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VIRAL IMMUNOLOGY Volume 17, Number 4, 2004 © Mary Ann Liebert, Inc. Pp. 481–497
Review Hantaviruses: Immunology, Treatment, and Prevention PIET MAES,1 JAN CLEMENT,1 IRINA GAVRILOVSKAYA,2 and MARC VAN RANST1
ABSTRACT Hantaviruses are rodent-borne bunyaviruses that are associated with two main clinical diseases in humans: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. It has been suggested that host-related immune mechanisms rather than direct viral cytopathology may be responsible for the principal abnormality (vascular dysfunction) in these syndromes. This review summarizes the current knowledge on hantaviral host immune responses, immune abnormalities, laboratory diagnosis, and antiviral therapy as well as the current approaches in vaccine development.
INTRODUCTION
A
N OUTBREAK in the early 1950s of Korean hemorrhagic fever (KHF), a form of hemorrhagic fever with renal syndrome (HFRS) that occurred on the front line of the Korean war, brought hantaviruses to the attention of the western world. During this conflict, more than 3000 United Nations soldiers were hospitalized as a result of an acute prostrating febrile illness with renal failure and shock (58). The mortality of the hospitalized soldiers was about 7% (138). Despite many research efforts, the agent of KHF remained unknown until 1978 when a new virus, Hantaan virus (HTNV), was isolated from its rodent host, Apodemus agrarius or striped field mouse (82). Soon thereafter, other hantaviruses were identified in Asia and Europe. Hantaviruses form a separate genus within the family of Bunyaviridae, forming a group of closely related negative-stranded RNA viruses (131). These viruses are lipid-enveloped, spherical viruses of about 80–110 nm in diameter with a trisegmented genome. The large (L) segment of approximately
1Laboratory 2Department
6500 nucleotides, encodes a RNA-dependent RNA polymerase; the medium (M) segment, approximately 3600 to 3800 nucleotides long, encodes two glycoproteins (G1 and G2) and the small (S) segment of approximately 1700–2100 nucleotides long, encodes a nucleocapsid protein (Np) (124,131,142). Minor open reading frames (ORF) have been reported in the genome of hantaviruses, but there is no evidence for any protein products (131). In contrast to viruses of the other four Bunyaviridae genera, hantaviruses are not transmitted to humans by an arthropod vector, but via aerosols of infected excreta (urine, faces, saliva) from chronically infected but apparently healthy small mammals, mainly wild rodents (97). Person-to-person transmission is presumed to be non existent, but has been described for Andes hantavirus (ANDV), causing high mortality (116). So far, more than 30 different hantavirus genotypes have been distinguished, whereas about 20 of them are of pathogenic relevance for humans (Table 1) (24,122). All known hantaviruses have been isolated from murid rodents (order of Rodentiae, family of Muridae) except Thottapalayam
of Clinical Virology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium. of Medicine, Stony Brook University, Stony Brook, New York.
481
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MAES ET AL. TABLE 1.
Hantavirus serotype Amur (AMRV) Andes (ANDV) Araraquara (ARAV) Bayou (BAYV) Bermejo (BRMV) Black Creen Canal (BCCV) Castelo dos Sonhos (CASV) Choclo (CHOV) Dobrava-Aa (DOBV-Aa) Dobrava-Af (DOBV-Af) Hantaan (HTNV) Hu39694 Juquitiba (JUQV) Laguna Negra (LNV) Lechiguanas (LECHV) Maciel (MACV) Monongahela (MONV) New York (NYV) Orán (ORNV) Puumala (PUUV) Rio Mamoré (RMV) Seoul (SEOV) Sin Nombre (SNV) Tula (TULV)
HANTAVIRUSES KNOWN
TO
BE PATHOGENIC
TO
HUMANS
Main rodent vector (geographic spread)
Disease
Apodemus peninsulae (Far Eastern Russia) Korean field mouse Oligoryzomys longicaudatus (Argentina, Chile, Uruguay) Long-tailed rice rat Unknown (Brazil) Oryzomys palustris (Louisiana) Marsh rice rat Oligoryzomys chacoensis (Central Argentina, Bolivia) Chacoan pygmy rice rat Sigmodon hispidus (Eastern and Southern USA, Venezuela, Peru) Hispid cotton rat Unknown (Brazil) Oligoryzomys fulvescens (Panama) Fulvous pygmy rice rat Apodemus Agrarius (Eastern, Northeastern and Central Europe) Striped field mouse Apodemus flavicollis (Balkan and Southeastern Europe, Middle-East) Yellow necked field mouse Apodemus agrarius (Asia, Eastern Russia, Southern Europe) Striped field mouse Unknown (Central Argentina) Unknown (Brazil) Calomys laucha (Paraguay, Bolivia) White paunch mouse Oligoryzomys flavescens (Central Argentina) Yellow pygmy rice rat Necromys benefactus (Central Argentina) Dark field mouse Peromyscus maniculatus nubiterrae (Canada, Eastern USA) Cloudland Deer mouse Peromyscus leucopus (Canada, Eastern USA) White-footed mouse Oligoryzomys longicaudatus (North Western Argentina) Long-tailed rice rat Clethrionomys glareolus (Eurasian continent) Red bank vole Oligoryzomys microtis (Bolivia, Peru) Small-eared rice rat Rattus norvegicus and Rattus rattus (Worldwide) Norway rat and Black rat Peromyscus maniculatus (Canada, USA) Deer mouse Microtus arvalis (Europe) Common vole
HFRS HPS HPS HPS HPS HPS HPS HPS HFRS HFRS HFRS HPS HPS HPS HPS HPS HPS HPS HPS NE HPS HFRS HPS HFRS
HFRS, hemorrhagic fever with renal syndrome; HPS, hantavirus pulmonary syndrome; NE, nephropathia epidemica.
