Why i uses some imes dispe se in g oups
†
Ra ael Sanjua´n
1,
* and Ma ı´a-Isabel Thoulouze
2,‡
1
Ins i u e o In eg a i e Sys ems Biology (I2SysBio), Consejo Supe io de In es igaciones Cien ı´ icas-
Uni e si a de Vale`ncia, C/Ca ed a´ ico Agus ı´n Esca dino 9, Pa e na, Vale`ncia 46980, Spain and and
2
Ins i u
Pas eu , S uc u al Vi ology Uni , Bio ilm & Vi al T ansmission G oup, Pa is, F ance
*Co esponding au ho : E-mail: [email p o ec ed]
‡
P esen add ess: IHAP, Uni e si e´ de Toulouse, INRA, ENVT, Toulouse, F ance.
Abs ac
Many o ganisms dispe se in g oups, ye his p ocess is unde s udied in i uses. Recen wo k, howe e , has unco e ed di -
e en ypes o collec i e in ec ious uni s, all o which lead o he join deli e y o mul iple i al genome copies o a ge
cells, a o ing co-in ec ions. Collec i e sp ead o i uses can occu h ough widely di e en mechanisms, including i ion
agg ega ion d i en by speci ic ex acellula componen s, cloaking inside lipid esicles, encasemen in p o ein ma ices, o
binding o cell su aces. Cell- o-cell i al sp ead, which allows he ansmission o indi idual i ions in a con ined en i on-
men , is ye ano he mode o clus e ed i us dissemina ion. Ne e heless, he selec i e ad an ages o dispe sing in g oups
emain poo ly unde s ood in mos cases. Collec i e dispe sal migh ha e eme ged as a means o sha ing e icacious i al
ansmission ehicles. Al e na i ely, inc easing he cellula mul iplici y o in ec ion may con e ce ain sho - e m bene i s
o i uses, such as o e whelming an i i al esponses, a oiding ea ly s ochas ic loss o i al componen s equi ed o ini ia -
ing in ec ion, o complemen ing gene ic de ec s p esen in di e en i al genomes. Howe e , inc easing in ec ion mul iplic-
i y may also en ail long- e m cos s, such as mu a ion accumula ion and he e olu ion o de ec i e pa icles o o he ypes
o chea e i uses. These cos s and bene i s, in u n, should depend on he gene ic ela edness among collec i e in ec ious
uni membe s. Es ablishing he gene ic basis o collec i e i al dispe sal and pe o ming con olled expe imen s o pinpoin
i ness e ec s a di e en spa ial and empo al scales should help us cla i y he implica ions o hese sp ead modes o i al
i ness, pa hogenici y, and e olu ion.
Key wo ds: i al sp ead; dispe sal; collec i e in ec ious uni ; mul iplici y o in ec ion; i al ansmission
1. Vi uses some imes a el in g oups
The i al pa icle, o i ion, has been adi ionally iewed as he
s uc u e ha media es i al sp ead wi hin and be ween indi-
iduals o hos s. Al hough his is p obably be ue in many
cases, i is also well es ablished ha single i ions o en ail o
es ablish p oduc i e in ec ions. Such low in ec i i y can be
explained by di e en ac o s, including s uc u al o gene ic
de ec s o i al pa icles esul ing om de icien mo phogenesis
o om deg ada ion, bu also om hos ac o s ela ed o cellu-
la pe missi i y o he i us (Klasse 2015;Sanjua´n 2018).
In e es ingly, o e he las yea s, se e al lines o e idence ha e
indica ed ha i al dissemina ion can also occu h ough p o-
cesses ha in ol e di e en ypes o complex mul i- i ion
s uc u es in addi ion o ee indi idual i ions. An expec ed
consequence o hese collec i e in ec ious uni s is ha hey
should inc ease he cellula mul iplici y o in ec ion (MOI), de-
ined as he a e age numbe o i al genomes ha ini ia e a cell
in ec ion. Ele a ing he MOI locally may con ibu e o inc easing
in ec i i y and may a o co-in ec ions. This migh be impo -
an o ensu e i us p opaga ion in ce ain issues o
†
Special Issue San a Fe Ins i u e Wo kshop on In eg a ing C i ical Phenomena and Mul i-Scale Selec ion in Vi us E olu ion, suppo ed by he NSF Ruleso
Li e P og am g an DEB-1830688.
