JOURNAL OF VIROLOGY, Mar. 2008, p. 2040–2055
Vol. 82, No. 5
Viral and Host Factors in Human Respiratory Syncytial
Peter L. Collins1* and Barney S. Graham2
Laboratory of Infectious Diseases1and Vaccine Research Center,2National Institute of Allergy and
Infectious Diseases, Bethesda, Maryland 20892
Human respiratory syncytial virus (RSV) was first isolated in
1956 from a laboratory chimpanzee with upper respiratory
tract disease (for general reviews, see references 21, 57, 102,
and 145). RSV was quickly determined to be of human origin
and was shown to be the leading worldwide viral agent of
serious pediatric respiratory tract disease. In a 13-year pro-
spective study of infants and children in the United States,
RSV was detected in 43%, 25%, 11%, and 10% of pediatric
hospitalizations for bronchiolitis, pneumonia, bronchitis, and
croup, respectively (110). Approximately two-thirds of infants
are infected with RSV during the first year of life, and 90%
have been infected one or more times by 2 years of age. The
rate of hospitalization for primary infection is approximately
0.5% but can vary by situation and ethnic group and can be as
high as 25% (77).
RSV also is a significant cause of morbidity and mortality in
the elderly, with an impact approaching that of nonpandemic
influenza virus (39). RSV readily infects severely immunocom-
promised individuals, most notably allogeneic bone marrow
transplant recipients, causing high mortality. RSV also makes
a substantial contribution to upper respiratory tract disease in
individuals of all ages (59, 65). Globally, the World Health
Organization estimates that RSV causes 64 million infections
and 160,000 deaths annually (Initiative for Vaccine Research:
respiratory syncytial virus, World Health Organization [http:
accessed 5 December 2005]).
Although RSV has a single serotype, reinfection can occur
throughout life. RSV in yearly winter/early spring epidemics in
temperate regions; elsewhere, the timing of RSV activity can
vary widely with the locale. The RSV reservoir in the off-
season is unknown. Strains circulate quickly around the earth
(150). Neither a vaccine nor an effective antiviral therapy is
available, although there is active research in both areas (23,
78, 138). However, infants at high risk for serious disease can
receive passive immunoprophylaxis during the epidemic sea-
son by a monthly injection of a commercial RSV-neutralizing
monoclonal antibody, palivizumab (Synagis), which provides a
55% reduction in RSV-associated hospitalization (17).
RSV (family Paramyxoviridae, order Mononegavirales) is an
enveloped virus with a single-stranded negative-sense RNA
genome of 15.2 kb (21). There are animal versions of RSV,
including bovine RSV (BRSV) and pneumonia virus of mice
(PVM), suggesting that species jumping occurred during the
evolution of these viruses. However, there is no animal reser-
voir for human RSV.
Efficient infection by RSV of established cell lines in vitro
involves binding to cell-surface glycosaminoglycans (62). How-
ever, it is not known how closely this binding models attach-
ment in vivo or whether it is an initial interaction that is
followed by a second, higher-affinity step that remains to be
identified. The nucleocapsid gains entry to the cytoplasm by
membrane fusion; surprisingly, this may involve clathrin-medi-
ated endocytosis rather than surface fusion typical of
paramyxoviruses (85). Viral gene expression and RNA repli-
cation occur in the cytoplasm, and virions acquire a lipid en-
velope by budding through the plasmid membrane (Fig. 1).
Virions are pleomorphic and include spheres and long, fragile
filaments. Studies with RSV are impeded by modest viral yields
in cell culture and physical instability of the particle; interest-
ingly, this instability may reside in the glycoproteins (133).
The negative-sense RNA genome contains a short 3?-extra-
genic leader region, 10 viral genes in a linear array, and a
5?-trailer region (Fig. 1). Each gene is transcribed into a sep-
arate, capped, polyadenylated mRNA encoding a single viral
protein, except in the case of the M2 mRNA, which contains
two overlapping open reading frames that are expressed by a
ribosomal stop-restart mechanism into two distinct proteins,
M2-1 and M2-2 (52).
Five RSV proteins are involved in nucleocapsid structure
and/or RNA synthesis (21). The nucleocapsid N protein tightly
encapsidates genomic RNA as well as its positive-sense repli-
cative intermediate, called the antigenome. This provides pro-
tected, flexible templates and probably reduces detection of
these viral RNAs by host cell toll-like receptors (TLRs) and
intracellular RNA recognition helicases that initiate innate
immune responses through interferon (IFN) regulatory factors
and nuclear factor ?B (NF-?B) (3, 94). The large L protein is
the major polymerase subunit and contains the catalytic do-
mains. The P phosphoprotein is an essential cofactor in RNA
synthesis (31) and also is thought to associate with free N and
L to maintain them in soluble form for assembly of and inter-
action with nucleocapsids. The M2-1 and M2-2 proteins are
* Corresponding author. Mailing address: NIAID, NIH, 50 South
Drive, MSC 8007, Bethesda, MD 20892. Phone: (301) 594-1590. Fax:
(301) 496-8312. E-mail: firstname.lastname@example.org.
