Authors: Justin Lee, Jennifer L. Malmberg, Britta A. Wood, Sahaja Hladky, Ryan Troyer, Melody Roelke, mark Cunningham, … present All … , Roy McBride, Winston Vickers, Walter Boyce, Erin Boydston, Laurel Serieys, Seth Riley, Kevin Crooks, and Sue VandeWoude display Fewer

Owing to a complex history the host-parasite coevolution, lentiviruses exhibition a high level of species specificity. Offered the well-documented viral archeology of person immunodeficiency virus (HIV) introduction following human exposures to simian immunodeficiency virus (SIV), an knowledge of procedures that promote effective cross-species lentiviral transmissions is very relevant. We previously reported organic cross-species infection of a subtype of feline immunodeficiency virus, puma lentivirus A (PLVA), between bobcats (Lynx rufus) and also mountain lions (Puma concolor) because that a small number of animals in California and Florida. In this study, we investigate host-specific choice pressures, within-host famous fitness, and also inter- versus intraspecies transmission patterns among a bigger collection of PLV isolates native free-ranging bobcats and mountain lions. Analyses of proviral and viral RNA levels demonstrate that PLVA fitness is severely restricted in hill lions contrasted to the in bobcats. We paper evidence of diversifying choice in 3 of 6 PLVA genomes from hill lions, but we did no detect selection among 20 PLVA isolates native bobcats. These findings support the theory that PLVA is a bobcat-adapted virus i beg your pardon is much less fit in mountain lions and under intense an option pressure in the novel host. Ancestral reconstruction of transmission occasions reveals the intraspecific PLVA transmission has occurred amongst panthers (Puma concolor coryi) in Florida complying with the early cross-species infection from bobcats. In contrast, interspecific infection from bobcats to hill lions predominates in California. These findings paper outcomes that cross-species lentiviral transmission events among felids the compare to the emergence of HIV from nonhuman primates.

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IMPORTANCE Cross-species infection episodes have the right to be singular, dead-end events or can an outcome in viral replication and spread in the new species. The components that identify which outcome will occur are complex, and also the danger of brand-new virus emergence is therefore complicated to predict. We used molecular methods to evaluate the transmission, fitness, and adaptation that puma lentivirus A (PLVA) in between bobcats and mountain lions in two geographical regions. Ours findings illustrate that mountain lion exposure come PLVA is relatively common but does not routinely result in communicable epidemic in the new host. This is attributed come efficient varieties barriers that mainly prevent lentiviral adaptation. However, the evolutionary capacity for lentiviruses to it is adapted to novel atmospheres may at some point overcome hold restriction mechanisms end time and under specific ecological circumstances. This phenomenon offers a distinctive opportunity to examine cross-species transmission events leading to brand-new lentiviral emergence.
The Lentivirus genus comprises complicated retroviruses through a propensity for rapid mutation and recombination that results in a high rate of famous evolution. Lentiviruses typically infect master in a species-specific manner, and also distinct viral subtypes or clades are characteristically linked with single host species. Transmission of these host-adapted viruses to new species is unusual (1, 2). Organize restriction is deadline to number of factors, consisting of lower famous fitness in the novel host, intrinsic antiviral defense mechanisms, and/or limited contact sufficient for transmission in between different host types (3–7). Notable examples of successful cross-species lentiviral infection incorporate multiple transmissions the simian immunodeficiency viruses (SIVs) from nonhuman primates to humans, which provided rise come the various circulating subtypes of human being immunodeficiency virus (HIV) (reviewed in referral 8). That is assumed that a convergence that social, cultural, and behavioral determinants resulted in famous transmission and also subsequent adaptation, culminating in a disastrous pandemic infecting an approximated 35 million people worldwide (9).