V
CThe Au ho (s) 2019. Published by Ox o d Uni e si y P ess.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/
licenses/by-nc/4.0/), which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Fo comme cial e-use, please con ac [email p o ec ed]
‡
P esen add ess: IHAP, Uni e si e´ de Toulouse, INRA, ENVT,
Toulouse, F ance.
1
Vi us E olu ion, 2019, 5(1): ez014
doi: 10.1093/ e/ ez014
Re iew a icle
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
physiological compa men s. Howe e , esea ch in his opic is
s ill oo incipien o d aw solid conclusions. Below we e iew
di e en p ocesses whe eby mul iple i al genomes a e deli -
e ed simul aneously o hos cells, and we hen discuss possible
ad an ages and cos s o dispe sing in g oups o i uses. A sum-
ma y o di e en ypes o collec i e sp ead in i uses is p o-
ided in Fig. 1. These sp ead modes ha e been classi ied
acco ding o whe he hey media e he ans e o mul iple i al
pa icles o igina ing om he same cell o om di e en cells.
1.1 Cell- o-cell sp ead
P obably he bes s udied p ocess whe eby mul iple i ions a e
co- ans e ed be ween cells is cell- o-cell sp ead, which is
used by many di e en i uses. Cell- o-cell sp ead does no
ac ually in ol e ex acellula mul i- i ion s uc u es, ye i
enables he massi e ans e o indi idual i ions o he same
a ge cell in a con ined en i onmen by exploi ing s uc u es
ha b idge cells. By limi ing di usion o indi idual i al pa -
icles, cell- o cell sp ead locally inc eases he MOI and a o s
en y o mul iple i ions pe cell. Cell–cell con ac s can be
ei he p e-exis ing junc ions such as plasmodesma a, immu-
nological synapses and neu al synapses, o speci ic
i us-induced s uc u es such as i ological synapses, unnel-
ing nano ubes o synci ia esul ing om he usion o in ec ed
cells (Mo hes e al. 2010;Sa en au 2011;Zhong e al. 2013b;
Symeonides e al. 2015;G aw and Pe elson 2016). The abili y o
cell- o-cell sp ead o p omo e co-in ec ion was shown o HIV-
1(Del Po illo e al. 2011;Duncan e al. 2014;Law e al. 2016).
Howe e , expe imen s wi h e o i uses and plan i uses
also e ealed ha a e y small ac ion o he deli e ed
genomes es ablish success ully in he new cell (Jose sson e al.
2013;Miyashi a e al. 2015). Al hough cell- o-cell sp ead is gen-
e ally local, en i e in ec ed cells can also se e as ehicles o
he sys emic dissemina ion o he in ec ion in blood-bo ne i-
uses, and his can cons i u e a ele an mode o ansmission
among hos s, as shown o HIV-1 (Mo hes e al. 2010;Mu ooka
e al. 2012;Real e al. 2018).
1.2 O he collec i e sp ead modes in ol ing cell su aces
A ela ed bu sligh ly di e en i al sp ead mode is he accumu-
la ion o i al pa icles in clus e s a he su ace o he in ec ed
cell, as shown o human T-cell leukemia i us (HTLV-1) (Pais-
Co eia e al. 2010). A e eg ess om he cell, HTLV-1 pa icles
a e physically linked oge he in a i ally-induced ex acellula
ma ix ne wo k composed by collagen, ag in, and linke p o-
eins including e he in and galec in-3, o ming so-called i al
bio ilms a ound in ec ed cells. Pieces o HTLV-1 bio ilms con-
aining mul iple i ions a e hen ans e ed upon con ac o
in ec ed cells wi h a ge T lymphocy es, enabling he ‘en bloc’
ansmission o i ions p oduced by a unique cell.