?Published ahead of print on 10 October 2007.
FIG. 1. RSV virion, RNA genome, and encoded proteins. (A) The negative-sense RNA genome (strain A2) is depicted 3? to 5? showing the
extragenic 3? leader (le) and 5? trailer (tr) regions and the intervening 10 viral genes (rectangles) that are each expressed as a separate mRNA (21). M2-1
and M2-2 are overlapping open reading frames of the M2 mRNA. The M2 and L genes overlap slightly, and L is expressed by polymerase backtracking
(25). (B) Electron photomicrographs showing an RSV virion budding through the plasma membrane of an infected cell (left) and a free virion (right).
Protein functions and amino acid lengths (in parentheses, unmodified form) are indicated. (C) Schematic diagrams of the F, G, and SH proteins, with
lengths approximately to scale (21). Filled rectangles indicate the hydrophobic cleaved signal sequence (sig.), transmembrane anchors (TM), and fusion
peptide (FP). Cross-hatched rectangles indicate heptad repeats (HR) that drive conformational changes involved in fusion. CT, cytoplasmic domain.
Potential acceptor sites for N-linked sugars are indicated as downward-facing stalks with an N. For the F protein, the locations and amino acid positions
of the two cleavage sites are indicated, as are the cleavage products (F2, p27, F1). For the G protein, the 25 potential acceptor sites for O-linked sugars
predicted to be the most likely to be utilized are indicated as downward-facing lollipops. The sequence and disulfide-bonding pattern (dotted lines) of
the central domain are shown with the CX3C fractalkine motif boxed and the highly conserved 13-amino-acid sequence of unknown significance
underlined. The M-48 translational start site for the secreted form and the mature secreted form is indicated.
VOL. 82, 2008 MINIREVIEW2041
factors involved, respectively, in transcription (42) and in mod-
ulating the balance between transcription and RNA replication
Four other RSV proteins associate with the lipid bilayer to
form the viral envelope (21). The matrix M protein lines the
inner envelope surface and is important in virion morphogen-
esis (147). The heavily glycosylated G, fusion F, and small
hydrophobic SH proteins are transmembrane surface glyco-
proteins (Fig. 1). G and F are the only virus neutralization
antigens and are the two major protective antigens (21).
The G glycoprotein plays a major but not exclusive role in
viral attachment (148). It contains several N-linked carbohy-
drate side chains and an estimated 24 to 25 O-linked side
chains. This increases the apparent molecular weight of the
polypeptide backbone from 32,500 to 90,000. Most of the
ectodomain is thought to have an extended, unfolded, heavily
glycosylated, mucin-like structure that is unique to RSV and its
close relatives and appears to be very distinct from the globular
attachment proteins of other paramyxoviruses. The signifi-
cance of the similarity to mucin is unknown, although it is
tempting to speculate that it might alter the physicochemical
properties of the virus so as to facilitate spread or evade trap-
ping by mucus. G is anchored in the membrane by a signal/
anchor sequence near the N terminus and also is expressed as
a secreted form. This secreted form arises from translational
initiation at the second methionine (codon 48) in the open
reading frame followed by proteolytic trimming to yield a final
form that lacks the N-terminal 65 amino acids, including the
entire signal/anchor (129). The G ectodomain contains a highly
conserved domain of 13 amino acids whose significance is
unknown (146). This conserved sequence overlaps a disulfide-
bonded tight turn that is called a cystine noose and contains a
CX3C motif that is discussed later.
The F protein directs viral penetration by membrane fusion
and also mediates fusion of infected cells with their neighbors
to form syncytia. F is synthesized as a precursor, F0, which is
activated by cleavage by furin-like intracellular host protease.
Unusual for a viral penetration protein, cleavage occurs at two
sites (amino acids 109/110 and 136/137) (Fig. 1) (51). This
yields, in amino-to-carboxy-terminal order, F2(109 amino ac-
ids), p27 (27 amino acids), and F1(438 amino acids). F2and F1
remain linked by a disulfide bond and represent the active
The remaining two RSV proteins, NS1 and NS2, are small
species that do not appear to be packaged significantly in the
virion. As described below, they are nonessential accessory
proteins involved in modulating the host response to infection.
Gene expression and RNA replication by RSV broadly fol-
low the mononegavirus model, although admittedly there are
substantial gaps in our understanding of these processes even
for prototypical mononegavirues (25). The polymerase enters
the genome at or near its 3? end, and the genes are transcribed
into individual mRNAs by sequential start-stop-restart synthe-
sis that is guided by short transcription signals flanking the
genes. There is a polar gradient of mRNA abundance due to
polymerase fall-off. RNA replication involves synthesis of the
full-length positive-sense antigenome that in turn is copied into
RSV adds some complexity of its own with the M2-1 and
M2-2 proteins, which are found only in close relatives of RSV.
