Opinion
Can viruses form biofilms?
Maria-Isabel Thoulouze1,2 and Andrés Alcover1,2
1
Institut Pasteur, Lymphocyte Cell Biology Unit, Department of Immunology, 28 rue du Dr Roux, F-75724 Paris, France
2
CNRS-URA-1961, F-75724 Paris, France
The recent finding that the human T-cell leukemia virus
type 1 (HTLV-1) encases itself in a carbohydrate-rich
adhesive extracellular ‘cocoon’, which enables its effi-
cient and protected transfer between cells, unveiled a
new infectious entity and a novel mechanism of viral
transmission. These HTLV-1 structures are observed at
the surface of T cells from HTLV-1-infected patients and
are reminiscent of bacterial biofilms. The virus controls
the synthesis of the matrix, which surrounds the virions
and attaches them to the T cell surface. We propose that,
similar to bacterial biofilms, viral biofilms could repre-
sent ‘viral communities’ with enhanced infectious ca-
pacity and improved spread compared with ‘free’ viral
particles, and might constitute a key reservoir for chronic
infections.
Different modes of cell–cell virus spread
As strict intracellular parasites, viruses are completely
dependent on their host cells to replicate. Following a viral
replication cycle, newly formed viral particles produced by
infected cells have to reach the surface of other non-
infected target cells to start a new viral replication cycle.
This extracellular state represents a crucial step for viral
dissemination, because viral particles are exposed to ex-
tracellular constraints, including physicochemical varia-
tions (such as desiccation and pH variations), or host
immune defenses.
It is commonly accepted that the spread of most viruses
occurs via the diffusion of ‘cell-free’ viral particles. In
support of this, infectious viruses have been found in
biological fluids and aerosols, and could be propagated
in vitro using virus stocks produced from infected cell-
culture supernatants. This mode of viral dissemination
requires high numbers of stable viral particles released
by the infected cell into the extracellular environment,
such as the host bodily fluids. ‘Free’ viral particles were
associated with a variety of components, such as lipids or
proteins [1,2], which might reinforce virus envelop integri-
ty and prevent envelope glycoprotein shedding.
However, for other viruses, few viral particles are re-
leased, or they are poorly infectious when separated from
infected cells. In such cases, virus propagation largely
requires the presence of infected cells, suggesting that cell
contacts mediate viral spread [3]. This type of dissemina-
tion is mainly reported for enveloped viruses, such as some
herpes viruses and some retroviruses, particularly deltar-
etroviruses such as the human T-cell leukemia virus type 1
(HTLV-1) [4]. Many aspects of this mode of virus dissemi-
nation are largely unknown, such as (i) the nature and the
Corresponding author: Thoulouze, M.-I. (marie-isabelle.thoulouze@pasteur.fr).
0966-842X/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2011.03.002 Trends in Microbiology, June 2011, Vol. 19, No. 6