Ano he way o using cells as i al dissemina ion ehicles is
ans-in ec ion media ed by dend i ic cells (DCs), which has
been ex ensi ely s udied o HIV-1 (McDonald, 2010). Du ing
hei jou ney be ween in ec ed issues and lymphoid o gans,
DCs end o cap u e i al pa icles a hei su ace, which can
o igina e om di e en in ec ed cells. These pa icles accumu-
la e in memb ane in agina ions be o e being deli e ed collec-
i ely o CD4þlymphocy es du ing an igen p esen a ion.
Finally, al hough mechanis ically e y di e en , a sp ead
mode analogous o ans-in ec ion has been desc ibed o en-
e ic i uses du ing ansmission be ween indi iduals. Simila ly
o DCs, he su ace o some gu mic obial cells appea s o unc-
ion as a concen a o o en e ic i al pa icles, which u he
p omo es hei a achmen o hos cells (Kuss e al. 2011;Jones
e al. 2014;Robinson, Jesudhasan and P ei e 2014). In he case
o polio i us and eo i us, he ‘p o i al’ e ec o gu mic obio a
Figu e 1. Summa y o collec i e dispe sal modes in i uses. In some cases, i ions in he ex acellula milieu, which can po en ially o igina e om di e en cells, a e
subsequen ly clus e ed by di e en mechanisms, including HIV-1 concen a ion in dend i ic cells (DCs) a achmen o bac e ial cells om he hos mic obio a (en e o-
i uses), o i ion agg ega ion (VSV in semen, VSV in sali a). In o he cases, pools o i ions o igina ing om he same cell unde go co-dispe sion. This is he case o i-
al bio ilms (HTLV-1), i ions encapsula ed in ex acellula esicles (HAV, en e o i uses, ma seille i uses, o a i uses, and no o i uses), and baculo i us OBs. Cell- o-
cell sp ead is ye ano he p ocess whe eby mul iple i ions a e join ly ans e ed be ween cells.
2|Vi us E olu ion, 052019, Vol. 5, No. 1
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
is media ed by he polysaccha ide chains exposed a he su ace
o some speci ic commensal bac e ia (Robinson, Jesudhasan
and P ei e 2014). These bac e ium-bound i al pa icles a e
hen deli e ed o hos cells, hus enabling a local inc ease o he
MOI (E ickson e al. 2018).
1.3 Ex acellula esicles
In addi ion o en i e cells, i uses can use subcellula s uc u es
o he join sp ead o mul iple i al pa icles. I has been shown
ha non-en eloped en e ic i uses can be eleased om cells
be o e lysis as pools o i ions cloaked in o ex acellula
esicles. The en e ic hepa i is A i us (HAV) is p oduced as
small pools o i ions clus e ed in exosome-like esicles ha
a e ully in ec ious, o ming so-called quasi-en eloped i ions
(Feng e al. 2013). These appea o be he main in ec ious o m
o he i us ci cula ing in he blood du ing acu e in ec ion, while
indi idual non-en eloped HAV is mainly shed in eces.
In e es ingly, he HAV en elope is sensi i e o he de e gen ac-
ion o bile acids, s ongly sugges ing ha indi idual naked HAV
ound in eces could also de i e om en eloped HAV upon
s ipping o he memb ane in he bilia y ac (Hi ai-Yuki e al.
2016). Whe he he in ec i i y o HAV can be subsequen ly en-
hanced by he clus e ing capaci y o en e ic commensal bac e ia
emains o be s udied.
