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The prevalent status and genetic diversity of porcine reproductive and respiratory syndrome virus in China: a molecular epidemiological perspective

  • Zhenhua Guo1Email author,
  • Xin-xin Chen1,
  • Rui Li1,
  • Songlin Qiao1 and
  • Gaiping Zhang1, 2, 3
Contributed equally
Virology Journal201815:2

https://doi.org/10.1186/s12985-017-0910-6

Received: 30 October 2017

Accepted: 12 December 2017

Published: 4 January 2018

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) has been epidemic more than 30 years in America and 20 years in China. It is still one of the most important causative agents to the worldwide swine industry. Here, we systematically analyzed the prevalence status of PRRSV in China by a molecular epidemiological perspective. Now both PRRSV-1 and PRRSV-2 are circulating and approximately more than 80% of pig farms are seropositive for PRRSV. For PRRSV-2, there are four lineages (lineage 1, lineage 3, lineage 5, lineage 8) circulating in the fields. Lineage 8 (CH-1a-like) and lineage 5 (BJ-4-like) appeared almost at the same time during 1995-1996. Notably, BJ-4 shares 99.6% and 99.8% identity with VR2332 and RespPRRS MLV, respectively. It means that lineage 5 is likely to be imported from America. Now highly pathogenic PRRSV (HP-PRRSV) which was considered to be evolved from local diversity of lineage 8 strains is predominant with different variants. Lineage 3 appeared in 2010 which is mainly sporadic in south of China. Lineage 1, also known as NADC30-like strains in China, has been prevalent since 2013 and leads to PRRS pandemic again. For PRRSV-1, although sporadic at present, more than 9 provinces/regions have been reported. All the circulating strains belong to subtype I. It should be paid more attention since there are no vaccines available. Our analysis would help to deeply understand the prevalent status of PRRSV in China and provide useful information for prevention and control of porcine reproductive and respiratory syndrome (PRRS).

Keywords

Porcine reproductive and respiratory syndrome virus (PRRSV)Molecular epidemiologyPRRSV-1PRRSV-2Control strategies

Background

Porcine reproductive and respiratory syndrome (PRRS) is one of the most important economically diseases to the swine industry worldwide. It is estimated that the total economic losses caused by PRRS is about $664 million annually in the America, an increase from the $560 million annual cost estimated in 2005 [1]. PRRS was firstly described in America in 1987 [2], followed in Europe and Asia (1990-1992) [36]. The causative agent, porcine reproductive and respiratory syndrome virus (PRRSV), was isolated in 1991 in the Netherlands and 1992 in the United States with originally isolated strains named Lelystad Virus (the European prototypic strain) and Swine Infertility and Respiratory Syndrome (SIRS) virus (also known as ATCC VR-2332, the North American prototypic strain), respectively [7, 8]. The retrospective studies showed that the conserved serum samples were PRRSV antibody positive as early as 1979 in Canada [9]. It suggested that PRRSV had already circulated in swine population before 1979.

PRRSV is an enveloped, single positive-stranded RNA virus. It belongs to the family Arteriviridae of the order Nidovirales along with equine arteritis virus, lactate dehydrogenase-elevating virus and simian hemorrhagic fever virus [10]. Its genome size is about 15.4 kb, which contains at least 10 open reading frames (ORFs) flanked by two untranslated regions 5′ and 3′ (5’UTR-ORF1a-ORF1b-ORF2a-ORF2b-ORF3-ORF4-ORF5/ORF5a-ORF6-ORF7-3’UTR). ORF1a and ORF1b encode two large polypeptides which produce 14 non-structural proteins by the viral enzymatic cleavage. ORF2 through ORF7 code eight structural proteins including GP2, E, GP3, GP4, GP5a, GP5, M and N [1114]. Among them, ORF5 (gp5) is usually used for phylogenetic analyses because of its high variability. There are two genotypes of PRRSV: PRRSV-1 (European type) and PRRSV-2 (North American type) [15, 16]. Although these two types of PRRSV cause similar clinical disease to the infected pigs, they share only 55–70% nucleotide and 50–80% amino acid similarity in their various genes [17].

High genetic diversity is a significant characteristic of PPRSV. Mang Shi et al. constructed the global classification system of PRRSV based on the comprehensive analysis of the complete ORF5 gene sequence. According to the classification system, the PRRSV-1 was divided into three subtypes (subtype 1-3) and the PRRSV-2 was classified as 9 lineages with several sublineages of each lineage [18, 19]. The virulence and antigenicity are also different and variable due to the genetic diversity. There are several highly pathogenic PRRSV (HP-PRRSV) strains which cause severe reproductive and/or respiratory diseases and the emergence of new HP-PRRSV often leads to the widespread re-pandemic of PRRS. For example, although the vaccine was used in the late 1990s, the “abortion storm” swept through the America and an atypical PRRSV strain MN184 was isolated in 2001 [20, 21]. In Eastern Europe, a highly pathogenic PRRSV, Lena strain, was reported by Belarus in 2010 [22]. In China, the emergence of HP-PRRSV variants in 2006 led to atypical PRRS pandemics and 20% mortality in pigs [23]. Since 2013, PRRS became prevalent again in China caused by new PRRSV variants, NADC30-like strains, which are considered to be imported from North American and adapted in China [24, 25].