(TPMV) (Fig. 1) (19,149). Topografov hantavirus (TOPV) and Khabarovsk hantavirus (KBRV) are viruses that have been isolated from eastern and central Europe, but have not been associated with a known human dis-
ease. These hantaviruses are genetically related to PUUV. HTNV is the prototype species of the genus Hantavirus and remains until now the epidemiologically most important species in the genus. In China alone, HTNV to-
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HANTAVIRUSES
483
FIG. 1. Neighbor joining phylogenetic tree of the complete coding region of the S segment of hantaviruses for which a complete nucleocapsid gene sequence is available. The virus groups carried by the Rodentiae family Arvicolinae, Sigmodontinae and Murinae, and by the Insectivorae family Suncus are indicated. Hantaviruses known to be pathogenic to man are written in bold. Genbank accession numbers of the S segment nucleotide sequences: Amur virus (AB127997), Andes virus (NC003466), Bayou virus (L36929), Black Creek Canal virus (L39949), Bermejo virus (AF482713), Dobrava virus Aa strain (AJ009773), Dobrava virus Af strain (AJ131673), El Moro Canyon virus (U11427), Hantaan virus (AB127998), Hu39694 virus (AF482711), Isla Vista virus (U19302), Khabarovsk virus (U35255), Laguna Negra virus (AF005727), Lechiguanas virus (AF482714), Maciel virus (AF482716), Monongahela virus (U32591), Muleshoe virus (U54575), Orán virus (AF482715), Pergamino virus (AF482717), Prospect Hill virus (M34011), Puumala virus (NC005224), Rio Segundo virus (U18100), Seoul virus (AY273791), Sin Nombre virus (NC005216), Tchoupitoulas virus (AF329389), Thottapalayam virus (AY526097), Topografov virus (AJ011646) and Tula virus (NC005227).
gether with Seoul hantavirus (SEOV) accounts for at least 100,000 cases of hantavirus-associated HFRS each year (23). Approximately 150,000 HFRS cases occur annually worldwide (23). In Europe, Dobrava hantavirus (DOBV), Puumala hantavirus (PUUV), and recently also Tula hantavirus (TULV) are known to cause HFRS (71,126). DOBV, found in the Balkans and Greece, seems to be the most virulent European hantavirus and can bear a fatality rate up to 12%, mainly due to severe hemorrhagic manifestations (8). Interestingly, two genetically closely related subspecies of DOBV are carried by two unrelated rodent species, the yellow-necked mouse (Apodemus flavicollis) and the striped field mouse (Apodemus agrarius) (72). In Southeastern Europe, Apodemus flavicollis is the natural reservoir for DOBV (DOBV-Af strain) (7). In the eastern, northeastern and central part of Europe,
DOBV is carried by Apodemus agrarius (DOBV-Aa strain) (126). Only recently, the first pathogenic DOBVAa case was molecularly identified in a patient suffering of HFRS (73). PUUV, which is carried by bank voles (Clethrionomys glareolus) and found almost throughout North and Central Europe, generally causes a milder form of HFRS, called nephropathia epidemica (NE), mainly characterized by fever and renal dysfunction, sometimes with hemorrhagic manifestations (79,90). In the New World, the first pathogenic hantaviruses to be isolated during the 1980s were all without exception SEOV strains (81). The first report of serologically confirmed cases were in fact SEOV-induced HFRS cases in Recife, Brazil, originally suspected of leptospiroris (46). In May 1993, a major outbreak of an acute respiratory syndrome with a high fatality rate, occurred in the southwestern part
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of the United States (34). This outbreak led to the discovery of Sin Nombre hantavirus (SNV) and other SNV-related hantaviruses, that cause hantavirus pulmonary syndrome (HPS) in the New World (47,113,118). Around 1,000 HPS cases have been reported so far, with a case fatality rate of 50% (24). However, milder lung involvement has been documented in European HFRS cases as well, consisting also of non-cardiogenic acute lung edema (21), that can occur even before the renal involvement (65).