In he case o polio i us, pools o i ions a e eleased in
au ophagosome-de i ed esicles and hese pools a e subse-
quen ly deli e ed en bloc o ecipien cells (Bi d e al. 2014;
Robinson e al. 2014;Chen e al. 2015). Mo e ecen ly, a ian s o
his sp ead mode ha e been also demons a ed o wo o he
en e ic i uses, o a i us and no o i us (San iana e al. 2018).
Pools o o a i uses we e ound o be encapsula ed in la ge
esicles appa en ly de i ed om he plasma memb ane,
whe eas esicles con aining smalle g oups o no o i uses a e
p obably o igina ed o m he exosomal sec e o y pa hway.
Vesicle-cloaked o a i uses we e obse ed in s ool om expe i-
men ally in ec ed animals and we e capable o ansi ing
h ough he gas oin es inal ac ollowing o al inges ion.
Thus, en e ic i uses seem o combine wo dis inc in ec ious
o ms: an en eloped o m ha con ains se e al genomes, and
non-en eloped i ions con aining a single genome, whose in-
ec i i y migh be enhanced by he clus e ing capaci y o en e ic
commensal bac e ia.
Ye o he simila o ms o esicle-encapsula ed i al sp ead
has been desc ibed o non-en e ic i uses, including he en el-
oped hepa i is C i us (HCV) (Ramak ishnaiah e al. 2013) and
he la ge DNA ma seille i us, which can in ec ameba in he
o m o i ion-con aining esicles in addi ion o indi idual i al
pa icles. In e es ingly, esicle-encapsula ed ma seille i uses
use an al e na e en y pa hway h ough phagocy osis, while in-
di idual ee i ions ollow a canonical endocy osis ou e om
he plasma memb ane (A an es e al. 2016).
1.4 Occlusion bodies
Vi ion sp ead in g oups has also long been known o baculo i-
uses. Whe eas baculo i uses dissemina e sys emically in in-
sec la ae in he o m o ee indi idual pa icles (budding
i ions), g oups o ens o i ions a e encapsula ed du ing la e
in ec ion s ages in a p o ein ma ix made mainly o polyhed in,
o ming so-called occlusion bodies (OBs). These OBs se e as
ehicles o he co-dispe sal o mul iple i ions a he in e -hos
le el (Slack and A i 2007). Upon inges ion by la ae, OBs a e dis-
sol ed unde he alkaline pH condi ions o he mid gu ,
eleasing occlusion-de i ed i uses. Hence, OBs do no ensu e
he join ansmission o i ions o he same cells bu , ins ead,
o he same hos . Ye , baculo i uses p esen ano he laye o i-
ion clus e ing since, in mul iple nucleopolyhed o i uses,
occlusion-de i ed i uses a e in u n made o small g oups o
i ions w apped in a common memb ane, pe mi ing hei join
deli e y o cells.
1.5 Vi ion agg ega es
Vi al pa icles can also dispe se oge he i hey agg ega e in he
ex acellula milieu ollowing hei elease as independen pa -
icles by in ec ed cells. Ea ly elec on mic oscopy s udies no-
iced a endency o pu i ied i ions o agg ega e, a p ocess
ini ially hough o depend p ima ily on physicochemical condi-
ions (Bald and B iggs 1937;Galasso and Sha p 1962;Galasso
1967;Wallis and Melnick 1967;Floyd 1979). Howe e , he biolog-
ical ele ance o his p ocess was no in es iga ed in much de-
ail. Mo e ecen s udies ha e cha ac e ized i al pa icle
agg ega ion in bodily luids, as well as i s implica ions o in ec-
i i y. Fo ins ance, he p os a ic acidic phospha ase na u ally
ound in seminal luid o ms amyloid ib ils ha ac as so-called
semen-de i ed enhance s o i us in ec ion (SEVI) o HIV-1.
These ib ils a ach o HIV-1 i ions, a o hei clus e ing and
p omo e hei binding o CD4 cells and mac ophages, inc easing
in ec i i y by se e al o de s o magni ude in i o (Munch e al.
