new ape adenovirus sequences( as well as the 4 chimpanzee adenovirus sequences we have previously reported) together with 22 complete adenovirus genomes available from GenBank revealed that( a) the ape adenoviruses could clearly be classified into species corresponding to human adenovirus species B, C, and E,( b) there was evidence for intraspecies recombination between adenoviruses, and( c) the high degree of phylogenetic relatedness of adenoviruses across their various primate hosts provided evidence for cross species transmission events to have occurred in the natural history of B and E viruses. The high degree of asymptomatic shedding of live adenovirus in non-human primates and evidence for zoonotic transmissions warrants caution for primate handling and housing. Furthermore, the presence of persistent and/or latent adenovirus infections in the gut should be considered in the design and interpretation of human and non-human primate studies with adenovirus vectors.
Introduction:
Adenoviruses were first discovered in the 1950s as outgrowths from human adenoid and tonsil explants. They naturally infect many different vertebrates including humans. Isolates were originally found to differ in their ability to agglutinate rat and rhesus erythrocytes and these properties were used to classify adenoviruses into four subgroups[1]. Subsequently, other prominent attributes of adenoviruses, e. g., the ability to induce tumors in rodents, the molecular masses of capsid proteins as determined by electrophoresis[2] and GC content of the genome[3] were used to augment the four initial subgroups to the six( subgroups A to F, currently referred to as species HAdV-A through HAdV-F) that are commonly accepted today. As complete sequences of the human adenoviruses have become available and phylogenic analyses of the component proteins have become possible, the original classifications have been confirmed to be reasonably valid although some reservation has been expressed regarding the justification of assigning a separate subgroup( E) to its only defined human adenovirus member, HAdV-4[4]. Infections with HAdV-C are a common cause of pediatric upper respiratory tract infections worldwide; later in life HAdV-B has been found to the cause of epidemics in adults. Both HAdV-B and HAdV-E have been found to the etiologic agents for infections in the setting of military boot camps[5]. Surveys for the prevalence of neutralizing antibodies have been conducted in order to determine the probable success of recombinant adenoviral vaccines[6], where the prevalence of antibodies to HAdV-C has found to be high in Europe, USA and Africa[7]. In contrast, the prevalence of antibodies to HAdV-B has been found to be comparatively lower in a European cohort[8]. HAdV-F is frequently implicated as a cause of infectious diarrheas worldwide[9]–[14], but other adenovirus serotypes were also frequently co-isolated under these conditions. The molecular biology of primate adenoviruses has been defined in substantial detail[15]. Less is known about the natural history of naturally occurring adenovirus infections. Recombinant forms of human adenoviruses have been aggressively pursued as vectors for human gene therapy and genetic vaccines[16]. Natural history studies of large cohorts of families in Seattle[17] and Long Island[18] showed that clinical sequelae of adenovirus infections and recovery of virus in immune competent humans are self–limited, although prolonged shedding was observed in stool from a subset of individuals. An early clue to the biology of adenovirus infections in great apes was provided by Hillis in 1963 in a study which attempted to isolate the cause of transmissible hepatitis in chimpanzees[19]. He recovered from stool of 25/87 chimpanzees an uncharacterized cytopathic virus that grew in vitro but was not related to hepatitis. He concluded that “there are a number of enterically excreted viruses in the chimpanzee, some or all of which may be part of the animal's ‘normal flora’ ”.
Discussion:
We have detected a high prevalence of adenoviruses in the stools of apparently healthy animals of several great ape and macaque species. The high rate of shedding was surprising and suggests that adenoviruses are capable of establishing chronic infections following an initial exposure that may or may not be clinically relevant. The presence of adenovirus in stools from wild chimpanzees and gorillas across several countries in central Africa confirmed that this was not an artifact of animals being maintained in captivity. Our studies cannot rule out an alternative explanation in which animals are repeatedly infected although these infections would have to be prolonged and frequent to explain the high prevalence. There is substantially less shedding of virus in human stool although adenovirus genomes are highly prevalent and abundant in gut associated lymphoid tissue( data not shown). Analyses of host responses to these persistent/latent infections suggests that better control of the chronic infection in humans may be due to a more effective T cell response to the virus[28]. Our studies also suggest that the gut may serve as a source of the disseminated and often lethal adenovirus infections observed in human patients who are immune suppressed[30],[31]. Sequencing the complete genomes of the 33 novel adenoviruses( 30 different sequences were found) that we have isolated from chimpanzees and gorillas has allowed us to examine the phylogenetic relationships among hominid adenoviruses. Overall, we found that the viruses isolated from great apes fall into the three species groups( B, C, and E) previously believed to be primarily of human origin. Generally, most DNA viruses are thought to have evolved with their host in a mechanism referred to as co-evolution[32] in which the virus was a pathogen of a common ancestor. Subsequent viral speciation is then expected to mirror primate speciation. In fact, the primate species C adenovirus phylogeny in this study is largely consistent with this hypothesis. However, several elements of the data, particularly in adenoviral species B and E, suggest that co-evolution alone may not fully explain the observed diversity and indicate a contribution of cross-species transmission to the primate adenoviral evolutionary history. Indeed, within species B and species D, the distances between certain human and ape adenovirus proteins are smaller than predicted by co-evolution, which is supported by high bootstrap values. In addition, partial hexon sequence of chimpanzee species C isolates that we were unable to grow out to obtain a full length sequence were found to cluster tightly with gorilla isolates indicating a possible cross-species transmission event in this species C subclade( data not shown). In addition, under the co-evolution hypothesis, one would expect the evolutionary distances between adenovirus species from humans to be similar to those from apes, assuming similar selective pressures. On the contrary, we observe that these distances are indeed very variable. For example, in clade B, SAdV-33 is only 0. 