mechanism for forming cellular junctions that mediate
cell–cell virus spread, and (ii) the nature of the infectious
material transferred. Both of these factors depend on the
virus and the type of infected cells.
Of note, the spread of two human retroviruses that
infect leukocytes, HIV-1 and HTLV-1, occurs between
mobile cells forming dynamic contacts with other cells.
Both retroviruses cause severe chronic viral infections.
Their transmission between individuals occurs through
sexual contact and blood transfusion, and vertically from
mother to child, including through breastfeeding.
In addition to HTLV-1 dissemination through division
of infected cells carrying viral genomes, transmission of
HTLV-1 viral particles is known to occur mainly through
cell contact in vitro and in vivo [5], with the exception of
dendritic cells, which can be infected by cell-free viral
particles [6]. By contrast, HIV-1 spread can occur by both
diffusion and direct cell–cell transfer. Nevertheless, com-
pelling evidence indicates that direct spread through cell
contact is the most efficient mode of HIV-1 dissemination
in vitro, and might play a crucial role in vivo [7,8].
During the past two decades, important aspects con-
cerning the way that retroviruses spread from cell to cell
were discovered [3,[4]. Thus, although the existence of
tight cell contacts between infected and uninfected cells,
where viral particles accumulated, were described in the
1990 s [9,10], it has only been within the past 8 years that
the so-called ‘virological synapses’ have raised much inter-
est (see Glossary). These are ‘virus-induced organized cell–
cell contacts’, which were proposed to optimize virus cell–
cell transmission while limiting the exposure of virions
to the host immune defenses [11–13]. They share some
features with immunological synapses formed between T
cells and antigen-presenting cells, such as microtubule
polarization or the reorganization of some cytoskeletal
proteins [14]. The HTLV-1-encoded transactivator Tax
Glossary
Virological synapse: virus-induced, specialized cell–cell contact area that
promotes the directed transmission of viruses between cells, by concentrating
virions and viral receptors. Virological synapses are thought to maximize the
efficiency of transmission and limit the exposure of the virus to the host
defense mechanisms.
Bacterial biofilms: can be defined as microbial aggregates encased in a matrix
of extracellular polymeric substances highly enriched in exopolysaccharides
produced by the bacteria. Biofilms are usually found on solid, liquid or
biological surfaces. Extracellular matrix proteins (such as fibrinogen) or lectins
(such as galectin-3) produced by host cells can also cooperate with bacterial
proteins, and enhance cohesion and adhesiveness. Biofilms protect microbial
colonies from the environment, modify their metabolism, and are a mode of
symbiotic life between different bacterial strains present in the biofilm, and
between bacteria and the colonized tissue.
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()TD$FIG][ Opinion Trends in Microbiology June 2011, Vol. 19, No. 6