At least 11 felid varieties have to be diagnosed with infections v lentiviruses well-known as feline immunodeficiency viruses (FIVs), which stand for the most well-defined lentiviral group outside the SIVs (10, 11). Just like other lentiviruses, FIV phylogenetic relationships assistance a pattern of species-specific viral evolution (12, 13). In domestic cats (Felis catus), reported morbidity and also mortality vary widely, indigenous mild or inapparent infection to a terminal AIDS-like syndrome (14–17). In nondomestic felids, epidemic are supposedly subclinical, though lessened CD4 T-lymphocyte counts and also an increased prevalence that opportunistic pathogens have actually been documented for some feline master (18–20). Speculative transmission the FIVs diverted from mountain lions (Puma concolor; also referred to as pumas, cougars, and also panthers) to residential cats result in fertile yet avirulent epidemic (21). Host-mediated cytidine deamination ultimately produced defective viral genomes (21, 22), saying that adaptation the FIVs to brand-new host species does not conveniently occur.
An exemption to the pattern of lentiviral hold specificity is puma lentivirus A (PLVA; additionally referred to together FIVpcoA), an FIV subtype recorded to infect 2 different varieties in the wild: bobcats (Lynx rufus) and also mountain lions (23). Hill lions inhabit a geographic range from western Canada to southerly Chile, while bobcats space sympatric mesopredators throughout much of phibìc America (Fig. 1). Both varieties are habitat generalists however are sensitive to anthropogenic influences and also have experienced local extinctions and populace subdivision as result of overhunting and also habitat deterioration (24–27). PLVA is the only FIV that has been isolated native bobcats, and also it is endemic in California and Florida yet has no been identified in other geographic regions (23, 28–31). PLVA has actually been determined in hill lions only for populaces that space sympatric through PLVA-infected bobcats (Fig. 1), is lacking throughout many of the mountain lion geographical range, and also is lot less typical in mountain lions than a second FIV subtype, puma lentivirus B (PLVB; likewise referred to as FIVpcoB), in regions where the two viruses cocirculate (2, 11, 13, 23, 25, 28). In contrast to PLVA, PLVB has been displayed to infect hill lions throughout their entire geographic variety and thus has likely coevolved with mountain lions because prior to your proposed recolonization of phibìc America ~ the last Ice age (10,000 come 15,000 year ago) (28, 32). The hereditary distance between PLVA and also PLVB is comparable to that separating the other species-specific strains of FIV and is suggestive that divergent evolutionary histories in separate host varieties (11, 13).
FIG 1 Host species geographic ranges and also sample repertoire sites for PLVA isolates native bobcats and mountain lions in California and Florida. Irradiate gray shading represents local sympatry; the geographic variety of bobcats overlaps that of hill lions throughout the United states (
We previously explained several aspects of PLV evolution, consisting of the functions of mutation, recombination, and natural an option in generating genetic diversity over time and room (30). Specifics both PLVA and -B evolve under predominantly purifying selection, with high prices of identified mutations emerging at the nucleotide level but reasonably infrequent nonsynonymous substitutions leading to diversity in the corresponding proteins. Multiple recombination breakpoints were detected throughout the PLV genomes, indicating the this is crucial mechanism for generating genetic diversity, which can lead come fit viral variants the differ from both parental isolates. Finally, us were may be to file through famous phylogenies that PLV diversity shows the populace structure the its hosts, with large genetic distances separating geographically distinctive host populaces but noticeable admixture within populations.
In this study, we present brand-new findings adhering to examination of an expanded set of samples to specifically characterize the dual-host tropism of PLVA. This report represents the an initial analysis that cross-species transmission, famous fitness, and also viral adaptation in relationship to the development of PLVA in the native hold (bobcat) and also a second host (mountain lion). Our results indicate that PLVA viral fitness is severely diminished in the mountain lion compared to the in the bobcat and that adaptation (episodic diversifying selection) has arisen in hill lion PLVA isolates. In California, many mountain lion isolates have developed from cross-species infection from bobcats. In contrast, the phylogeny the PLVA isolates indigenous Florida panthers (Puma concolor coryi; a local subspecies of hill lion) is regular with mostly intraspecific transmission events, suggesting possible PLVA adaptation in this population. The dual-host tropism the PLVA provides a distinctive opportunity to understand the ecological and also evolutionary factors affiliated in lentivirus host selection expansion, analogous to the infection of SIVs to humans leading come the introduction of HIV.