HUMAN HANTAVIRUS DISEASE AND PATHOGENESIS Both HFRS and HPS are associated with acute thrombocytopenia and changes in vascular permeability, and both diseases may have pulmonary or renal symptoms (65,73,90,115). Hantaviruses cause diseases in humans but not in their animal hosts, and both pathogenic and nonpathogenic hantaviruses have the same tissue tropism, replicating predominantly in endothelial cells and macrophages (159). Although less distinct in HPS than in HFRS, the clinical course can be divided into five distinct phases and viremia is thought to occur subsequent to infection of alveolar macrophages, leading to infection of kidney and lung endothelial cells were hantaviruses replicate (80,159). A first phase in human hantavirus disease, the febrile phase, occurs 2–4 weeks after infection, with an abrupt onset of disease with high fever, chills, malaise, headache, and after the second day of onset, gastrointestinal symptoms, vomiting and abdominal pain, normally lasting about 3–7 days. Lumbal pain caused by renal swelling, often announces renal involvement in HFRS. In some HFRS cases, conjuntival hemorrhages and fine petechiae occur at the end of this phase, together with (often massive) proteinuria. A characteristic drop of the blood platelet number (thrombocytopenia) is the beginning of the second phase, the hypotensive phase both in HFRS and HPS, lasting from several hours to 2 days. At this stage, some cases of HFRS and HPS, die of irreversible shock. In the third phase, the oliguric phase of HFRS, lasting about 3–7 days, anuria and renal failure define severity in HFRS, whereas acute lung edema can rapidly worsen in this stage of HPS, prompting mechanical ventilation. The beginning of the fourth, diuretic phase is a positive sign for the patient. Diuresis of 3–6 L/24 h is observed. The last phase, the convalescent phase is characterized by slow normalization of the clinical markers and recovery of the patients during several weeks (79). The cellular entry of pathogenic hantaviruses is mediated by 3-integrins (V3-integrin receptor) (37). These integrins are heterodimeric receptors composed of and subunits that mediate cell-to-cell adhesion and platelet aggregation (123). Endothelial cells and platelets are
prominent regulators of vascular functions and integrins play key roles in barrier functions of these cells (37,122). Hantaviruses that are thought to be nonpathogenic seem to use another yet unidentified integrin receptor (102). The occurrence of large intracellular inclusion bodies, likely to contain viral Np, is typical for hantavirus infections (83). Although hantaviruses have been shown to replicate in cultured human endothelial cells, there is considerable evidence that immune mechanisms rather than direct viral cytopathology, are responsible for the principal abnormality, vascular dysfunction resulting in plasma leakage in HFRS and HPS (25,162). The lack of suitable animal models for most of the frequently occurring hantaviruses is a significant obstacle in the understanding of hantavirus disease pathogenesis.
HUMORAL IMMUNE RESPONSE TO HANTAVIRUS IgA response. IgA is the key immunologic component of the mucosa. Specific secretory IgA can inhibit initial pathogen colonization by performing immune exclusion both on the mucosal surface and within virus-infected secretory epithelial cells without causing tissue damage (12). The levels of total serum IgA and virus-specific IgA1, but not IgA2, have been reported to be elevated during the acute phase of the disease in patients infected with ANDV and PUUV (28,44,65,117). In other HPS patients, SNV-specific IgA was detected in acute phase samples, whereas post-acute and convalescent serum samples showed only relatively low titers (11). Interestingly, a study that investigated NE-convalescent sera after 2 and 10 years, found that seven out of nine convalescent sera still contained neutralizing virus-specific IgA1 (28). IgE response. IgE is the least common serum immunoglobulin (Ig) since it binds tightly to Fc receptors on basophils and mast cells even before interacting with antigens. As a consequence of its binding to basophils and mast cells, IgE is mostly involved in allergic reactions. Both total IgE and virus-specific IgE have been reported to be elevated in the acute phase of HFRS (3). According to the findings of the same study, the IgE response is initiated before the appearance of clinical symptoms, suggesting that IgE may be involved in the pathogenesis of the disease. Elevated levels of both total IgE and virus-specific IgE have also been found in dengue hemorrhagic fever patients, hepatitis C virus and HIV (13,77,120). Proinflammatory cytokines like IL-1 and TNF- can be triggered by IgE, which may increase vascular permeability (10). There is however, no correlation between the IgE levels and the clinical severity of HFRS. Several studies found elevated levels of soluble
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HANTAVIRUSES CD23 (sCD23) in the acute phase of HFRS. CD23 is a low-affinity receptor for IgE and is expressed by B cells and other antigen-presenting cells. Moreover, CD23 can be cleaved from the host cell membrane into soluble fragments and these sCD23 fragments may interact with surface IgE, thereby promoting the production of IgE antibodies. A negative signal occurs when antigen-bound IgE interacts with membrane-bound CD23, and in this way inhibits the release of sCD23 and IgE (4). CD4 T helper2 (Th-2) cells can stimulate IgE production by release of IL-4 , while CD4 Th-1 cells can inhibit the IgE release by IFN- production (130). The elevated levels of IgE in the acute phase of HFRS, may suggest a role for T cells in the pathogenesis of HFRS. IgM response. Both HPS and HFRS initially induce high levels of virus-specific IgM, directed against all three of the structural proteins of hantavirus. Hantavirusspecific IgM antibodies appear early after onset of disease and persist for up to 6 months (11,22,43,44,59, 117,136,163). The PUUV Np has been demonstrated to be the major antigen in the acute human antibody response to PUUV infections and high levels of PUUV Npspecific IgM antibodies are detected during the acute phase (95). It has been shown that PUUV G1-specific IgM antibodies were present in acute and early convalescent period just before PUUV Np-specific IgM could be detected (43). IgG response. IgG is the most abundant antibody. It has antitoxin, antiviral and antibacterial functions and makes up 80% of the total immunoglobulin concentration. IgG has a half-life of 20–25 days. Hantavirus-specific IgG antibodies appear during the acute phase of HPS and HFRS, but an increase of IgG levels is seen during the early convalescent phase, 2 weeks after the onset of hantavirus disease (43,44,85,100,122). The early IgG re-
485 sponse is predominantly directed towards Np and IgG antibodies directed against G1 and G2 proteins appear later in the early convalescent phase (64). Hantavirus-specific IgG1 is the predominant antibody subclass against all three hantavirus proteins at all times during hantavirus infection (57,96). Even several years after PUUV infection, IgG1 remains the dominant IgG subclass (personal communication). IgG2 antibodies are rarely detected (11,44). Np and G1 protein-specific IgG3 antibodies are detected during the late convalescent phase, whereas for G2 protein-specific IgG3 antibodies, a peak is seen during the acute phase of HPS and HFRS (11,44,96). No hantavirus-specific IgG4 antibodies could be detected in HPS patients (11). For HFRS however, one study did not detect any hantavirus-specific IgG4 antibodies (44), whereas another study found hantavirus-specific IgG4 antibodies against all three hantavirus proteins, in sera of patients who were infected several years ago (96). It is believed that hantaviruses raise life-long immunity. PUUV IgG antibodies directed against Np have been detected in convalescent sera several decades after infection (96). B cell epitopes, cross-reactivity, and neutralizing antibodies. The human IgG immune response in HFRS is primarily directed against epitopes located within the amino acid (AA) residues 1–119 of the amino-terminal part of Np (42) (Fig. 2). DOBV, HTNV, PUUV and TULV have epitopes within the first 118 AA of the amino terminal part of Np (42,60,98). The epitope pattern, however, varies considerably between individuals (154). There is only limited data available about the localization of virus-neutralizing epitopes on the G1 and G2 envelope proteins, probably because of their conformational nature or dependence on glycosylation. An amino-terminal region on the G1 protein spanning from AA 59 to
FIG. 2. B-cell epitopes of hantavirus nucleocapsid proteins. Monoclonal antibody (mAb) epitopes and recognition regions of mAb against the different hantaviruses. DOBV, Dobrava virus; HTNV, Hantaan virus; PUUV, Puumala virus; SNV, Sin Nombre virus; TULV, Tula virus (42,57,60,98,101,154).