Here, we retrospectively and phylogenetically analyzed the prevalence and genetic diversity of PRRSV in China through a molecular epidemiological perspective. We hope to provide valuable information and new insights for the PRRSV epidemic trends and control strategies. Genome analyses were performed using the DNASTAR package. The unrooted phylogenetic tree was generated by the distance-based neighbor-joining method using MEGA 6.0 and the amino acid sequences were aligned by Clustal W method (MEGA 6.0) [26]. The recombination events were detected by RDP4 program using seven different algorithms (RDP, GeneConv, BootScan, MaxChi, Chimera, SiScanm and 3Seq) with Bonferroni correction and a highest acceptable p-value of 0.01 [27].

PRRSV history and prevalent status in China

PRRS was firstly described in 1995 in China and the etiological agent, PRRSV, was isolated by Guo et al. (1996) and Yang et al. (1997). The isolated strains were named CH-1a (Genbank ID: AY032626) and BJ-4 (Genbank ID: AF331831), respectively. Both of them belong to PRRSV-2 [28, 29]. Serological studies showed that the percent of positive serum is more than 40% in the east and north of China [30], and it means that PRRSV circulated in China earlier than 1995. It is not clear how the PRRSV was introduced into pig population in China. One possibility is the import of breeding pigs. The evidences are: (i) Chen et al. (1996) successfully isolated PRRSV strain from the imported breeding pigs from Canada [31]; (ii) The genome homology of BJ-4 with VR2332 is about 99.6% and the genome homology of CH-1a with JA142 (Genbank ID: AY424271) is about 94.5%. Both of them (especially BJ-4) are closely related to North American isolates and PRRSV was endemic during 1995~2005.

During the summer of 2006, a new PRRSV variant, also known as highly pathogenic PRRSV (HP-PRRSV), caused atypical PRRS and led to a devastating destruction to swine industry with 20% motality to pigs. The new PRRSV variants show a unique discontinuous 30 amino acids (482aa, 534-562aa) deletion in Nsp2 gene [22]. The representative virus strains are JXA1 (Genbank ID: EF112445), TJ (Genbank ID: EU860248) and HuN4 (Genbank ID: EF635006) which are also the parent strains for attenuated vaccine strains JXA1-R, TJM-F92 and HuN4-F112, respectively [3234]. The HP-PRRSV-like strains are predominantly epidemic strains in the pig farms after 2006. Since 2013, there was a markedly increased PRRSV infection during routinely clinical investigation. The reason for this re-pandemic of PRRS is considered as the emergence of NADC30-like strains which were probably imported from North America and went though extensive variation in China [24, 25, 35]. Now both HP-PRRSV-like and NADC30-like strains are mainly circulating in the fields and have a high clinical detection rate.

For the PRRSV-1, B13 (Genbank ID: AY633973) was the earliest strain reported in China. It was conserved in Dalian Animal and Plant Quarantine Bureau, whose original source is not clear [36]. The retrospective studies showed that the PRRSV-1 strains could be detected from clinical samples as early as 2006 in mainland of China [37]. And now they are sporadic in more than nine provinces/regions (Inner Mongolia, Heilongjiang, Liao-ning, Beijing, Fujian, Guizhou, Guangdong, Shanghai, Hong Kong) [38]. We should pay more attention to the prevalence of European type in China since more and more clinical investigation reported their existence and there are no authorised vaccines yet.

The epidemic of PRRSV-2 in China

Based on the global PRRSV classification system and ORF5 sequence information in the Genbank, we chose 127 PRRSV-2 ORF5 sequences, including 9 reference strains and 118 prevalent strains (Table 1). As shown in Fig. 1, the prevalent PRRSV-2 strains in China were clustered into four lineages: lineage 1, lineage 3, lineage 5 (sublineage 5.1) and lineage 8 (sublineage 8.7). Lineage 8 is predominant since the emergence of PRRSV in China which included classical PRRSV strains (CH-1a-like) prevalent before 2006 and HP-PRRSV-like strains prevalent after 2006. The epidemic of lineage 1, also known as NADC30-like strains, which spread rapidly around the country since 2013 and now the clinical detection rate is comparable with lineage 8 (HP-PRRSV-like). Lineage 3 was another newly emerged variants since 2010 which is mainly circulating in south of China (Jiangxi, Fujian, Guangdong, Guangxi) and the clinical detection rate is less than 10% [39, 40]. Although the lineage 5 (BJ-4-like/VR2332-like) appeared as early as in 1996, it is always non-pandemic in China and the clinical detection rate is low. It is still a puzzle that how the lineage 8 (HP-PRRSV-like) and lineage 1 (NADC30-like) become the major epidemic strains, while lineage 8 (CH-1a-like) and lineage 5 are always endemic in China. One reasonable explain is that HP-PRRSV-like and NADC30-like strains show high genetic variations and incidence of recombination, compared with lineage 8 (CH-1a-like) and lineage 5. These characteristics probably made current vaccines ineffective and confer them much easier to escape the immune surveillance. Thus, they adapted well during the pig populations.
Table 1

The reference sequence information of PRRSV-2

No.