(a) (b) (c)

TRENDS in Microbiology

Figure 1. ‘Viral biofilms’ at the surface of HTLV-1-infected cells. See [26] for a more detailed description and characterization of these infectious structures. (a) Viral
components are clustered and tightly attached to the surface of infected cells. Confocal microscopy of primary CD4+ T cells from HTLV-1-infected individuals showing cell-
surface glycoproteins stained with Con A (green) and viral proteins stained with HTLV-1 specific serum (red) and with Gag antibody (blue) (arrow). (b) Scanning electron
microscopy of T cells chronically infected with HTLV-1 displaying virus clusters on their surface, as assessed by Env staining with immunogold (white dots, arrows)
surrounded by cell-surface ruffles (smooth surface). (c) Transmission electron microscopy of T cells chronically infected with HTLV-1. Mature virus particles (dense core
surrounded by an envelope, arrows) are embedded in an electron-dense mesh corresponding to the ECM.

was reported to modulate T-cell polarization processes
[14,15]. Less intimate cell–cell contacts made by filopodia
or nanotubes were also reported to convey retroviral par-
ticles between cells [16–18]. Finally, several cell–cell con-
tacts made between one infected cell and several target
cells, through which HIV-1 could spread, were also ob-
served, indicating that stable cell polarization was not
required for HIV-1 cell–cell transmission [19].
However, the nature of the infectious material trans-
ferred between cells and its organization at cell–cell con-
tacts remained poorly documented. For both HTLV-1 and
HIV-1, it was proposed that ‘free’ viral particles could bud
in synaptic clefts at cell contacts [11,20,21]. In addition for
HIV-1, formation of cell-surface structures called ‘synaptic
buttons’ has also been proposed to have a role during
transmission [22]. The transfer of non-enveloped viral
nucleocapsids was also envisaged, but never reported.
Several reports show that HIV-1 viral particles remain
partially exposed to neutralizing antibodies, suggesting
that their transfer does not take place through hermetic
synaptic clefts [23,24]. Moreover, studies indicating that
most infectious viral particles were transferred as viral
clusters outside tight contact zones suggested the existence
of extracellular infectious structures containing partially
exposed viral particles at the surface of infected cells [22].
Finally, how viral particles are organized when ‘surfing’ on
filopodia or nanotubes remains to be determined.
Definition of a new extracellular viral infectious entity
Although some viruses were found in biological fluids
associated with particular lipids [25] or proteins, which
enhanced virus transmission [2], the involvement of more
complex, virally induced, extracellular infectious struc-
tures was not expected. The discovery on the surface of
HTLV-1-infected T cells of carbohydrate-rich adhesive
extracellular viral assemblies, which efficiently transfer
viruses between cells, led to the characterization of a new
extracellular infectious entity and a novel mechanism of
viral transmission [26,27].
Extracellular assemblies of HTLV-1 are formed by clus-
ters of enveloped viral particles embedded in a matrix of
glycoproteins produced by the infected cell under the con-
trol of the virus. They have been observed tightly adhered
to the surface of infected T lymphocytes from HTLV-1-
infected patients or on transformed, chronically infected,
T-cell lines (Figure 1). The matrix was found to be enriched
in highly glycosylated proteins, as assessed by their label-
ing with a panel of fluorescently labeled plant lectins
recognizing particular carbohydrate residues, including
sialyl LewisX. Extracellular matrix (ECM) components,
including collagen, some specific heparan sulfate proteo-
glycans such as agrin, and several linker proteins such as
galectin-3 and tetherin, were found to be enriched in these
structures [26]. No evidence has been found to date for the
involvement of the HTLV-1 receptor and attachment-mol-
ecule complexes in the formation of the HTLV-1 extracel-
lular viral assemblies, although this cannot be completely
excluded. Furthermore, most of the ECM components
concentrated in HTLV-1 viral assemblies are overex-
pressed or specifically relocalized in cells naturally infected
with HTLV-1 (Figure 2). Importantly, these extracellular
viral assemblies were key to HTLV-1 spread from cell to
cell; treating HTLV-1-infected cells with agents competing
with ECM interactions disrupted HTLV-1 assemblies,
strongly inhibiting the capacity of virus-producing cells
to infect other cells. When detached from the infected cell,
viral clusters and released viral particles were far less
infectious [26].
Extracellular viral assemblies share some structural and
functional features with bacterial biofilms
Most bacteria do not exist in their natural environment as
isolated cells, but instead grow in organized communities
that can adhere to inert or biological surfaces by forming
carbohydrate-rich structures termed ‘biofilms’ (see Glossa-
ry). These can form on solid or liquid surfaces, and on the
tissues of living organisms [28]. Biofilms have been defined
as a mode of microbial ‘growth on a surface within a
polymeric matrix that confers increased resistance proper-
ties to external influence such as antibiotics, host defenses
and shear forces’ [29]. The matrix that surrounds the
biofilm is broadly defined as extracellular material that
can derive from directed synthesis and secretion, or from
lysis of a fraction of the biofilm bacteria [28,30,31].
With time, the definition of biofilms has evolved to
include other aspects. It is now thought that biofilm for-
mation is driven by a genetic reprogramming of the bacte-
ria, resulting in important changes in metabolism, pili