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486 401 has also been shown to contain several epitopes. For SNV, a linear B-cell epitope has been shown on the amino terminus of G1 (AA residues 59–89) (57). Both PUUV G1 and G2 proteins contain at least one neutralizing domain unique for PUUV (94). Some studies have suggested the presence of different PUUV and HTNV neutralizing epitopes on both G1 and G2 proteins (6,94). Neutralizing antibodies to G1 and G2, but not Np, have been identified. Using HFRS patients-derived neutralizing recombinant antibodies, two HTNV G1-specific epitopes were revealed. Epitope-specific IgG could bind to and neutralize HTNV but not SEOV (87). Neutralizing antibodies develop early after infection and they are usually already present at the onset of disease (52). Patients who recovered from a mild course of HPS have higher titers of neutralizing antibodies against SNV. Even after 3 years, high titers of SNV-specific neutralizing antibodies could be detected (160). Little is known about the degree of cross-reaction of neutralizing antibodies to other hantaviruses. A recent study tested Amur virus (AMRV) for cross-reactivity with other viruses. Sera from Apodemus peninsulae naturally infected with AMRV neutralized Far East virus and HTNV, but antiHTNV serum did not neutralize AMRV (92). Acute and early convalescent phase sera could not be used for typing of the causative hantavirus in one study (100). The sera showed specificity for DOBV, HTNV and PUUV in neutralization tests. The presence of high cross-neutralizing titers of IgM antibodies during the acute phase of the disease, can explain this phenomenon. The humoral cross-reactivity between the different members of the hantavirus genus is high, especially between members carried by the same rodent genus. A high cross-reactivity has been found in DOBV-infected human sera. During the acute phase of the disease, cross-reactivity with HTVN and PUUV was high (137). Until now, nothing is known about the serological responses to the L segment of hantaviruses. Laboratory diagnosis of hantavirus infections. Several studies have demonstrated the production of Np-specific antibodies during the acute phase of the disease, whereby detection of Np-specific IgM antibodies in clinical samples appeared to be a good indicator of a recent hantavirus infection (22,154). The detection of hantavirus-specific IgM using recombinant Np in an ELISA format, is by far the most valuable and widely used test for diagnosing acute phase hantavirus infections (86,117). Exceptional clinical situations like the application of therapeutic plasma-exchange however, can create iatrogenic IgM negativity during the acute period, obviating a correct serodiagnosis (65). Truncated recombinant Np were shown to be even more specific, moreover in most cases specific enough to differentiate the involved hantavirus serotype (5,32,103). The plaque reduction
MAES ET AL. neutralization test is considered to be the gold standard serological test as reliable discrimination of the hantavirus serotype involved in the infection. Reverse transcriptase PCR with type-specific primers has been shown to be a useful tool in the diagnosis of hantavirus (53,113,146,156), although hantaviral RNA is only detected in the first days after onset of disease in NE (125). SNV RNA could be detected up to ten days after onset of disease in serum specimens of HPS patients (146). When using quantitative reverse transcriptase PCR, it is possible to detect less than 10 TCID50 mL1 PUUV RNA (36). Immunochromatographic assays for rapid and reliable laboratory diagnosis of hantavirus infection are more commonly used in recent years (56,135). These tests have the same sensitivity as ELISA assays, in some cases they had even a higher sensitivity. The immunochromatographic rapid tests gave relatively low serological crossreactivity between DOBV, HTNV and PUUV (56), which makes these tests a good alternative for the timeconsuming ELISA assays.