Virus strain

Origin

Accession no.

No.

Virus strain

Origin

Accession no.

1

ATCC VR2332

USA, 1992

U87392

40

HN2007

China, 2008

EU880437

2

RespPRRS MLV

USA, 1994

AF066183

41

SX2007

China, 2008

EU880434

3

SDSU73

USA, 1996

JN654458

42

SD-CXA/2008

China, 2008

GQ359108

4

JA142

USA, 1997

AY424271

43

XL2008

China, 2008

EU880436

5

Ingelvac ATP

USA, 1999

DQ988080

44

YN2008

China, 2008

EU880435

6

MN184A

USA, 2001

DQ176019

45

GS2008

China, 2008

EU880431

7

P129

USA, 2002

AF494042

46

PRRSV01

China, 2008

FJ175687

8

NADC30

USA, 2008

JN654459

47

KP

China, 2008

GU232735

9

NADC31

USA, 2008

JN660150

48

YN9

China, 2008

GU232738

10

CH-1a

China, 1996

AY032626

49

JN-HS

China, 2008

HM016158

11

CH-1R

China, 2008

EU807840

50

GDBY1

China, 2008

GQ374442

12

BJ-4

China, 1996

AF331831

51

ZP-1

China, 2009

HM016159

13

S1

China, 1999

DQ459471

52

SD1-100

China, 2009

GQ914997

14

SCQ

China, 2000

DQ379479

53

GS2002

China, 2009

EU880441

15

HB-1(sh)/2002

China, 2001

AY150312

54

CH2002

China, 2009

EU880438

16

HB-2(sh)/2002

China, 2001

AY262352

55

YD

China, 2009

JF748717

17

HB-1/3.9c

China, 2002

HQ233605

56

SX-1

China, 2009

GQ857656

18

GS2003

China, 2003

EU880442

57

SY0909

China, 2009

HQ315837

19

HN1

China, 2003

AY457635

58

09HEB

China, 2009

JF268679

20

Henan2

China, 2004

AY613349

59

09HEN1

China, 2009

JF268684

21

NB-04

China, 2004

FJ536165

60

09HUB1

China, 2009

JF268682

22

FJ04A

China, 2004

DQ246451

61

HN-0902

China, 2009

JX162590

23

SHB

China, 2005

EU864232

62

HN-09

China, 2009

JX174280

24

JXA1

China, 2006

EF112445

63

SD0901

China, 2009

JN256115

25

JXA1-p80

China, 2008

FJ548853

64

DC

China, 2010

JF748718

26

JXA1-P120

China, 2009

KC422727

65

GX1003

China, 2010

JX912249

27

JXA1-P170

China, 2009

JQ804986

66

QY2010

China, 2010

JQ743666

28

HuN4

China, 2006

EF635006

67

10-10HEB-3

China, 2010

JQ663553

29

TJ

China, 2006

EU860248

68

Shanxi-6

China, 2010

KJ855518

30

HEB1

China, 2006

EF112447

69

GX1001

China, 2010

JQ955657

31

R98

China, 2006

DQ355796

70

10-FUJ-2

China, 2010

JQ663547

32

HUB1

China, 2006

EF075945

71

10-FUJ-1

China, 2010

JQ663546

33

BJ0706

China, 2007

GQ351601

72

JX

China, 2010

JX317649

34

GD

China, 2007

EU825724

73

GM2

China, 2011

JN662424

35

WUH1

China, 2007

EU187484

74

QYYZ

China, 2011

JQ308798

36

Henan-1

China, 2007

EU200962

75

GD-2011

China, 2011

KC527830

37

NM1

China, 2007

EU860249

76

NJ-1106

China, 2011

JX880029

38

GDQJ

China, 2007

GQ374441

77

NVDC-JS2-2011

China, 2011

JQ715698

39

NT0801

China, 2008

HQ315836

78

HH08

China, 2011

JX679179

79

SDA3

China, 2011

JX878380

104

CHsx1401

China, 2014

KP861625

80

SDA2

China, 2011

JX878379

105

14LY01-FJ

China, 2014

KP780881

81

WUH4

China, 2011

JQ326271

106

14LY02-FJ

China, 2014

KP780882

82

YN-2011

China, 2011

JX857698

107

TJbd14-1

China, 2014

KP742986

83

HZ-31

China, 2012

KC445138

108

HENZMD-1

China, 2014

KT424216

84

GX1002

China, 2012

JQ955658

109

HENJZ-2

China, 2014

KT424217

85

SD16

China, 2012

JX087437

110

HENZK-2

China, 2014

KT424218

86

10-10JL

China, 2012

JQ663554

111

GDsg

China, 2015

KX621003

87

JL-04/12

China, 2012

JX177644

112

FJXS15

China, 2015

KX758250

88

SD16

China, 2012

JX087437

113

TJnh1501

China, 2015

KX510269

89

FJFS

China, 2012

KP998476

114

HNjZ15

China, 2015

KT945017

90

NT1

China, 2012

KP179402

115

HNyc15

China, 2015

KT945018

91

MY-376

China, 2013

KJ609517

116

JL580

China, 2015

KR706343

92

Henan-A4

China, 2013

KJ534539

117

HLJ58

China, 2015

KR706344

93

HeNan-A1

China, 2013

KJ002451

118

HENXC-4

China, 2015

KU950371

94

HENAN-HEB

China, 2013

KF416334

119

JXja15

China, 2015

KR149645

95

HENAN-XINX

China, 2013

KF611905

120

15LY01-FJ

China, 2015

KU215416

96

HLJA1

China, 2013

KT351739

121

15LY02-FJ

China, 2015

KU215417

97

HENAN-LUOY