We previously evaluated PLV phylogenetic relationships in the context of broad-scale geographical patterns and gene-by-gene evolution (30). In the existing analysis, we report on together yet uncharacterized traits of PLV diversity that administer insight into the evolutionary dynamics that this two-host, two-virus system. The PLVB clade includes only mountain lion isolates, and ancestral host state repair of the basal node of this clade caused a 0.99 posterior probability of hill lion family tree (Fig. 2A and also Fig. 3). In contrast, the PLVA clade comprises 15 hill lion isolates and also 32 bobcat isolates, and the basal node the PLVA to be assigned a probability of bobcat genealogy of 0.84.
FIG 2 PLVA and also PLVB space separated by big genetic distances, and each comprises geographically associated subgroups. (A) maximum likelihood phylogenetic tree created from a 474-bp region of pol. Isolates original to this study are highlighted in bold text. Nodes with Table 3), (iv) sampling location, and also (v) sample year (1984 come 2011). Local PLVA subtrees and also pairwise identity matrices demonstrate different trends of host-virus relationships. Isolates in Florida (B) have tendency to form well-supported clusters by host species, while many California hill lion isolates (C) are more closely pertained to sympatric bobcat isolates than to viruses from other hill lions.
FIG 3 An ancestral reconstruction of host states throughout the PLVA phylogeny depicts different patterns the intra- and also interspecies transmissions in California and Florida. (A) preferably clade credibility tree built from the pol sequences supplied for Fig. 2, showing historic and contemporary transmission dynamics. Hold state posterior probability values relevant to infection directionality are shown by shaded one at nodes. Asterisks indicate predicted cross-species transmission events (3 in Florida and 6 in California). (B) The relationship of inferred host state transitions across the PLVA phylogeny depicts substantial bobcat-to-mountain lion transmission rates at each site (15% of Florida and also 25% that California transmissions). Predicted mountain lion-to-mountain lion transmissions happen with much greater frequency in Florida (25%) than in California (4%). (C) The gray shaded an ar of dashboard A corresponds to host states for the sampled isolates illustrated here. More sampled hill lion isolates to be predicted to arise native intrahost transmission events in Florida (7 of 8 isolates) 보다 in California (2 that 7 isolates).
PLVA isolates type two distinctive groups of viral sequences solely from California or Florida (Fig. 2). Samples from Florida cluster by host species: 14 that 14 bobcat and 7 the 8 panther isolates have actually predicted many recent common ancestors from a bobcat and also a panther, dong (Fig. 2B and 3). In California, 18 the 18 bobcat PLVA isolates developed from predicted bobcat ancestors; however, in comparison to the instance in Florida, 5 the 7 California hill lion isolates to be predicted come have emerged from a many recent typical ancestor from a bobcat (Fig. 2C and 3). No mountain lion-to-bobcat infection was inferred because that either population. In assistance of these outcomes from the organize state ancestral reconstruction analysis, pairwise identity matrices demonstrate different trends of host-virus relationships in California and also Florida (Fig. 2B and also C). In Florida, the majority of panther isolates share higher pairwise identity with various other panther isolates than through bobcat isolates, when in California, the most carefully related isolate to many mountain lion isolates is a bobcat isolate.
One famous isolate native a Florida panther (Pco87.FL1984) is paraphyletic to every PLV isolates, through high bootstrap assistance for its exemption from PLVA and also PLVB (Fig. 2A). This isolate clusters with residential cat FIV isolates and is most similar to FIVFca subtype B (92% pairwise identity) (data no shown).