With RSV, processive transcription depends on the M2-1 pro-
tein, which is essential for viral viability (42). In its absence,
transcription terminates nonspecifically within several hundred
nucleotides and results in (reduced) expression of NS1 and
NS2 alone (42). It is tempting to speculate that a reduction in
the level of M2-1 might facilitate persistent infection by down-
regulating the expression of most of the viral genes while
maintaining some expression of the NS1 and NS2 host defense
antagonists. The other product of the M2 gene, the M2-2
protein, is not essential but appears to downregulate transcrip-
tion in favor of RNA replication as infection progresses (9). It
is unclear why RSV needs these extra proteins while other
mononegaviruses, which seem to have a very similar RNA
synthetic program, do not. Interestingly, the M2-1 protein of
human metapneumovirus (HMPV) shares substantial se-
quence identity with that of RSV but is not essential for pro-
cessive transcription or viral viability (15). It may be that there
are other M2-1 functions that remain to be identified.
CLINICAL INFECTION AND DISEASE
Inoculation of the nose or eyes occurs by large particle
aerosol or direct contact and results in viral replication in the
nasopharynx, with an incubation period of 4 to 5 days, and can
be followed over the next several days by spread to the lower
respiratory tract (21, 57, 102). Rhinorrhea, cough, and low-
grade fever are common. Signs of lower airway infection are
common even in infants with mild disease. Clinical signs of
bronchiolitis include increased airway resistance, air trapping,
and wheezing. Pneumonia accounts for the hypoxia frequently
detected in RSV-infected infants.
Infection normally is highly restricted to the superficial cells
of the respiratory epithelium (72, 159). Ciliated cells of the
small bronchioles and type 1 pneumocytes in the alveoli are
major targets of infection in the lower airway. It is likely that
other cells, including nonciliated epithelium and intraepithelial
dendritic cells (DCs), are also infected (Fig. 2), but the basal
cells appear to be spared (72). Pathological findings include
necrosis of epithelial cells, occasional proliferation of the bron-
chiolar epithelium, infiltrates of monocytes and T cells cen-
tered on bronchiolar and pulmonary arterioles, and neutro-
phils between vascular structures and small airways. Infection
and tissue damage tends to be patchy rather than diffuse.
There are abundant signs of airway obstruction due to slough-
ing of epithelial cells, mucus secretion, and accumulated im-
mune cells. Syncytia are sometimes observed in the bronchio-
lar epithelium but are not common. However, syncytium
formation and giant-cell pneumonia are hallmarks of infection
in individuals with extreme T-cell deficiency.
Fifty percent or more of infants hospitalized with RSV lower
respiratory tract disease have subsequent episodes of wheezing
that in some cases can persist until 11 years of age or more (57,
140). It is of interest whether infection is a causal factor or
whether severe infection and wheezing are comarkers of an
underlying vulnerability. Evidence for causality in at least a
subset of individuals comes from a recent study in which suc-
cessful palivizumab prophylaxis of preterm infants was associ-
ated with reduced wheezing compared to untreated controls
when assessed at approximately 3.5 years of age (140). There
also is evidence that congenital vulnerability is involved and an
2042 MINIREVIEWJ. VIROL.
82. Kim, H. W., S. L. Leikin, J. Arrobio, C. D. Brandt, R. M. Chanock, and
R. H. Parrott. 1976. Cell-mediated immunity to respiratory syncytial virus
induced by inactivated vaccine or by infection. Pediatr. Res. 10:75–78.
83. King, J. C., Jr., A. R. Burke, J. D. Clemens, P. Nair, J. J. Farley, P. E. Vink,
S. R. Batlas, M. Rao, and J. P. Johnson. 1993. Respiratory syncytial virus
illnesses in human immunodeficiency virus- and noninfected children. Pe-
diatr. Infect. Dis. J. 12:733–739.
84. Kochva, U., H. Leonov, and I. T. Arkin. 2003. Modeling the structure of the
respiratory syncytial virus small hydrophobic protein by silent-mutation
analysis of global searching molecular dynamics. Protein Sci. 12:2668–2674.
85. Kolokoltsov, A. A., D. Deniger, E. H. Fleming, N. J. Roberts, Jr., J. M.
Karpilow, and R. A. Davey. 2007. siRNA profiling reveals key role of
clathrin-mediated endocytosis and early endosome formation for infection
by respiratory syncytial virus. J. Virol. 81:7786–7800.
86. Krempl, C. D., A. Wnekowicz, E. W. Lamirande, G. Nayebagha, P. L.
Collins, and U. J. Buchholz. 2007. Identification of a novel virulence factor
in recombinant pneumonia virus of mice. J. Virol. 81:9490–9501.
87. Krishnan, S., M. Craven, R. C. Welliver, N. Ahmad, and M. Halonen. 2003.
Differences in participation of innate and adaptive immunity to respiratory
syncytial virus in adults and neonates. J. Infect. Dis. 188:433–439.