China, 2013

KF416330

122

FZ16A

China, 2016

KY761966

98

FJZ03

China, 2013

KP860909

123

HeNhx

China, 2016

KX766379

99

FJW05

China, 2013

KP860911

124

HeNws16

China, 2016

MF474322

100

FJ1402

China, 2014

KX169191

125

HeNzm1-16

China, 2016

MF474323

101

HENJZ-2

China, 2014

KT424217

126

HeNzm2-16

China, 2016

MF474324

102

HENPDS-1

China, 2014

KT424228

127

HeNmz16

China, 2016

MF474321

103

FJ1405

China, 2014

KM453701

    
Figure 1
Fig. 1

The phylogenetic analysis based on ORF5 genes from 127 reference virus strains of PRRSV-2. The unrooted phylogenetic tree was constructed using the distanced-based neighbor-joining method in MEGA6.0 with bootstrap values (1000 replicates). The PRRSV-2 circulating in China were clustered into four lineages. Lineage 8 is predominant in 1996-2016 in China and could be further subdivided into five subgroups. Lineage 1 spreads rapidly since 2013 in China. The lineages are according to previous report. The circles () indicate the representative virus strains of each lineage in China. The triangles (▲) mean the attenuated live vaccine strains or vaccine derivatives. The squares (■) represent two transition virus strains

Lineage 8/sublineage 8.7

According to the phylogenetic assay of ORF5 sequence, sublineage 8.7 could be divided into five subgroups—subgroup I~subgroup V (Fig. 1). Subgroup I is PRRSV strains that are closely related with CH-1a. CH-1a was the first isolated PRRSV strain in China and was recognized as an ancestor strain of classical PRRSV. The genome homology is 94.5% with JA142 (Genbank ID: AY424271) and SDSU73 (Genbank ID: JN654458) (sublineage 8.9) and 91.5% with VR2332 (sublineage 5.1). Subgroup II was considered as intermediate subgroup between classical and HP-PRRSV. BJ0706 (Genbank ID: GQ351601) and NB-04 (Genbank ID: FJ536165) were the representative strains of transition [41]. They have been found 1aa deletion at the 481th residue site in Nsp2 gene and they showed a genome identity of 95.1~95.8% with CH-1a and 97.1~98% with JXA1. Subgroup III~V belong to HP-PRRSV derivative strains or HP-PRRSV vaccine derivative strains. HP-PRRSV leaded to the outbreak of PRRS in China in 2006. The representative strains JXA1, TJ, HuN4 show 95.3% of genome homology with CH-1a and 89.6% with BJ-4. At present more consistent view is that HP-PRRSV is originated from lineage8 strains that have been circulating in China for about 10 years before the outbreak in 2006 [19]. The genetic diversity is still expanding and shows different evolutionary clusters following circulation of HP-PRRSV and extensive vaccination of modified live vaccines (JXA1-R, TJM-F92, HuN4-F112). Subgroup III is genetically closer with JXA1, also called JXA1-like group. Subgroup IV is evolutionarily close to TJ and HuN4 strains. Subgroup V is closely related with HP-PRRSV attenuated live vaccines. Considering modified live vaccines could circulate in the fields, it is expected to see many vaccines related sequences. And this also pose a challenge for a rapidly accurate diagnosis and control of PRRS.

Lineage 5/sublineage 5.1 and lineage 3

Sublineage 5.1 appeared very early in China. The representative strain BJ-4 was isolated by Yang et al. in 1997 [29]. It shows 99.6% and 99.8% of genome homology with VR2332 and RespPRRS MLV (Boehringer Ingelheim, Germany), respectively. It suggests that sublineage 5.1 is more likely to be imported into China from North American. It is still not known why the prevalence of sublineage 5.1 is limited compared with lineage 8. Lineage 3 was firstly reported in 2010 and considered as a novel lineage originally [42, 43]. It is mainly endemic in southeast of China (Jiangxi, Fujian, Guangdong, Guangxi) [38]. The representative strains GM2 (Genbank ID: JN662424) and QYYZ (Genbank ID: JQ308798) show 86.2~88.7% of genome homology with VR2332, CH-1a, BJ-4 and JXA1. Lineage 3 is genetically distant from previous epidemic strains and its source remains to be further clarified. Clinical detection rate of both sublineage 5.1 and lineage 3 is less than 10%.