258
()TD$FIG][ Opinion
CD4+ T lymphocyte
Overexpression and/or reorganization at the cell surface of
Key:
Proviral genome
Infectious virus
Defective virus
Extracellular matrix
and linker proteins
( ) Increased production
(⇔) Reorganization at the cellsurface
Figure 2. Model of ‘viral biofilm’ development on HTLV-1 infected lymphocytes. Viral-genome expression drives both the production of viral particles and of a matrix
enriched in certain carbohydrate moieties (e.g. sialyl Lewis X), ECM components (e.g. agrin and collagen), and some linker proteins (e.g. galectin-3 and tetherin). Some
components of this matrix are reorganized at the surface of infected cell (,), while the production of others is increased ([TD$INLE] ) upon infection. Together, infectious and
defective viral particles embedded in the carbohydrate-rich matrix form the infectious structure we name a ‘virus biofilm’.
formation and matrix synthesis, and in quorum-sensing
mechanisms that detect cell population density ensuring
controlled biofilm growth [32,33]. In addition, it has been
recognized that biofilms can display heterogeneous struc-
tures formed by a mosaic of microzones, characterized by a
spectrum of differentiated states of one type of bacterium,
or by a consortium of different bacteria [34].
Since the initial description of biofilms in 1978, many
species of bacteria have been shown to grow as biofilms,
and the ability to grow as a biofilm has been further
generalized to include yeast and fungi [35,36]. Can viruses
form biofilms? Extracellular viral assemblies described for
HTLV-1 display noticeable similarities to bacterial bio-
films in composition, organization and dissemination. Both
are complex adhesive structures containing microbial col-
onies intermingled in a complex, carbohydrate-rich, mul-
timolecular network. The particular composition and
organization of this virus community probably ensure its
protection, persistence in a particular environment and
capacity to spread, which are all hallmarks of bacterial
biofilms.
Some of the proteins and carbohydrate moieties present
in bacterial biofilms are enriched in extracellular viral
assemblies. For instance, HTLV-1-infection induces remo-
deling of the glycan pattern at the cell surface, resulting in
enrichment of specific glycan residues in extracellular viral
assemblies, as assessed by the labeling with a panel of
plant lectins previously used to characterize glycan com-
position of bacterial biofilms [37]. Sialyl LewisX, a tetra-
Trends in Microbiology June 2011, Vol. 19, No. 6
Viral ‘biofilm’
HTLV-1 infection
and
viral genome
expression
Production of viral particles:
(Infectious and defective)
- Extracellular matrix molecules:
Collagen ( )
Heparan sulfates including agrin (⇔)
- Linker proteins
Galectin-3 ( )
Tetherin (⇔)
- Extracellular matrix-modifying enzymes:
Fucosyltransferase-7 (FUT-7) ( )
Sialyl Lewis X synthesis ( )
TRENDS in Microbiology
saccharide present in some glycosylated proteins, was
found in both types of structures [26,38]. Other carbohy-
drate moieties, not yet characterized, which are recognized
by common plant lectins, might also be shared by bacterial
biofilms and extracellular viral assemblies.
The coordinate properties of highly glycosylated ECM
proteins could promote the generation of cocoon-type struc-
tures able to concentrate the microorganism in a protective
structure. Consistent with the protective properties of
HTLV-1 assemblies, supernatants obtained after cell
washes were much less infectious than infected cells,
indicating that the integrity of viral assemblies is required
for full HTLV-1 infectious capacity [26]. Concentration of
viral particles might be particularly relevant because ret-
roviral progeny are poorly infectious, and viral reverse
transcriptase generates a large pool of mutated genomes
[39]. Each viral biofilm might thus cluster a viral commu-
nity harboring the genomic diversity of viral particles
produced by a single infected cell (quasispecies) with a
concentrated infectivity. In addition, accumulating HTLV-
1 virions in these complex structures could protect them
from shearing forces experienced during cell migration
through the bloodstream or lymphatics, and from compo-
nents of the host immune system.
Hyperglycosylation of viral envelope glycoproteins
diminishes its recognition by neutralizing host antibodies.
The envelope protein of HTLV-1 is highly conserved and
poorly glycosylated [40], and protective structures
enriched in carbohydrate moieties could represent an
259
 Opinion Trends in Microbiology June 2011, Vol. 19, No. 6