88. Kristjansson, S., S. P. Bjarnarson, G. Wennergren, A. H. Palsdottir, T.
Arnadottir, A. Haraldsson, and I. Jonsdottir. 2005. Respiratory syncytial
virus and other respiratory viruses during the first 3 months of life promote
a local TH2-like response. J. Allergy Clin. Immunol. 116:805–811.
89. Kunzelmann, K., J. Sun, J. Meanger, N. J. King, and D. I. Cook. 2007.
Inhibition of airway Na?transport by respiratory syncytial virus. J. Virol.
90. Kurt-Jones, E. A., L. Popova, L. Kwinn, L. M. Haynes, L. P. Jones, R. A.
Tripp, E. E. Walsh, M. W. Freeman, D. T. Golenbock, L. J. Anderson, and
R. W. Finberg. 2000. Pattern recognition receptors TLR4 and CD14 me-
diate response to respiratory syncytial virus. Nat. Immunol. 1:398–401.
91. Laham, F. R., V. Israele, J. M. Casellas, A. M. Garcia, C. M. Lac Prugent,
S. J. Hoffman, D. Hauer, B. Thumar, M. I. Name, A. Pascual, N. Taratutto,
M. T. Ishida, M. Balduzzi, M. Maccarone, S. Jackli, R. Passarino, R. A.
Gaivironsky, R. A. Karron, N. R. Polack, and F. P. Polack. 2004. Differ-
ential production of inflammatory cytokines in primary infection with hu-
man metapneumovirus and with other common respiratory viruses of in-
fancy. J. Infect. Dis. 189:2047–2056.
92. Lee, F. E., E. E. Walsh, A. R. Falsey, M. E. Lumb, N. V. Okam, N. Liu, A. A.
Divekar, C. B. Hall, and T. R. Mosmann. 2007. Human infant respiratory
syncytial virus (RSV)-specific type 1 and 2 cytokine responses ex vivo during
primary RSV infection. J. Infect. Dis. 195:1779–1788.
93. Legg, J. P., I. R. Hussain, J. A. Warner, S. L. Johnston, and J. O. Warner.
2003. Type 1 and type 2 cytokine imbalance in acute respiratory syncytial
virus bronchiolitis. Am. J. Respir. Crit. Care Med. 168:633–639.
94. Liu, P., M. Jamaluddin, K. Li, R. P. Garofalo, A. Casola, and A. R. Brasier.
2007. Retinoic acid-inducible gene I mediates early antiviral response and
Toll-like receptor 3 expression in respiratory syncytial virus-infected airway
epithelial cells. J. Virol. 81:1401–1411.
95. Lo, M. S., R. M. Brazas, and M. J. Holtzman. 2005. Respiratory syncytial
virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 ex-
pression and alpha/beta interferon responsiveness. J. Virol. 79:9315–9319.
96. Lukacs, N. W., M. L. Moore, B. D. Rudd, A. A. Berlin, R. D. Collins, S. J.
Olson, S. B. Ho, and R. S. Peebles, Jr. 2006. Differential immune responses
and pulmonary pathophysiology are induced by two different strains of
respiratory syncytial virus. Am. J. Pathol 169:977–986.
97. Malley, R., J. DeVincenzo, O. Ramilo, P. H. Dennehy, H. C. Meissner, W. C.
Gruber, P. J. Sanchez, H. Jafri, J. Balsley, D. Carlin, S. Buckingham, L.
Vernacchio, and D. M. Ambrosino. 1998. Reduction of respiratory syncytial
virus (RSV) in tracheal aspirates in intubated infants by use of humanized
monoclonal antibody to RSV F protein. J. Infect. Dis. 178:1555–1561.
98. Martinez, F. D. 2005. Heterogeneity of the association between lower
respiratory illness in infancy and subsequent asthma. Proc. Am. Thorac.
99. Martinez, F. D., W. J. Morgan, A. L. Wright, C. J. Holberg, and L. M.
Taussig. 1988. Diminished lung function as a predisposing factor for wheez-
ing respiratory illness in infants. N. Engl. J. Med. 319:1112–1117.
100. McNamara, P. S., B. F. Flanagan, C. A. Hart, and R. L. Smyth. 2005.
Production of chemokines in the lungs of infants with severe respiratory
syncytial virus bronchiolitis. J. Infect. Dis. 191:1225–1232.
101. McNamara, P. S., P. Ritson, A. Selby, C. A. Hart, and R. L. Smyth. 2003.
Bronchoalveolar lavage cellularity in infants with severe respiratory syncy-
tial virus bronchiolitis. Arch. Dis. Child. 88:922–926.
102. McNamara, P. S., and R. L. Smyth. 2002. The pathogenesis of respiratory
syncytial virus disease in childhood. Br. Med. Bull. 61:13–28.