CELLULAR IMMUNE RESPONSE TO HANTAVIRUS T cell response. In humans, cytotoxic T cells (CTL) specific for hantavirus appear to play an important role in the pathogenicity of HPS and HFRS. At the same time, T cells are utmost important in the clearance of the virus. At the onset of disease, increased amounts of CD8 T cells, increased levels of cytokines (IFN-, TNF-, IL-2 and IL-6) and a reversed CD4/CD8 ratio are observed (89,162). T cell activation occurs very early in HFRS and is associated with an increase in the absolute numbers of neutrophils, monocytes, B and T cells. The increased expression of both early and late T cell activation antigens, CD25, CD71, HLA-DR, memory cells and soluble CD23 positively correlates with biochemical parameters like AST, ALT, urea and 2-globulin, during the acute phase of HFRS (106). Among the earliest activation changes are transient expression of the early activation markers CD25 and CD71, with later upregulation of HLA-DR. The memory T cell population rises shortly after onset of disease, and memory T cell maturation continues throughout the infection. For PUUV, increased expression of cytokines is seen mainly in the peritubular area of the distal nephron, where infiltrating cells are abundant. In the same locations, the expression of the adhesion molecules ICAM-1, VCAM and PECAM is increased (148). CD8 T cells remain the predominant lymphocyte throughout the infection. Increased numbers of CD8 T cells, and increased numbers of TNF-, IL2 and IFN- producing cells were found in the lungs of patients who died from HPS (69). PUUV-specific mem-
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HANTAVIRUSES ory CTL were found at high frequencies in individuals who had clinical infections with PUUV 6 to 15 years earlier, without evidence of persistent hantavirus infection, and clinical reinfections with PUUV or other human hantaviruses have never been reported (153). To our knowledge, repeated human illness due to infection by a same serotype has not been reported so far; nor is there any published evidence that humans can develop a second illness after infection with another, serologically different hantavirus. The severity of disease is also correlated with a higher amount of CD8 lymphocytes. Significantly higher frequencies of SNV-specific T cells were found in patients with severe HPS requiring mechanical ventilation. In contrast to the rodent reservoirs, specific for each hantavirus serotype, humans are an unnatural host and in fact a dead end for hantaviruses, which may explain the intense CD8 T cell responses to after infection. Fas and FasL expression on peripheral blood lymphocytes is increased in patients with PUUV associated HFRS. During acute viral infections, programmed cell death of lymphocytes by apoptosis is necessary for removing the excess of activated antigen-reactive T cells and down-regulation of the immune response. Apoptosis is also the key mechanism in eliminating viral-infected cells (2). T cell epitopes. CTL epitopes of PUUV are mainly located in the highly immunogenic amino-terminal part and in the highly variable central part of Np (Table 2) (28). CTL epitopes on the Np of SNV and HTNV are also located in the amino-terminal part and the central part of the Np (33,152). Bulk T cell responses are directed against HTNV Np and G1 protein in HPS. One study recognized HTNV-specific CD8 epitopes to Np and CD4 epitopes to G1 protein (152). Towards the carboxy-terminal part of the G2 protein of SNV two CTL TABLE 2. Protein Np Np Np Np Np Np Np Np Np Np Np G2 G2 G2
Epitope AA AA AA AA AA AA AA AA AA AA AA AA AA AA
12–20 131–139 164–178 173–181 204–212 212–220 236–250 243–251 334–342 333–341 421–429 664–673 731–739 746–755
KNOWN CTL EPITOPES
epitopes are defined. Interestingly, three of the four CD8 T cell epitopes defined in SNV, are presented by HLA-B*3501 (69). In mice challenged with PUUV, several Th cell recognition sites were identified, spanning amino acids 6–27, 96–117, 211–232 and 256–277 of the PUUV-Np (28). All regions have been shown to react with antibodies in human NE sera (154). Further studies are needed to define the specific hantavirus epitopes and role of these epitopes in the immune responses and protection against other hantaviruses. Natural killer cells. Natural killer (NK) cells participate in natural and adaptive immunity, as effector and regulatory cells, essentially by their cytotoxic potential and by the secretion of cytokines and chemokines. The changes in the NK cell population during hantavirus infection are poorly described and are rather controversial. One study documents a significantly higher number of NK cells in HPS patients (115), whereas others described no changes or decreased numbers (85). A significantly lower number of NK cells has been found during the first week of HFRS in comparison to the second week after disease onset (4). It has been suggested that decreases in the percentage of circulating NK cells might be the result of migration of these NK cells into infected tissue (67), which is supported by the findings of Linderholm and colleagues who described significantly higher numbers of NK cells in bronchoalveolar lavages of NE patients (88). HLA involvement. An upregulation of HLA class I molecules has been described in endothelial target cells after HTNV, NYV, PHV and TULV infection (38,78). A genetic susceptibility to a severe course of NE caused by PUUV has been reported in patients bearing HLA-B8 and DRB1*0301 alleles. The HLA-B27 allele was associated with a mild course of PUUV infection in the same study
OF THE
DIFFERENT HANTAVIRUS PROTEINS
Amino acid sequence
HLA restriction
Virus
Reference
NAHEGQLVI LPIILKALY TSFEDINGIRRPKHL RPKHLYVSM GLFPTQIQV VRNIMSPVM IREFMEKECPFIKPE ECPFIKPEV ILQDMRNTI ILQDMRNTI ISNQEPLKL TAHGVGIIPM HWMDATFNL YPWQTAKCFF
B51 B35.01 A28 B7/B8 A2 Unknown Unknown B8 A2.01 A2.01 A1 B35.01 A24 B35.01
HTNV SNV PUUV PUUV PUUV PUUV PUUV PUUV HTNV SNV HTNV, SNV SNV PUUV SNV