Lineage 1

Lineage 1, also known as NADC30-like strains, has been reported since 2013 in China [44]. Now it’s epidemic in more than nine provinces/regions including northeast, southeast, central and east of China. The clinical detection rate is increasing every year and up to 50% in Henan Province [45]. The representative virus strain HENAN-XINX (Genbank ID: KF611905) and JL580 (Genbank ID: KR706343) share 86.7~87.8% genome homology with MN184A (Genbank ID: DQ176019) isolated in 2001 in America, 92.8~95.4% with NADC30 isolated in 2008 in America and 82.2~87.2% with CH-1a, BJ-4, JXA1 and QYYZ. Like MN184A and NADC30, the NADC30-like virus strain in China shows the identical deletion pattern of nsp2 including 131aa discontinuous deletion. NADC30 is likely to be introduced into China by import of breeding pigs [24, 25, 35].

Compared with the other PRRSV lineages in China, NADC30-like strains show more recombination possibilities and pathogenic diversity (Table 2). There are several reports about the recombination of NADC30-like strains including NADC30 with HP-PRRSV [24, 4648], NADC30 with vaccine strain (TJM-like, JXA1-P80) [4951] and with classical PRRSV (CH-1a, VR2332) [48, 52]. Besides, lineage 8 and lineage 3 also display different degrees of recombination [53, 54]. For the virulence difference, some NADC30-like strains (JL580, FJ1402 etc.) show high pathogenicity comparable with HP-PRRSV [24, 47, 51]. Some NADC30-like strains (TJnh1501, HNjz15 etc.) display intermediate virulence similar to the prototype strain-NADC30 [49, 55]. A reasonable explanation is that NADC30 underwent extensive mutations and recombination since it was introduced into China. Especially the exchange of gene fragment from different circulating strains which endow new biological characteristics to different variants, for example, the change of pathogenicity and antigenicity.

The epidemic of PRRSV-1 in China

Although there are more recent reports about the prevalence of European type PRRSV in China, the clinical detection rate is still low [37, 5658]. Now the research mainly focuses on the molecular epidemiology of PRSSV-1 in China. Here we did a genetic diversity assay based on the ORF5 sequence by choosing 20 strains isolated in China and 23 reference strains (Table 3). The results showed all the Chinese isolated strains belong to subtype 1 (pan-European type) and could be further divided into four subgroups (Fig. 2). Our analysis may provide valuble information for the classification of future PRRSV-1 strains for other researchers.
Table 2

The recombinant virus strains and the recombination regions

No.

Recombinant strains

Major parent

Minor parent

Recombination regions

Virulence

Reference

1

JL580a

NADC30a

HP-PRRSV (09HEN1)

Nsp2, Nsp3~Nsp7, ORF2a~ORF4

Highly Pathogenic

[23]

2

FJ1402a

NADC30a

HP-PRRSV (GD)

Nsp2~Nsp3, Nsp12~ORF3

Highly Pathogenic

[47]

3

HENAN-HEBa

15HEN1a

HP-PRRSV (JXA1)

Nsp2

 

[48]

4

TJnh1501a

CHsx1401a

TJbd14-1b

Nsp2

intermediate virulence

[49]

5

FJW05a

JXA1-P80b

FJZ03a

Nsp1-ORF5

Highly Pathogenic

[50]

6

FJXS15a

[51]

7

HNhxa

HENAN-HEBa

HP-PRRSV (JXA1)

Nsp4~Nsp9

 

[46]

8

HNyc15a

15SC3a

CH-1a/VR2332

ORF2~ORF4

 

[52]

9

HENAN-XINXa

NADC30a

VR-2332

Nsp2~Nsp5

 

[48]

10

Chsx1401a

HENAN-XINXa

VR-2332

Nsp11

intermediate virulence

[49]

11

SY0909

HP-PRRSV (JXA1)

NT0801

Nsp12~ORF5

 

This study

12

GDsg

QYYZ

JXA1-P80b

Nsp9~Nsp11

 

[82]

13

GM2

QYYZ

RespPRRS MLVb

Nsp7~Nsp11

 

[54]

14

HB-1(sh)/2002

HB-1/3.9c

CH-1a

ORF2a~ORF4

 

This study

15

HNjz15

/

/

/

intermediate virulence

[55]

a” means NADC30 or NADC30-like virus strains. “b” indicates modified live vaccine strains or vaccine derivative strain. The recombination events were detected by RDP4 program using seven different algorithms (RDP, GeneConv, BootScan, MaxChi, Chimera, SiScanm and 3Seq)

Figure 2
Fig. 2

The phylogenetic assay based on ORF5 gene sequences of PRRSV-1. All the Chinese isolated strains belong to subtype 1 (pan-European) and can be classified into 4 subgroups according to the phylogenetic relationships. The Chinese PRRSV strains are marked with black circles ()

Table 3

The reference sequence information of PRRSV-1

No.

Virus strain

Origin

Accession no.

Subtype

No.

Virus strain

Origin

Accession no.