103. Melero, J. A., B. Garcia-Barreno, I. Martinez, C. R. Pringle, and P. A.
Cane. 1997. Antigenic structure, evolution and immunobiology of human
respiratory syncytial virus attachment (G) protein. J. Gen. Virol. 78:2411–
104. Midulla, F., Y. T. Huang, I. A. Gilbert, N. M. Cirino, E. R. McFadden, Jr.,
and J. R. Panuska. 1989. Respiratory syncytial virus infection of human
cord and adult blood monocytes and alveolar macrophages. Am. Rev.
Respir. Dis. 140:771–777.
105. Miller, E. K., X. Lu, D. D. Erdman, K. A. Poehling, Y. Zhu, M. R. Griffin,
T. V. Hartert, L. J. Anderson, G. A. Weinberg, C. B. Hall, M. K. Iwane, and
K. M. Edwards. 2007. Rhinovirus-associated hospitalizations in young chil-
dren. J. Infect. Dis. 195:773–781.
106. Mills, J., V. J. E. Van Kirk, P. F. Wright, and R. M. Chanock. 1971.
Experimental respiratory syncytial virus infection of adults. Possible mech-
anisms of resistance to infection and illness. J. Immunol. 107:123–130.
107. Mobbs, K. J., R. L. Smyth, U. O’Hea, D. Ashby, P. Ritson, and C. A. Hart.
2002. Cytokines in severe respiratory syncytial virus bronchiolitis. Pediatr.
108. Monick, M. M., T. O. Yarovinsky, L. S. Powers, N. S. Butler, A. B. Carter,
G. Gudmundsson, and G. W. Hunninghake. 2003. Respiratory syncytial
virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin.
J. Biol. Chem. 278:53035–53044.
109. Murphy, B. R. 2005. Mucosal immunity to viruses. In J. E. A. Mestecky
(ed.), Mucosal immunity. Elsevier Academic Press, Amsterdam, The Neth-
110. Murphy, B. R., G. A. Prince, P. L. Collins, K. Van Wyke Coelingh, R. A.
Olmsted, M. K. Spriggs, R. H. Parrott, H. W. Kim, C. D. Brandt, and R. M.
Chanock. 1988. Current approaches to the development of vaccines effec-
tive against parainfluenza and respiratory syncytial viruses. Virus Res. 11:
111. Murphy, B. R., G. A. Prince, E. E. Walsh, H. W. Kim, R. H. Parrott, V. G.
Hemming, W. J. Rodriguez, and R. M. Chanock. 1986. Dissociation be-
tween serum neutralizing and glycoprotein antibody responses of infants
and children who received inactivated respiratory syncytial virus vaccine.
J. Clin. Microbiol. 24:197–202.
112. Murphy, B. R., D. D. Richman, E. G. Chalhub, C. P. Uhlendorf, S. Baron,
and R. M. Chanock. 1975. Failure of attenuated temperature-sensitive
influenza A (H3N2) virus to induce heterologous interference in humans to
parainfluenza type 1 virus. Infect. Immun. 12:62–68.
113. Openshaw, P. J., S. L. Clarke, and F. M. Record. 1992. Pulmonary eosino-
philic response to respiratory syncytial virus infection in mice sensitized to
the major surface glycoprotein G. Int. Immunol. 4:493–500.
114. Panuska, J. R., R. Merolla, N. A. Rebert, S. P. Hoffmann, P. Tsivitse, N. M.
Cirino, R. H. Silverman, and J. A. Rankin. 1995. Respiratory syncytial virus
induces interleukin-10 by human alveolar macrophages. Suppression of
early cytokine production and implications for incomplete immunity.
J. Clin. Investig. 96:2445–2453.
115. Paulus, S. C., A. F. Hirschfeld, R. E. Victor, J. Brunstein, E. Thomas, and
S. E. Turvey. 2007. Common human Toll-like receptor 4 polymorphisms:
role in susceptibility to respiratory syncytial virus infection and functional
immunological relevance. Clin. Immunol. 123:252–257.
116. Peebles, R. S., Jr., K. Hashimoto, R. D. Collins, K. Jarzecka, J. Furlong,
D. B. Mitchell, J. R. Sheller, and B. S. Graham. 2001. Immune interaction
between respiratory syncytial virus infection and allergen sensitization crit-
ically depends on timing of challenges. J. Infect. Dis. 184:1374–1379.
117. Perez, M., B. Garcia-Barreno, J. A. Melero, L. Carrasco, and R. Guinea.
1997. Membrane permeability changes induced in Escherichia coli by the
SH protein of human respiratory syncytial virus. Virology 235:342–351.
118. Phipps, S., C. E. Lam, S. Mahalingam, M. Newhouse, R. Ramirez, H. F.
Rosenberg, P. S. Foster, and K. I. Matthaei. 2007. Eosinophils contribute to
innate antiviral immunity and promote clearance of respiratory syncytial
virus. Blood 110:1578–1586.