(152) (69) (153) (153) (153) (153) (153) (153) (84) (84) (152) (69) (147) (69)
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488 (112). A Croatian group associated also the DQ2 allele with severe outcome of PUUV infections (14). Interestingly, this HLA-B8, DRB1*0301 haplotype has also been associated with a rapid progression of HIV infections to AIDS, a poor antibody response to hepatitis B vaccine and some autoimmune diseases like lupus erythematosus and Grave’s disease (63). Plyusnin and colleagues showed that PCR positivity in NE patients, was clearly associated with the presence of HLA alleles B8 and DRB1*0301 of NE patients (125). The mechanism of this association is not clear, but it points out to the role of the host immune response in the pathogenesis of severe NE. The hantaviral response of the host can be either dysfunctional which results in an inappropriate clearance of the virus, or may function with disturbed efficacy and in that way trigger autoimmune responses that eventually contribute to the hantaviral pathogenesis. The HLAB35*01 allele is associated with a higher CD8 CTL response in patients suffering from severe HPS caused by SNV. In one study, 71% of HPS patients with HLA-B35 had severe disease (69). During the acute phase of the disease, up to 25% CD8 T cells, specific for a single epitope, were detected in serum of patients bearing this epitope. This finding, together with the increased numbers of TNF-, IL-2 and IFN- producing cells found in the lungs and kidneys of patients who died from HPS (111), supports the hypothesis that virus specific CD8 T cells contribute to hantavirus disease outcome. Soluble HLA class I (sHLA-I) molecule levels in serum and urine of HFRS patients infected with HTNV are found to be significantly higher than those in control populations (119). Moreover, higher levels of sHLA-I molecules are associated with a severe course of the disease. Although the serum level of sHLA-I molecules is significantly increased due to an activation of immune responses in a variety of physiological and pathological conditions such as pregnancy, acute graft-versus-host disease following bone marrow transplantation, autoimmune diseases, viral infections and melanoma, sHLA-I molecule monitoring in serum and urine of HFRS patients can be used as an objective parameter for monitoring clinical severity in HFRS patients. Increased levels of sHLAI molecules can be interpreted as a means of immune escape, since sHLA-I molecules may modulate immune T cell function by receptor blockage or by apoptosis induction, which may lead to a more severe course of the disease. Upregulation of HLA class I molecules may theoretically lead to an inhibition of NK cells by overstimulation of the killer inhibitory receptors (KIR) on NK cells (30). Little is known about HLA class II regulation during hantavirus infections and the findings are rather controversial. One study found that HLA class II molecules were not upregulated in vitro in HTNV or TULV infected human umbilical vein endothelial cells
MAES ET AL. (HUVECs) (78). Another study found a steady increase in expression of HLA class II molecules after in vitro infection of HMVEC-Ls endothelial cells with SNV or HTNV (143). Immunoblasts. Immunoblasts are antigenically stimulated large lymphocytes with well-defined basophilic cytoplasm, a large nucleus with a prominent nuclear membrane, distinct nucleoli and clumped chromatin (Fig. 3). These immunoblasts, often interpreted as atypical lymphocytes, give rise to a population of B or T cells with specificity against the stimulating antigen. Immunoblasts are observed in pulmonary vessels and blood of patients suffering from HPS (111,115). They can make up 10% or more of the lymphocyte population. Although the appearance of immunoblasts in NE patients is not uncommon (Clement, J., Keynote lecture at 6th international conference on HFRS, HPS and hantaviruses, Seoul, 2004), it was only recently that circulating immunoblasts were described in a patient suffering from NE caused by PUUV (65). Mostly the presence of immunoblasts is associated with a more severe course of disease and they are only found in the blood during the first few days after onset of symptoms. The immunoblasts seen in HPS and probably also in HFRS patients are of the T cell type. They are CD4 and CD8 T cells that are also HLA-DR positive (122). Dendritic cells. Dendritic cells (DCs) comprise an essential component of the immune system. These cells, as antigen presenting cells to naive T cells, are crucial in the initiation of antigen specific immune responses. In vitro, HTNV virus is able to infect DCs (128), and in vivo SNV-infected DCs were found in lungs of patients suffering from HPS (162). HTNV-infected DCs produce a variety of proinflammatory cytokines like TNF- and IFN-, which are most likely responsibly for upregulating HLA class I expression on nearby endothelial cells (128).
CYTOKINE AND CHEMOKINE RESPONSE TO HANTAVIRUS Cytokines. The cytokine production during a hantavirus infection may be one of the major causes of HPS and HFRS symptoms. Cytokines, especially TNF-, IL1 and IL-6, are mediators responsible for fever, septic shock and acute phase protein induction. Overproduction of TNF- may lead to severe systemic toxicity (150). These cytokines are also thought to play an important role in vascular leakage observed in HPS and HFRS, although the exact mechanism of this increased permeability remains unclear (143). TNF- is one of the most important proinflammatory cytokines. Plasma levels of TNF- were found to be strongly increased in patients
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FIG. 3. Picture of immunoblasts found in the blood of a patient suffering of severe nephropathia epidemica caused by Puumala virus with high nuclear-cytoplasmic ratio, intense basophilic cytoplasm, small intracytoplasmatic vacuoles, and small nucleoli in the immunoblast nucleus.