Subtype

1

Lelystad

Netherlands, 1991

M96262

Subtype1

23

SDRPIV4A

France, 1992

AY035919

Subtype1

2

BJEU06-1

Beijing, China, 2006

GU047344

Subtype1

24

NY3-D769

England, 1992

AY035940

Subtype1

3

NMEU09-1

Inner Mongolia, China, 2009

GU047345

Subtype1

25

L1-D767

England, 1992

AY035939

Subtype1

4

NMEU09-2

Inner Mongolia, China, 2009

GU047340

Subtype1

26

24,554

Denmark, 1997

AY035910

Subtype1

5

SHE

Shanghai, China, 2009

GQ461593

Subtype1

27

28,639

Denmark, 1998

AY035912

Subtype1

6

NVDC-NM1

Inner Mongolia, China, 2011

JX187609

Subtype1

28

LV4.2.1

Netherlands, 2004

AY588319

Subtype1

7

NVDC-NM2

Inner Mongolia, China, 2011

KC492504

Subtype1

29

EuroPRRSV

USA, 1999

AY366525

Subtype1

8

NVDC-NM3

Inner Mongolia, China, 2011

KC492505

Subtype1

30

SD-01-08

USA, 2001

DQ489311

Subtype1

9

NVDC-FJ

Fujian, China, 2011

KC492506

Subtype1

31

MN-03-08_EU

USA, 2003

AY749385

Subtype1

10

FJEU13

Fujian, China, 2013

KP860912

Subtype1

32

MN-03-10_EU

USA, 2003

AY749389

Subtype1

11

FJQEU14

Fujian, China, 2014

KP860913

Subtype1

33

SDPRRS 04-40

USA, 2004

EF175566

Subtype1

12

B13

China, 1999

AY633973

Subtype1

34

SDPRRS 04-48

USA, 2004

AY749411

Subtype1

13

FJ0603

Fujian, China, 2006

HM114313

Subtype1

35

Amervac

Spain,Vaccine

GU067771

Subtype1

14

GZ11-G1

Guizhou, China, 2011

KF001144

Subtype1

36

BH_95/10-12

Germany, 2006

JN651738

Subtype1

15

LNEU12

Liaoning, China, 2012

KM196101

Subtype1

37

2.46

Germany, 1993

AY035923

Subtype1

16

HKEU16

Hong Kong, China, 2007

EU076704

Subtype1

38

Vas

Belarus, 2005

DQ324689

Subtype2

17

HLJB1

Heilongjiang, China, 2014

KT224385

Subtype1

39

SHV

Russia, 2006

EU071236

Subtype2

18

HK3

Hong Kong, China, 2003

KF287129

Subtype1

40

Bor-41

Belarus, 2004

DQ324671

Subtype2

19

HK5

Hong Kong, China, 2004

KF287130

Subtype1

41

Lena

Belarus, 2007

JF802085

Subtype3

20

HK10

Hong Kong, China, 2004

KF287131

Subtype1

42

Zad-1

Belarus, 2004

DQ324694

Subtype3

21`

FJ0602

Fujian, China, 2006

HM755885

Subtype1

43

SOZ-6

Belarus, 2004

DQ324686

Subtype3

22

SDRPV4A

France, 1993

AY035920

Subtype1

     

Genetic variation

The genome homology between Chinese isolated strains and Lelystad virus ranges from 85.9% to 92.7%, and the similarity of ORF5 with Lelystad virus is about 83.5~94.6% except the B13 which shows 99.7%, only two nucleotides different from Lelystad virus. It suggests that B13 may be isolated from import breeding pigs or as a standard reference strain from some western European countries. Considering the close communication of pig breeding between China and Europe, it is not surprising to see the appearance of PRRSV-1 in China. As the phylogenetic tree showed, The Chinese PRRSV-1 isolations are further clustered into four subgroups. Subgroup I was closely related with Amervac PRRSV virus, a live vaccine virus of PRRSV-1 and SHE, a rescued virus from an infectious clone of Amervac PRRS virus. Subgroup II was mainly limited in HongKong and it is geographically restrictive. Subgroup III is NMEU09-1/2-like isolates and subgroup IV is BJEU06-1-like strains. According to the amino acid alignment of ORF5 (Fig. 3), the 8/60/63/106 sites were highly variable which have 3 to 7 different amino acid mutations. The 37 (N/DLV), 100 (V/TLV), 101 (T/ALV), 112 (S/CLV), 123 (L/FLV), 155 (I/VLV), 173 (G/DLV) and 175 (D/NLV) are much conserved mutations in Chinese virus strains.
Figure 3
Fig. 3

The amino acid alignment of ORF5 for PRRSV-1. The amino acid sequences were aligned by Clustal W method in MEGA 6.0. The signal sequence(1-32aa) and hypervariable domains (33-67aa, 89-110aa) were indicated by solid boxes. Potential N-glycosylation sites were shown in the red boxes. The hypervariable mutation sites were marked with dark spot () and the highly conserved mutation sites were indicated by asterisk (*)

N protein polymorphism

Normally the N protein is highly conserved. In genotype 1 PRRSV, N protein, as well as the high variable ORF5 and Nsp2 genes, is found to be very pleomorphic. The length of N protein ranges from 124 to 132aa [5961]. Concretely, subtype 1 is 128aa (occasional 126/129/132aa), subtype 2 is 125aa (occasional 124/131aa), while subtype 3 is 124aa (occasional 128aa) [62]. In China, the N protein length of all the isolates is 128aa excepted NVDC-NM2 (Genbank ID: KC492504) strain which is 129aa and a Ser was inserted between 87th and 88th site. Based on the alignment assay (Fig. 4), the 13 (N/SLV), 100(G/SLV), 128(N/SLV) sites are conserved mutations among Chinese isolated virus strains.
Figure 4
Fig. 4