119. Polack, F. P., P. M. Irusta, S. J. Hoffman, M. P. Schiatti, G. A. Melendi,
M. F. Delgado, F. R. Laham, B. Thumar, R. M. Hendry, J. A. Melero, R. A.
Karron, P. L. Collins, and S. R. Kleeberger. 2005. The cysteine-rich region
of respiratory syncytial virus attachment protein inhibits innate immunity
elicited by the virus and endotoxin. Proc. Natl. Acad. Sci. USA 102:8996–
120. Polack, F. P., M. N. Teng, P. L. Collins, G. A. Prince, M. Exner, H. Regele,
D. D. Lirman, R. Rabold, S. J. Hoffman, C. L. Karp, S. R. Kleeberger, M.
Wills-Karp, and R. A. Karron. 2002. A role for immune complexes in
enhanced respiratory syncytial virus disease. J. Exp. Med. 196:859–865.
121. Prescott, S. L., C. Macaubas, B. J. Holt, T. B. Smallacombe, R. Loh, P. D.
Sly, and P. G. Holt. 1998. Transplacental priming of the human immune
system to environmental allergens: universal skewing of initial T cell re-
sponses toward the Th2 cytokine profile. J. Immunol. 160:4730–4737.
122. Prince, G., A. Mathews, S. Curtis, and D. Porter. 2000. Treatment of
respiratory syncytial virus bronchiolitis and pneumonia in a cotton rat
model with systemically administered monoclonal antibody (palivizumab)
and glucocorticosteroid. J. Infect. Dis. 182:1326–1330.
123. Prince, G. A., S. J. Curtis, K. C. Yim, and D. D. Porter. 2001. Vaccine-
enhanced respiratory syncytial virus disease in cotton rats following immu-
nization with Lot 100 or a newly prepared reference vaccine. J. Gen. Virol.
124. Prince, G. A., V. G. Hemming, R. L. Horswood, P. A. Baron, and R. M.
Chanock. 1987. Effectiveness of topically administered neutralizing anti-
bodies in experimental immunotherapy of respiratory syncytial virus infec-
tion in cotton rats. J. Virol. 61:1851–1854.
2054 MINIREVIEW J. VIROL.
125. Puthothu, B., J. Forster, J. Heinze, A. Heinzmann, and M. Krueger. 2007.
Surfactant protein B polymorphisms are associated with severe respiratory
syncytial virus infection, but not with asthma. BMC Pulm. Med. 7:6.
126. Puthothu, B., J. Forster, A. Heinzmann, and M. Krueger. 2006. TLR-4 and
CD14 polymorphisms in respiratory syncytial virus associated disease. Dis.
127. Puthothu, B., M. Krueger, J. Heinze, J. Forster, and A. Heinzmann. 2006.
Haplotypes of surfactant protein C are associated with common paediatric
lung diseases. Pediatr. Allergy Immunol. 17:572–577.
128. Richardson, L. S., R. B. Belshe, W. T. London, D. L. Sly, D. A. Prevar, E.
Camargo, and R. M. Chanock. 1978. Evaluation of five temperature-sen-
sitive mutants of respiratory syncytial virus in primates: I. Viral shedding,
immunologic response, and associated illness. J. Med. Virol. 3:91–100.
129. Roberts, S. R., D. Lichtenstein, L. A. Ball, and G. W. Wertz. 1994. The
membrane-associated and secreted forms of the respiratory syncytial virus
attachment glycoprotein G are synthesized from alternative initiation
codons. J. Virol. 68:4538–4546.
130. Roe, M. F., D. M. Bloxham, D. K. White, R. I. Ross-Russell, R. T. Tasker,
and D. R. O’Donnell. 2004. Lymphocyte apoptosis in acute respiratory
syncytial virus bronchiolitis. Clin. Exp. Immunol. 137:139–145.
131. Roman, M., W. J. Calhoun, K. L. Hinton, L. F. Avendano, V. Simon, A. M.
Escobar, A. Gaggero, and P. V. Diaz. 1997. Respiratory syncytial virus
infection in infants is associated with predominant Th-2-like response.
Am. J. Respir. Crit. Care Med. 156:190–195.
132. Sakurai, H., R. A. Williamson, J. E. Crowe, J. A. Beeler, P. Poignard, R. B.
Bastidas, R. M. Chanock, and D. R. Burton. 1999. Human antibody re-
sponses to mature and immature forms of viral envelope in respiratory
syncytial virus infection: significance for subunit vaccines. J. Virol. 73:2956–
133. Sastre, P., A. G. Oomens, and G. W. Wertz. 2007. The stability of human
respiratory syncytial virus is enhanced by incorporation of the baculovirus
GP64 protein. Vaccine 25:5025–5033.
134. Schlender, J., V. Hornung, S. Finke, M. Gunthner-Biller, S. Marozin, K.
Brzozka, S. Moghim, S. Endres, G. Hartmann, and K. K. Conzelmann.