018 substitutions/site removed from the human clade B. 1 whereas the SAdV-35 viruses are almost 10 times more removed from the human clade B. 2 viruses( 0. 170 substitutions/site). We may interpret these data as either evidence for dramatic differences in selective pressures or an indication of at least one, possibly two, independent cross-species transmission events at distinct points in time. When one applies conservative molecular clock estimates for DNA viruses[33], the time estimates of the divergence between close human and ape viruses in species B and E are also inconsistent with the date of the human-chimpanzee divergence. Thus, we have demonstrated that cross-species transmission can be invoked to explain some of the phylogenetic relationships among human- and ape-infecting adenovirus isolates within the B and E species. We speculate that this transmission occurred from great apes to humans. The opposite direction of transmission cannot be ruled out, but is unlikely given the epidemiological evidence in favor of great apes as the natural host species. Several limitations to the data prevent us from delineating a definitive model of evolutionary history of primate adenoviruses. First, the inability to isolate adenoviruses from certain clades or host species of non-human hosts may indicate either their extinction in that particular host or a failure to detect the virus to date due to limitations in sampling or assaying. These limitations make it extremely difficult to perform an exhaustive study and nor can the data be interpreted as such. This study does, however, provide the most extensive survey of non-human primate adenoviruses to date. It is clear that more extensive studies in primates, particularly those in great apes in the wild are warranted. All full-length adenoviral genomes presented here were isolated from animals in captivity yet limited pol sequence data from gorillas and chimpanzees in the wild provide preliminary evidence to confirm the fecal shedding of species B and E viruses. As stated in Results, the samples from the wild harbored predominantly species E sequences as determined by PCR amplification of the polymerase gene( 24 belonging to species E and 3 to species B) whereas we were able to detect considerable numbers of species C adenoviruses( in addition to species E and B) in captivity. It can be speculated that the prevalence of the different adenovirus species in the gut of captive apes may be skewed as a result of captivity, but clearly more data including virus isolation in the wild is necessary in order to definitively confirm this observation. The high prevalence of adenovirus shedding in great apes and their close relation to existing human adenoviruses suggest a potential risk of ape-to-human transmission. This risk will likely be higher where contacts are more prevalent, such as with captive and habituated animals. The limited available sero-epidemiological data for chimpanzee species B and E adenoviruses suggests this may be the case in areas home to common chimpanzee species[34]. In addition, the possibility that the adenoviruses that were isolated from animals in combines and zoos were an artifact of their captivity needs to be addressed. In fact these concerns were aired following the isolation of SAdV-22, SAdV-23, SAdV-24, SAdV-25[27]. In that study, none of the animal handlers who were exposed to the chimpanzees were found to harbor antibodies to the chimpanzee adenoviruses. More recently, serum samples from 50 zoo workers were tested for the presence of neutralizing antibodies to SAdV-E( SAdV-23 and SAdV-25) and SAdV-B( SAdV-21), and none was found[35]. Although macaques shed adenovirus at high levels, transmission to humans seems unlikely since the macaque viruses are quite distinct from most known human adenoviruses. It is interesting however that an adenovirus similar to the macaque viruses was isolated from a patient with gastroenteritis[36]. These studies should also be considered in the context of applications of recombinant adenoviruses as vectors for human gene therapy and genetic vaccines. Chronic infections and latency of viruses and the associated host immune responses may confound the application of vectors that are related to these endogenous viruses.
Adenoviruses were originally discovered as a causative agent for upper respiratory infections , especially in children . They are now recognized as being responsible for disease in several other settings , e . g . , as the cause of infectious diarrheas or of kerato-conjunctivitis . In the 1960s , chimpanzees were found to shed adenoviruses in their stools . We now find that normal great apes ( chimpanzees , gorillas , and orangutans ) and monkeys frequently shed adenoviruses in their stools , corroborating the older finding . In contrast , data from humans have showed that adenoviral shedding in stools is fairly uncommon , being restricted to patients recovering from adenoviral infections , although adenoviruses can frequently be recovered from lymphoid tissue such as the adenoids from normal people . In the course of these investigations we have purified and characterized 30 different adenoviruses from great apes by genomic sequencing . We have compared the gene sequences of these adenoviruses to 22 human adenoviruses whose complete genome sequences are available . Even though human adenoviruses are not found in apes and vice versa , based on these sequence data we propose that it is possible that cross-species transmission events may have contributed to the natural evolution of adenoviruses found to infect humans today .