alternative mechanism to counteract immune recognition.
As proposed for bacterial biofilms [41], the development of
such viral assemblies might favor the development of a
chronic infection, explaining the persistence of high num-
bers of HTLV-1-infected cells in HTLV-1-infected individ-
uals despite high levels of neutralizing antibodies [42].
Similar to bacterial biofilms that disperse, and then
adhere and colonize other surfaces, the physicochemical
properties of HTLV-1 extracellular assemblies could allow
viral dissemination. An appropriate balance between ad-
hesiveness, cohesiveness and the fractionation capacity of
these structures is likely to be crucial for virus spread (see
below) (Figure 3).
One major difference between bacterial biofilms and
viral assemblies is that the matrix composing conventional
biofilms is mainly synthesized by the microbe itself, where-
as the matrix of viral assemblies is produced by the
infected cell. Viruses are devoid of any intermediate me-
tabolism, and as strict parasites, they redirect the cell
machinery to synthesize viral-particle components and
cellular proteins required for their assembly, budding
and dissemination. Furthermore, HTLV-1 infection drives
the composition of the viral-assembly matrix, modulating
the expression and organization of several ECM and linker
proteins (Figure 2) [43–46].
Interestingly, the formation of bacterial biofilms on
tissues from living organisms might also result in the
secretion of matrix proteins by the colonized cells. These
[()TD$FIG]
matrix components assemble with those secreted by bac-
teria, forming a more complex and probably better-adapted
biofilm composition [30,47]. For instance, some biofilms
from Helicobacter pylori or Pseudomonas aeruginosa con-
tain sialyl LewisX-containing glycans synthesized by bac-
teria, together with galectin-3 produced by bystander cells;
both are essential for biofilm formation [38,48,49]. Both
sialyl LewisX and galectin-3 have been found in HTLV-1
extracellular viral assemblies.
Thus, extracellular viral assemblies and conventional
biofilms share some structural and molecular features,
resulting in the adhesive and protective properties that
characterize both infectious structures.
A model for viral biofilms: a new mode of viral
dissemination
The finding of extracellular viral assemblies with the
structural and functional features of biofilms opens novel
perspectives for the understanding of virus dissemination
(Figure 3). Virions could bud from the infected cell, and be
transiently concentrated in biofilm-like protective struc-
tures that remain adhered to the surface of the virus-
producing cell, but ready to adhere and spread to other
cells. Despite being resistant to shear forces, HTLV-1
extracellular assemblies can break down and adhere to
the surface of other lymphocytes during cell contacts,
facilitating their infection. Biofilm fragments, containing
both viral particles and the matrix, are transferred [26],
allowing the spread to multiple cells. It is likely that the
composition of the embedding matrix is tightly regulated to

(a) Infected T
lymphocyte

Target T
Viral ‘biofilm’ lymphocyte

(b)
Infected
cell Infected
cell Direct infection
(i) (ii) (iii)
Target (permissive)
Infected
cell cell
Target (permissive)
cell
Indirect infection
Target
(permissive)
Infected Infected cell
cell
(iv) cell
(v)
Key:
Infectious virus
Defective virus Viral DC or
Extracellular matrix ‘biofilm’ nonpermissive cell DC or
DC or
and linker proteins
nonpermissive cell nonpermissive cell
Viral capsid

TRENDS in Microbiology

Figure 3. ‘Viral biofilms’, a new mode of virus dissemination. (a) Transfer of viral ‘biofilms’ at the contact site between two primary CD4+ T cells from a person infected with
HTLV-1 Confocal microscopy was performed as in Figure 1a (for more details, see [26]). (b) Model of viral transmission through viral ‘biofilms’, including (i) viral biofilm
formation at the surface of infected cells, (ii) transfer of these infectious adhesive structures through dynamic interactions between infected and uninfected cells (permissive
or nonpermissive cells). The rupture and adhesion of biofilm fragments to the surface of these cells might lead to both the direct infection of permissive target cells (iii) and/
or the indirect infection through contacts with other cells [e.g. dendritic cells (DC) or nonpermissive cells] that might capture viral biofilms on their cell surface (iv), and
transfer them to target permissive cells (v) (‘transinfection’).