suffering from severe NE (89). In line with these results, the expression of TNF- was found to be increased in the peritubular areas of kidney biopsies of NE patients (145). High levels of TNF- have been associated with a severe course of NE (74). TNF- is preferentially released at the sites of inflammation by infiltrating monocytes and macrophages (155). IL-1, IL-1, IL-6 and TNF- producing cells were detected within the alveolar walls and in the alveolar air spaces, whereas IFN-, IL-2, IL-4 and TNF- producing cells were detected mainly in within the alveolar walls. The TNF-(-308) G/A polymorphism or TNF-2 is in linkage disequilibrium with the HLA-B8-DR3 haplotype and has been associated with enhanced TNF- transcriptional activity (104). The clinical course of NE has been shown to be more severe in TNF-2 positive patients with NE than in TNF-2 negative patients (63). However, there were no differences in the clinical severity of NE when TNF-2 positive/HLA-B8-DR3 negative patients were compared with TNF-2 negative/HLA-B8-DR3 negative patients. The HLA-B8-DR3 haplotype is more strongly associated with a more severe clinical course of NE than the TNF-2 allele (104). The serum concentrations of soluble IL-2 receptor (sIL-2R) and soluble IL-6 receptor (sIL-6R) were increased in HTNV infected patients. The serum concentration of sIL-2R increased 2 days after onset of
HFRS, whereas sIL-6R increased 6 days after HFRS onset (107). Endothelial cell monolayers infected with remained irreversibly hyper permeable, whereas the uninfected monolayers completely recovered the barrier function (114). Another study found no significant changes in the levels of IL-1 and IL-6 after HTVN infection of human endothelial cells (121). Plasma IL-6 concentrations and urinary IL-6 excretion were markedly increased in patients with acute NE, but there was no correlation between plasma and urinary IL-6 levels (105). In vitro infection of HUVECs with SNV showed an insignificant increase of permeability, which could be a sign of structural changes in interendothelial junctions. However, supernatant from infected human alveolar macrophages failed to induce endothelial monolayers leakage (66). Chemokines. Chemokines are important local inflammatory mediators and regulate disease due to viral infection. In vitro infection of human lung microvascular endothelial cells with either HTNV or SNV resulted in detectable levels of RANTES (regulated upon activation, normal T cell expressed and secreted) also known as CCL5 and the 10-kDa interferon-inducible protein, IP-10 (143). Another study described the induction of a variety of chemokines like IL-6, IL-8, RANTES and IP-10 by HTNV in human endothelial cells in vitro, whereas NYV
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virus failed to induce most cellular chemokines directed by HTNV (38). Acute respiratory viruses commonly induce inflammatory chemokines such as RANTES and monocyte chemotactic protein–1 (MCP-1), which can amplify inflammatory responses leading to immunopathology (41). A significant increase of RANTES mRNA is found in all supernatant cell lines infected with pathogenic hantaviruses (38,67). This finding supports the conclusion made for other viruses that chemokines play an important role in virus pathology. As these chemokines play both beneficial and harmful roles in viral diseases, blocking them or using them as immunomodulators, depending on the virus, may be a rational approach to treatment or attenuation of virus disease. In case of an hantavirus infection, the release of RANTES and IP-10 by endothelial cells may direct and perhaps enhance the effector immune response to the infected microvascular endothelium (143). A combination of antiviral and antichemokine therapy is a strategy worth considering as a general therapeutic approach to hantavirus infections.
VACCINE STRATEGIES AGAINST HANTAVIRUS A variety of vaccines has been developed using both killed virus and recombinant DNA technology. Several groups throughout Asia have made inactivated hantavirus vaccines. Most of these vaccines were made using formalin inactivated rodent brain-derived virus (16,158), similar to those used to prepare Japanese encephalitis virus and rabies vaccines (1,45). A commercial Korean inactivated HTNV vaccine, named Hantavax™, was shown to be effective in protecting mice and humans from HFRS (16,17,48). After three vaccinations, ELISA antibody seroprevalence was 100% in the study group. In the neutralization assay however, only 50% of vaccine recipients possessed measurable neutralizing antibodies after three vaccinations. A significant proportion of volunteers showed high hantavirus-specific IgG ELISA titers in the absence of detectable neutralizing antibodies (16,17). Another study found a neutralization response in only 33% of recipients after two immunizations (140). The absence of any serious adverse event despite the use of millions of doses during the last 10 year suggests that this formalin-inactivated vaccine is safe. Cell culturebased hantavirus vaccines are the basis of several vaccines like influenza virus vaccine and polio virus vaccine (109,110). Both HTNV and SEOV cell culture-based hantavirus vaccines, prepared in golden hamster kidney cells, Mongolian gerbil kidney cells or vero E6 cells, were shown to induce fewer side effects and provided a more
effective immunity, with high levels of neutralizing antibodies, in comparison to rodent brain-derived vaccines (18,48,50,93,141). Both the rodent brain-derived vaccines and the cell culture based vaccines, yielded only low levels of ELISA antibody titers as well as neutralizing antibody titers one year after vaccination, raising questions about the long-term efficacy of these vaccines. Several techniques have been used for the development of vaccines by expressing hantavirus proteins using recombinant DNA technology. Recombinant hantaviral antigens have been expressed in insect cells, mammalian cells, E. coli and transgenic plants. Recombinant hantavirus G1, G2 and Np expressed in several systems, have proven protective potential (27,29,39,68,99,132,161). To overcome problems of low immunogenicity of monomeric viral proteins, virus-like particles (VLP) can be used as immunogens. VLP are non-infectious, highlystructured, repetitive protein complexes that resemble the structural and immunological properties of the original virus particles. Ulrich and colleagues have successfully achieved protection in a bank vole model using HBV core-derived chimeric particles carrying a 45-AA segment of PUUV Np (75,151). This vaccine approach is promising due to the high immunological response these VLP provoke (127). Inoculation with life recombinant virus, like vaccinia virus and CMV, showed to be effective in protecting animals from challenge with hantavirus (20,108,129,133,147,157). A major disadvantage of this method is pre-existing immunity against the carrier virus in people who needs to be vaccinated. In a phase I clinical safety trial with a recombinant vaccinia vaccine expressing both HTNV Np and G1/G2 proteins, only 50% of the volunteers with a pre-existing immunity against vaccinia, exhibited neutralizing antibody responses after two vaccinations, whereas 100% of the vaccinia-naive volunteers exhibited neutralizing antibody responses after the second vaccination (108). Naked DNA vaccines, usually based on plasmid DNA, have been demonstrated to be promising vaccine approaches for various viral infections (31,40,70,91). Several groups have utilized the whole Np, G1 and G2 of ANDV, HTNV, PUUV, SEOV and SNV as immunogens, mostly driven by a mammalian RNA polymerase 2 promotor (9,26,49,50,51,61,76). These plasmids have been shown to offer protection against experimental infection in hamster, mouse or macaque models. Constructs expressing the G1 and G2 glycoproteins exhibited the desired neutralizing antibody responses. Sindbis virus replicons have also been evaluated as a possible DNA-based vaccine approach. But both Sindbis virus and packaged Sindbis virus replicons encoding for either the M or S segment of SEOV did not exhibit a protective immune response in Syrian hamsters (61).