2005. Inhibition of toll-like receptor 7- and 9-mediated alpha/beta inter-
feron production in human plasmacytoid dendritic cells by respiratory syn-
cytial virus and measles virus. J. Virol. 79:5507–5515.
135. Schlender, J., G. Walliser, J. Fricke, and K. K. Conzelmann. 2002. Respi-
ratory syncytial virus fusion protein mediates inhibition of mitogen-induced
T-cell proliferation by contact. J. Virol. 76:1163–1170.
136. Schwarze, J., D. R. O’Donnell, A. Rohwedder, and P. J. Openshaw. 2004.
Latency and persistence of respiratory syncytial virus despite T cell immu-
nity. Am. J. Respir. Crit. Care Med. 169:801–805.
137. Siber, G. R., D. Leombruno, J. Leszczynski, J. McIver, D. Bodkin, R. Gonin,
C. M. Thompson, E. E. Walsh, P. A. Piedra, V. G. Hemming, et al. 1994.
Comparison of antibody concentrations and protective activity of respira-
tory syncytial virus immune globulin and conventional immune globulin.
J. Infect. Dis. 169:1368–1373.
138. Sidwell, R. W., and D. L. Barnard. 2006. Respiratory syncytial virus infec-
tions: recent prospects for control. Antiviral Res. 71:379–390.
139. Sigurs, N., P. M. Gustafsson, R. Bjarnason, F. Lundberg, S. Schmidt, F.
Sigurbergsson, and B. Kjellman. 2005. Severe respiratory syncytial virus
bronchiolitis in infancy and asthma and allergy at age 13. Am. J. Respir.
Crit. Care Med. 171:137–141.
140. Simoes, E. A., J. R. Groothuis, X. Carbonell-Estrany, C. H. Rieger, I.
Mitchell, L. M. Fredrick, and J. L. Kimpen. 2007. Palivizumab prophylaxis,
respiratory syncytial virus, and subsequent recurrent wheezing. J. Pediatr.
141. Spann, K. M., K. C. Tran, and P. L. Collins. 2005. Effects of nonstructural
proteins NS1 and NS2 of human respiratory syncytial virus on interferon
regulatory factor 3, NF-?B, and proinflammatory cytokines. J. Virol. 79:
142. Srikiatkhachorn, A., and T. J. Braciale. 1997. Virus-specific CD8? T lym-
phocytes downregulate T helper cell type 2 cytokine secretion and pulmo-
nary eosinophilia during experimental murine respiratory syncytial virus
infection. J. Exp. Med. 186:421–432.
143. Sung, R. Y., S. H. Hui, C. K. Wong, C. W. Lam, and J. Yin. 2001. A
comparison of cytokine responses in respiratory syncytial virus and influ-
enza A infections in infants. Eur. J. Pediatr. 160:117–122.
144. Tal, G., A. Mandelberg, I. Dalal, K. Cesar, E. Somekh, A. Tal, A. Oron, S.
Itskovich, A. Ballin, S. Houri, A. Beigelman, O. Lider, G. Rechavi, and N.
Amariglio. 2004. Association between common Toll-like receptor 4 muta-
tions and severe respiratory syncytial virus disease. J. Infect. Dis. 189:2057–
145. Taylor, G. 2007. Immunology of RSV, p. 89–114. In P. A. Cane (ed.),
Respiratory syncytial virus, 14th ed. Elsevier, Amsterdam, The Nether-
146. Teng, M. N., and P. L. Collins. 2002. The central conserved cystine noose
of the attachment G protein of human respiratory syncytial virus is not
required for efficient viral infection in vitro or in vivo. J. Virol. 76:6164–
147. Teng, M. N., and P. L. Collins. 1998. Identification of the respiratory
syncytial virus proteins required for formation and passage of helper-de-
pendent infectious particles. J. Virol. 72:5707–5716.
148. Teng, M. N., S. S. Whitehead, and P. L. Collins. 2001. Contribution of the
respiratory syncytial virus G glycoprotein and its secreted and membrane-
bound forms to virus replication in vitro and in vivo. Virology 289:283–296.
149. Tortorolo, L., A. Langer, G. Polidori, G. Vento, B. Stampachiacchere, L.
Aloe, and G. Piedimonte. 2005. Neurotrophin overexpression in lower air-
ways of infants with respiratory syncytial virus infection. Am. J. Respir. Crit.
Care Med. 172:233–237.
150. Trento, A., M. Viegas, M. Galiano, C. Videla, G. Carballal, A. S. Mistch-
enko, and J. A. Melero. 2006. Natural history of human respiratory syncytial
virus inferred from phylogenetic analysis of the attachment (G) glycopro-
tein with a 60-nucleotide duplication. J. Virol. 80:975–984.
151. Tripp, R. A., L. P. Jones, L. M. Haynes, H. Zheng, P. M. Murphy, and L. J.
Anderson. 2001. CX3C chemokine mimicry by respiratory syncytial virus G
glycoprotein. Nat. Immunol. 2:732–738.