The alignment assay based on amino acid sequence of N protein for PRRSV-1. The sequence alignment was performed using Clustal W method. A2-12, B25-30, C40-46, D51-67 and D80-90 represent known epitopes in N protein; E50-58, E64-72, E105-113 and E113-121 indicate four porcine T –cell epitopes. The insertion site of amino acid was indicated by triangle (). The highly conserved mutation sites in Chinese PRRSV-1 strains were marked with asterisk (*)

Pathogenicity and recombination

To our knowledge, until now only two Chinese PRRSV-1 isolations, GZ11-G1 and HLJB1, to be evaluated the pathigenicity. These two strains are pathogenic to piglets and can lead to classic PRRSV-specific lesions. The infectious pigs showed mild clinical signs and no pigs died, which indicated they are less virulent [58, 63]. Interestingly, both of them belong to subgroup I—the Amervac PRRSV vaccine-related strains. HLJB1 and GZ11-G1 show 91.64% and 96.3% genome homology with the Amervac PRRSV virus, respectively [58, 63]. Additionally, recombination analyses showed that HLJB1 is a recombinant from the Amervac vaccine and the BJEU06-1 isolate [64]. It is necessary to routinely monitor the prevalence of PRRSV-1 in the fields and more research needs bo be done for better understanding the biological and pathogenic characteristics of PRRSV-1 in China.

Control strategies

Vaccination

It is still a controversial question about the usage of PRRSV vaccines. On one hand, the vaccine efficiency is low or not significant from the clinical observation. On the other hand, there are no better choices currently under the circumstances of PRRSV pandemics. In China, there are more than seven commercial PRRSV vaccines (CH-1a/CH-1R, VR2332/Ingelvac PRRS MLV, R98/R98 MLV, JXA1/JXA1-R, TJ/TJM-F92, HuN4/HuN4-F112, GD/GDr180, etc) used. These vaccines are effective in reducing clinical signs, decreasing viremia and shortening duration of viral shedding. They can provide an efficient protection against a lethal challenge with their respective parental HP-PRRSV isolates [3234, 6567]. However, they can not completely prevent infection and establish sterilizing immunity. Also, the vaccine efficiency significantly decreases against heterologous challenge, and they can only provide partial or limited protection [47, 65, 68, 69]. The outbreak of HP-PRRSV in 2006 is in the backgroud of vaccination with CH-1a and Ingelvac PRRS MLV. Since 2013, NADC30-like virus strains transmitted quickly around herds in China although massive vaccination with all the commercial vaccines.

Massive vaccination with live attenuated vaccines also leads to safety concern and more genetic divergence: (i) It has been demonstrated that vaccine viruses could spread from vaccinated pigs to non-vaccinated, suggesting their ability to circulate in the fields and form different vaccine-associated clusters [70, 71]; (ii) The extensive immune pressure maybe serve as a major driving force which greatly promotes genetic diversity of genotype 2 in China [72]; (iii) Revertants from the vaccine derivatives should be paid more attention to. Indeed, there are several reports about the attenuated vaccine reverting to a virulent type [49, 73]; (iv) The frequency of recombination is increasing, especially the emergence of NADC30-like virus strains (lineage1) which display a wide broad recombination ability with HP-PRRSV (JXA1), classical PRRSV (CH-1a,VR2332) and attenuated vaccines (JXA1-P80, TJM-F92-like) [46, 49, 52, 74]. It has been verified that recombination is associated with re-prevalence of HP-PRRSV during 2009 to 2010 and closely related with the pandemic of NADC30-like virus since 2013 in China [24, 53]. Accordingly, veterinarians and farmers become more cautious and re-evaluate the previous immune strategies. Some farmers are trying to reduce and stop the vaccination of PRRSV in China by taking other comprehensive PRRS prevention and control measures.

Production system and biosecurity

It is confirmed that multiple production sites and high quality biosecurity system are important in PRRSV prevention and control [75, 76]. Due to historical reasons, most of Chinese pig farms are one production site and the layout of gestation, farrowing, nursery and growing are also not reasonable. Many farms are still continuous flow sites and lack good biosecurity system. Following the development of swine production in China, more and more pig producers have recognized the significance of management, production system, environment control and good biosecurity. They have changed their views that only or over-dependent vaccination could prevent porcine diseases and would like to invest more in nutrition, management, environment, biosecurity and application of new technologies. For example, air-filtration ventilation systems were used by some breeding companines; gilts acclimation and strict batch production (also known as “All in All out”, AIAO) were accepted and implemented by more commercial pig farms.

The strategy of “load, close, homogenise” (LCH)

The load, close, homogenise (LCH) strategy (also known as load, close, expose) was extensively accepted in PRRV control and elimination for it’s inexpensive and easy operability [75, 77, 78]. To perform this strategy, the producer should load enough gilts once for minimum of 200 days and then implement herd closure. The key points are gilts acclimation and good biosecurity system. Poul H. Rathkjen and Johannes Dall summarized ten golden rules for biosecurity management and showed a good model for successful implement of LCH [76]. Uniform PRRS status could be achieved either by simultaneous vaccination or by inoculation with serum containing resident virus. Notably, it should be very cautious when used the virus positive serum for acclimation because of the virulence of HP-PRRSV.