260
Opinion
promote the cohesion of these structures, while allowing
disassembly of the structure and release of viral particles
during cell contacts. Permissive recipient cells would be
directly infected, as observed for T cells. Other cells, such
as dendritic cells, might also be infected, or act as platforms
for infection of other lymphocytes [6].
We propose that virus biofilms could represent an un-
explored mode of viral ‘life’ and dissemination, which could
be particularly important for viruses that spread via cell
contacts, such as HTLV-1, but also for other viruses whose
replication is largely improved by cell–cell transmission.
To date, this mode of dissemination has been unveiled in
only in highly motile cells (lymphocytes), but could also
exist in other tissues, having different consequences for
virus spread.
As occurs with bacterial biofilms, which adapt to the
environment in which they develop, extracellular viral
assemblies could be different when generated by T cells
present in different host tissues, because their dynamic
shape and metabolism might not be the same. Thus, in vivo
extracellular viral assemblies would be expected to be of
smaller size than those observed in cultured infected lym-
phocytes, because they would be rapidly transferred to
target cells, such as T lymphocytes or dendritic cells during
cell contacts in the epithelium, endothelium, or secondary
lymphoid organs. HTLV-1 assemblies captured by dendrit-
ic cells could infect them. or be re-transferred to, and infect,
other T lymphocytes [6]. Dendritic cells could also process
and present viral antigens to T lymphocytes, triggering
and maintaining the anti-HTLV-1 immune response. The
balance between HTLV-1 transmission and immune re-
sponse could condition the pathological progression of each
infected individual, resulting in a chronic infection.
Conclusions and future directions
We propose that viruses can form extracellular assemblies
that resemble in composition, organization and dissemi-
nation bacterial biofilms. Viral biofilms form in tight
equilibrium with the infected cell, which provides the
machinery for the synthesis and assembly of virus com-
ponents, and for matrix components that will hold togeth-
er the biofilm (Figure 2). Finally, the infected cells provide
the initial surface to which the biofilm will adhere. Ex-
pression of the viral genome would drive the expression
and post-translational modifications of matrix compo-
nents, while cell-surface rearrangements (e.g. ruffles
and filopodia) would help to maintain viral biofilms on
the cell surface. A tightly regulated balance between
adhesion, cohesiveness and dispersion would ensure the
equilibrium between viral biofilm generation and dissem-
ination to other cells. An attractive hypothesis is that the
production of the viral biofilm could be an antiviral mech-
anism developed by the infected cell to encase infectious
viral particles, but which has been hijacked by some
viruses to spread efficiently. The production of the ECM
modulated by viral-genome expression in infected cells
would favor both viral particles trapped on the surface of
the infected cells, and virus spread through cell contacts.
The finding of virus biofilms suggests many fundamen-
tal questions (Box 1). Furthermore, as extracellular infec-
tious entities involved in virus dissemination, could virus
Trends in Microbiology June 2011, Vol. 19, No. 6
Box 1. Outstanding questions
 What cellular machinery is hijacked by the virus for the generation
of viral biofilms?
 What is the structure and molecular composition of viral biofilms?
 Can viral biofilms concentrate other cellular factors necessary for
infection of target cells?
 What is the importance of viral biofilms for direct cell–cell spread,
versus indirect spread through nonpermissive cells?
 Can other types of viruses generate biofilm-type structures as part
of their life cycle, and what is their importance for virus
dissemination?
 Can we detect and study viral biofilms in vivo?
 Are viral biofilms involved in the host immune response to the
virus?
 Are viral biofilms characteristic structures of chronic or acute
infections?
biofilms be potential therapeutic targets? This could be
envisaged in two ways: first, virus biofilm formation could
be inhibited as a means to reduce virus transmission;
second, and probably more interesting, viral biofilms could
be modified as a way to allow or enhance specific host
immune responses that would reduce chronic infection.
Acknowledgments
This work received funding from Institut Pasteur, CNRS, La Ligue
Contre le Cancer, Association pour la Recherche sur le Cancer (ARC),
Agence Nationale de Recherche (ANR), Agence Nationale de Recherche
sur le SIDA (ANRS), Fundação para a Ciência e a Tecnologia, Portugal,
the European Commission Marie Curie Actions Early Stage Training
Program Intrapath and EMBO. We thank A. M. Pais-Correia, M. Sachse,
S. Guadagnini, A. Gessain and O. Gout for their key contribution to the
work discussed here, and to R. Mahieux, S. Wain-Hobson and J. M. Ghigo
for stimulating discussions.
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