152. Valarcher, J. F., J. Furze, S. Wyld, R. Cook, K. K. Conzelmann, and G.
Taylor. 2003. Role of alpha/beta interferons in the attenuation and immu-
nogenicity of recombinant bovine respiratory syncytial viruses lacking NS
proteins. J. Virol. 77:8426–8439.
153. Vallbracht, S., H. Unsold, and S. Ehl. 2006. Functional impairment of
cytotoxic T cells in the lung airways following respiratory virus infections.
Eur. J. Immunol. 36:1434–1442.
154. Varga, S. M., E. L. Wissinger, and T. J. Braciale. 2000. The attachment (G)
glycoprotein of respiratory syncytial virus contains a single immunodomi-
nant epitope that elicits both Th1 and Th2 CD4? T cell responses. J. Im-
155. Weitkamp, J. H., B. J. Lafleur, and J. E. Crowe, Jr. 2006. Rotavirus-specific
CD5? B cells in young children exhibit a distinct antibody repertoire
compared with CD5? B cells. Hum. Immunol. 67:33–42.
156. Weitkamp, J. H., B. J. Lafleur, H. B. Greenberg, and J. E. Crowe, Jr. 2005.
Natural evolution of a human virus-specific antibody gene repertoire by
somatic hypermutation requires both hotspot-directed and randomly-di-
rected processes. Hum. Immunol. 66:666–676.
157. Welliver, R. C. 2003. Review of epidemiology and clinical risk factors for
severe respiratory syncytial virus (RSV) infection. J. Pediatr. 143:S112–
158. Welliver, R. C., D. T. Wong, M. Sun, E. Middleton, Jr., R. S. Vaughan, and
P. L. Ogra. 1981. The development of respiratory syncytial virus-specific
IgE and the release of histamine in nasopharyngeal secretions after infec-
tion. N. Engl. J. Med. 305:841–846.
159. Welliver, T. P., R. P. Garofalo, Y. Hosakote, K. H. Hintz, L. Avendano, K.
Sanchez, L. Velozo, H. Jafri, S. Chavez-Bueno, P. L. Ogra, L. McKinney,
J. L. Reed, and R. C. Welliver, Sr. 2007. Severe human lower respiratory
tract illness caused by respiratory syncytial virus and influenza virus is
characterized by the absence of pulmonary cytotoxic lymphocyte responses.
J. Infect. Dis. 195:1126–1136.
160. Wenzel, S. E., R. L. Gibbs, M. V. Lehr, and E. A. Simoes. 2002. Respiratory
outcomes in high-risk children 7 to 10 years after prophylaxis with respira-
tory syncytial virus immune globulin. Am. J. Med. 112:627–633.
161. White, L. J., M. Waris, P. A. Cane, D. J. Nokes, and G. F. Medley. 2005. The
transmission dynamics of groups A and B human respiratory syncytial virus
(hRSV) in England & Wales and Finland: seasonality and cross-protection.
Epidemiol. Infect. 133:279–289.
162. Wilkinson, T. M., G. C. Donaldson, S. L. Johnston, P. J. Openshaw, and
J. A. Wedzicha. 2006. Respiratory syncytial virus, airway inflammation, and
FEV1 decline in patients with chronic obstructive pulmonary disease.
Am. J. Respir. Crit. Care Med. 173:871–876.
163. Wright, P. F., W. C. Gruber, M. Peters, G. Reed, Y. Zhu, F. Robinson, S.
Coleman-Dockery, and B. S. Graham. 2002. Illness severity, viral shedding,
and antibody responses in infants hospitalized with bronchiolitis caused by
respiratory syncytial virus. J. Infect. Dis. 185:1011–1018.
164. Zhang, L., A. Bukreyev, C. I. Thompson, B. Watson, M. E. Peeples, P. L.
Collins, and R. J. Pickles. 2005. Infection of ciliated cells by human para-
influenza virus type 3 in an in vitro model of human airway epithelium.
J. Virol. 79:1113–1124.
165. Zhang, L., M. E. Peeples, R. C. Boucher, P. L. Collins, and R. J. Pickles.
2002. Respiratory syncytial virus infection of human airway epithelial cells
is polarized, specific to ciliated cells, and without obvious cytopathology.
J. Virol. 76:5654–5666.
166. Zimmer, G., M. Rohn, G. P. McGregor, M. Schemann, K. K. Conzelmann,
and G. Herrler. 2003. Virokinin, a bioactive peptide of the tachykinin
family, is released from the fusion protein of bovine respiratory syncytial
virus. J. Biol. Chem. 278:46854–46861.
167. Zlateva, K. T., P. Lemey, E. Moes, A. M. Vandamme, and M. Van Ranst.
2005. Genetic variability and molecular evolution of the human respiratory
syncytial virus subgroup B attachment G protein. J. Virol. 79:9157–9167.
VOL. 82, 2008 MINIREVIEW2055