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ANTIVIRAL THERAPY Currently, no Food and Drug Administration approved antiviral drug or immunotherapeutic agent is available for treatment of the hantavirus diseases. Ribavirin (1--D-ribofuranosyl-1,2,4-triazole-3-carboxamide) has been shown to have in vitro activity and to some extent also in vivo activity against some hantaviruses (134). Huggins and colleagues (54) studied the efficacy of ribavirin therapy given to HTNV-infected suckling mice on days 6–20 after infection. The ribavirin-treated mice had a higher survival rate than the placebo control group. Based on these findings, Huggins’ group conducted a double-blind placebo-controlled trial with HFRS patients in several countries including China and Korea, showing a sevenfold reduction in morbidity in the ribavirin-treated group (55). A statistically significant reduction in fatal outcomes from 10 of 117 patients receiving placebo to three of 125 patients receiving ribavirin was reported. The results of a nonselective open-label trial in patients suffering from HPS however, showed disappointing results (15). Vero E6 cells, pretreated with human interferons IFN, IFN-, IFN- resulted in dose-dependent inhibition of HTNV replication. Of the three human interferons, IFN inhibited virus replication most effectively (144). Newborn mice treated with IFN- before infection with HTNV, showed a survival rate of 85–90% against less than 20% for non-treated mice. The same observations were described for PUUV and TULV. Human MxA protein, a type I interferon-inducible intracytoplasmic protein, mediates antiviral actions against several members of the Bunyaviridae family after interferon stimulation (35). The human MxA protein has the capacity to inhibit PUUV and TULV replication, and RNA accumulation in virus-infected Vero E6 cells (62). Kraus and colleagues studied the kinetics of MxA protein expression in HTNV and TULV infections. TULV-infected HUVECs showed an early onset (16 h post-infection) of MxA protein expression, whereas HTNV-induced MxA proteins appeared relatively late (48 h post-infection). Viral titers produced by TULV-infected cells were found to be much lower than those produced by HTNV-infected cells. On Vero E6 cells, which lack IFN-/ genes, TULV could grow as efficiently as HTNV (78). Interestingly, pathogenic and nonpathogenic hantaviruses regulate endothelial cell responses differently. HTNV and NYV seem to be able to postpone interferon stimulated genes synthesis in comparison with the nonpathogenic Prospect Hill hantavirus. This short period of delay seems to be enough to escape antiviral processes induced by INF. Replication of HTNV and NYV is still effective even in the presence of high levels of the MxA protein (38). These findings suggest that pathogenic hantaviruses, in contrast to
nonpathogenic hantaviruses, are able to block the early antiviral immune response in human endothelial cells (38,78). Tragacanthin polysaccharides from Astragalus brachycentrus and Astragalus echidnaeformis plants have been suggested as a potential therapeutic approach to hantavirus disease as these compounds have been shown to have antiviral activity against Punta Toro virus (a phlebovirus member of the Bunyaviridae family, used as a model for studying the treatment of hantavirus infections) in vitro and in vivo (139).
FUTURE PERSPECTIVES In the near future, there will be new endemic hantavirus species or hantaviruses discovered in other regions of the world via increased knowledge of new rodent reservoirs. It has become clear that both hantaviruses and their rodent hosts have coevolved since millions of years, therefore these viruses cannot be considered as new and perhaps not even as truly emerging. There is no other emerging zoonosis except maybe for arenavirus, where viruses are so closely linked to their rodent hosts. Specificities of the rodent host is the main factor in explaining the geographical spread of human hantavirus disease and the mechanisms of an outbreak or even a single sporadic occurrence. Although we stressed in this review the importance of a host-related immunologic response in the development of symptoms, clinical features and clinical severity of a hantavirus infection depend in the first place on the implicated hantavirus serotype. Two recent findings however, have made things even more complicated. First, the rather easy paradigm of “one hantavirus serotype for one rodent species” is no longer supported, since Apodemus agrarius can be the host for at least two different (but genetically related) hantavirus serotypes being HTNV and the recently described DOBV-Aa. The clinical course seems more severe for HTNV than for DOBV-Aa. Second, severe hantavirus infections have much more in common than originally thought. In particular, the cleavage between Old World and New World infections with respectively the kidney and the lung as target organ has to be reconsidered. Increased medical familiarity with these infections on both sides of the Atlantic explain why more renal involvement is documented in HPS cases particularly in South America and why recent reports confirm primary lung involvement in European HFRS cases. If a unifying hypothesis is to be found for explaining these uniformities rather than the differences, it will be via a better understanding of the intrinsic pathways of immunologic response in man.
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ACKNOWLEDGMENTS We would like to thank Dr. Sigrid Vanwetswinkel, Lic. Jannick Verbeeck, and our colleagues of the laboratory of Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Belgium for their helpful comments and discussion.
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