PLVA proviral lots in bobcats (mean = 103.8; typical deviation = 0.49) and also PLVB proviral loads in hill lions (mean = 104.7; SD = 0.50) were 1 come 2 order of magnitude higher than PLVA proviral lots in mountain lions (mean = 103.0; SD = 0.93) (P Fig. 4, left panel). This result was constant for proviral tons quantified native both blood and tissue samples. A quantitative PCR (qPCR) assay did no detect PLVA provirus in 6 PLVA-infected pumas, in spite of amplification of incorporated proviral DNA by nested PCR assays.
FIG 4 Within-host famous fitness different significantly amongst hosts and amongst viral clades. (Left) individual sample proviral tons (means because that triplicates) are illustrated for PLVA in bobcats (n = 30), PLVA in mountain lions (n = 10), and PLVB in mountain lions (n = 18). Horizontal currently represent typical values because that the host-virus relationships. The mountain lion PLVA proviral copy number was substantially lower than that for PLVA in bobcats and also PLVB in mountain lions (P ns n = 7), PLVA in mountain lions (n = 10), and PLVB in mountain lions (n = 14). PLVA viremia was listed below the limit of quantification because that all hill lion samples. PLVA viremia in bobcats to be not substantially different (ns) native the mean PLVB viremia in hill lions.
Analysis the the life data documented significantly higher viremia because that PLVA in bobcats and PLVB in hill lions than for PLVA in mountain lions (Fig. 4, ideal panel), and there to be no far-reaching difference in viremia worths for every virus in the apparent primary host. The majority of bobcat and mountain lion plwgc2010.orga viral tons for both PLVA and PLVB were below the lower limit that quantitation (LLOQ), and also 10 of 10 mountain lions with detectable PLVA provirus had actually no detectable viremia.
Full genome order of PLVA (n = 26) and PLVB (n = 33) were analyzed come detect separation, personal, instance isolates subject to episodic bursts of diversifying selection. Episodic diversifying selection (nonsynonymous substitution price > synonymous substitution price ) was detected in at least one genomic an ar in 50% (3/6 sequences) that the PLVA sequences secluded from mountain lions (Fig. 5). Selective pressure was detected in ~ vif and also several regions of env, consisting of those encoding the leader domain, the transmembrane domain, and also the an ar spanning the surface and transmembrane domains. In contrast, no evidence of diversifying choice was detected in any segments the 20 PLVA genome sequences native bobcats. Among 33 PLVB genome order had proof of an option in a single an ar of env (data not shown).
FIG 5 The choice results are regular with the theory that PLVA is not adjusted to the hill lion and also is thus under strong pressure come evolve in this host. All nonrecombinant areas of PLVA and PLVB genomes to be analyzed through branch-site REL without a priori designation the isolates as originating native a bobcat or a hill lion. Diversifying choice was recognize in 3 the 6 PLVA isolates from hill lions, 0 the 20 bobcat PLVA isolates, and 1 the 33 PLVB isolates from hill lions. The table in ~ the optimal lists the isolates evolving under diversifying selection, the equivalent genomic regions under selection, and also the ratio of web page (codons) diversifying in each region (L, leader; SU, surface; TM, transmembrane). Ns values displayed were derived via ANOVA and corrected because that multiple exam by making use of the Holm-Bonferroni method. The bottom panel depicts the areas of the PLVA regions determined as evolving under episodic diversifying selection. All segments under an option were in ~ the 3′ finish of the genome and included multiple loci within env and vif. Previously defined recombination breakpoints are indicated by arrows. The complete PLVA genome is outlined listed below for reference.

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The many common type of nucleotide substitution in 3 of 4 groups of master (California bobcats, California mountain lions, and Florida panthers) to be an A-to-G readjust (Table 1). G-to-A transitions to be slightly an ext common in ~ bobcat isolates from Florida, yet we did not determine a far-ranging bias for G-to-A substitutions in any type of group (Table 2).