It is a better choice to build regional elimination of PRRSV. This model was successfully implemented in the state of Minnesota of the United States and in Horne Peninsula of the Denmark [75, 76]. They are good examples for HP-PRRSV regional elimination in China. This project needs close collaboration among veterinarians, pig producers and regional governments.

Future perspective

Based on the ORF5 sequence analysis of PRRSV, we systematically retrospect the history and prevalence of PRRSV in China from a molecular perspective. PRRSV diverged earlier in the origin, and the early isolated strain CH-1a and BJ-4 only share 91.4% homology. CH-1a belongs to sublineage 8.7 and BJ-4 is clustered into sublineage 5.1. BJ-4 is likely to be imported from the North America or maybe as a vaccine strain since it shares 99.6% and 99.8% identity with VR2332 and RespPRRS MLV, respectively. It is still not clear why sublineage 5.1 is relatively stable and shows limited epidemicity. Nevertheless, sublineage8.7 is pandemic and goes through such genetic diversity, especially the emergence of HP-PRRSV which is devastating to swine production in China. Although the vaccines derived from HP-PRRSV play a role in reducing the severe clinical signs and slowing the prevalence of PRRS, it is still far away from expectation. And the massive usage of vaccines also lead to some side effects including virulence reversion of attenuated live vaccines [49, 73], markedly increase in virus recombination and variation [50, 53, 72, 74].

Recently, lineage 3 and lineage 1 are also circulating in Chinese swine herds. Lineage 3 is mainly limited in south of China (Jiangxi, Henan, Jiangsu, Guangdong, Guangxi) [38, 43]. Lineage 1 was firstly reported in Henan province in 2013 [45, 79], and then this lineage transmitted quickly in northeast, southeast, central and east of China. They lead to pandemic of PRRSV in China [38, 40, 80, 81]. The commercial vaccines seem not efficient since the dissemination of lineage 1 is under the background of massive vaccination. Several studies also show the commercial vaccines only provide limited or partial protection [38, 68, 69]. These facts prompt people to re-evaluate the strategies of prevention and control of PRRSV in China. And people become more cautious on massive vaccination. More and more farms try to improve management, biosecurity and environment instead of only over-dependent on vaccines.

Several studies showed the prevalence of PRRSV-1 in China, and up to 9 provinces and regions have been reported until now [38, 5658]. All the Chinese circulating strains share some special common amino acids compared with Lylestad virus. Although the PRRSV-1 PRRSV is sporadic in China, we should pay more attention since there are no vaccines to be provided.

It has been 30 years since the first PRRS report in 1987 in America. Originally, we call it Mystery Swine Disease (MSD) [3, 7]. Thirty years later, although we have a deep understanding on clinical onset characteristics of PRRS, molecular epidemiology, virus proliferation, pathogenic mechanism, immune response and immune escape mechanism, PRRSV is still mysterious to us and we have not found a successful prevention and eradication strategy. There are still more questions need to be elucidated: i) What is the molecular mechanism of high variation and recombination frequency of PRRSV; ii) The broad spectrum neutralizing antibodies need to be analyzed further; iii) It remains to be elucidated that determination factors of virulence difference among different PRRSV strains; iv) How to look for a new vaccine development strategy which is safe, high efficient and have a broad spectrum protection to different PRRSV lineages. The clarification of these problems would provide great help and support for ultimate PRRSV control.

Conclusion

PRRSV is still one of the most important causative agents to the swine production worldwide and causes huge economic losses every year. In China, although several commercial attenuated live vaccines have been widely used, PRRS is still severe in the pig industry. Moreover, the genetic diversity and complexity of PRRSV were further increasing. In this review, we systematically analyzed the PRRSV prevalent history and genetic evolution in China using a molecular epidemiological perspective. Additionally, we summarized the effective strategies and discussed the current problems in the prevention and control of PRRS. Our analysis would provide valuable information and new insights for the PRRSV epidemic trends and control strategies in China.

Abbreviations

HP-PRRSV: 

Highly pathogenic PRRSV

ORFs: 

Open reading frames

PRRS: 

Porcine reproductive and respiratory syndrome

PRRSV: 

PRRS virus

SIRS: 

Swine infertility and respiratory syndrome

UTR: 

Untranlated region

Declarations

Acknowledgements

Not applicable.

Funding

This work was funded by grants from the National Key Research and Development Progrom of China (2016YFD0500709), China Agriculture Research System (No.CARS 35).

Availability of data and materials

Not applicable.

Authors’ contributions

ZG and X-XC wrote the manuscript. RL and SQ revised the manuscript critically for important intellectual content. ZG and GZ conceived the outline and content of the review. All authors have read and approved the submitted manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Key Laboratory of Animal Immunology of the Ministry of Agriculture, Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, People’s Republic of China
(2)
College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, People’s Republic of China
(3)
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People’s Republic of China

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