2007). The amyloid ib ils ha e been imaged di ec ly in human
ejacula es, con i ming hei in e ac ion wi h he i us and
showing ha SEVI p omo e he o ma ion o i ion agg ega es
(Usmani e al., 2014). Howe e , hei con ibu ion o HIV-1 dis-
semina ion be ween indi iduals emains con o e sial since
inhibi o s o SEVI-media ed agg ega ion a e poo ly e icien
when es ed in i o o in e -indi idual ansmission (Allen
e al. 2015;Van Dis e al. 2016).
Vi ion agg ega ion has also been demons a ed o esicula
s oma i is i us (VSV) incuba ed wi h human o cow sali a
(Cue as, Du a´n-Mo eno, and Sanjua´n 2017). Co- luo escence
analysis wi h VSV cons uc s encoding GFP o mChe y showed
ha i ion agg ega ion s ongly inc eases he chances ha mul-
iple i al genomes a e join ly deli e ed o he same a ge cells.
Because he o al ca i y is a majo in ec ion si e o his i us,
in ec ed animals may shed i ion agg ega es h ough sali a,
wi h po en ial implica ions o VSV ansmission. Pu a i ely,
his p ocess migh also ake place in he ela ed, sali a-
ansmi ed, abies i us.
2. Possible ad an ages and cos s o dispe sing
as g oups
E e y hing else being equal, he clus e ed dispe sal o i al pa -
icles should incu a i ness cos . Indeed, a clus e (agg ega e,
esicle, OB, e c.) o K i al pa icles will in ec a single a ge
(cell o hos ) whe eas K a ge s could po en ially be in ec ed by
hese same pa icles i hey dispe sed independen ly. This cos
should be signi ican i mos a ge s ecei e a single in ec ious
uni , and is expec ed e en i a e y small ac ion o all pa icles
p oduced by a hos unde go ansmission. To see his, imagine
ha a i us p oduces N p ogeny i ions in agg ega es o size K,
hence p oducing N/K in ec ious uni s, and ha a e y low ac-
ion o he o al pa icles p esen in a hos will be ansmi ed,
such ha N <1. Then, he numbe o success ul ansmissions
pe hos should ollow a Poisson dis ibu ion o mean and a i-
ance equal o N /K, meaning ha inc easing K should educe
ansmissibili y. Assuming ha K is an e ol able ai , o K >1
R. Sanjua´n and M.-I. Thoulouze |3
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
o be main ained he ansmissibili y cos should be o se by
some o he i ness ad an ages. Some sugges ed bene i s a e
discussed below.
2.1 Selec ion o i ion s abili y
In some cases, i ion clus e ing could eme ge as an indi ec e -
ec o selec ion o p olong he in ec i i y o i ions in he ex a-
cellula milieu. Baculo i us OBs cons i u e an in e es ing
example. Baculo i uses expe ience long pe iods o ime in he
en i onmen . Hence, s uc u es ha inc ease esis ance o UV
adia ion, desicca ion, and o he ac o s p omo ing i ion deg-
ada ion should be s ongly selec ed. OBs p o ide a p o ein
shield o i al pa icles, which con ains polyhed on en elope
p o ein (PEP) among o he componen s, and i was ound ha
he hickness o he PEP laye co ela es wi h he in ec i i y o
occlusion-de i ed i uses (Sajjan and Hinchige i 2016).
Occlusion has e ol ed mul iple imes in di e en amilies o in-
sec i uses, such as in en omopox i uses and cy oplasmic pol-
yhed o i uses (Reo i idae)(Slack and A i 2007) in addi ion o
baculo i uses. Howe e , baculo i us OBs a e unique in ha bo -
ing mul iple i ions. Fu he mo e, his o m o i ion agg ega-
ion is p obably no a s uc u ally manda o y ea u e o
baculo i us OBs, since he g anulo i us genus in he amily
Baculo i idae o ms single- i ion OBs. The e o e, al hough he
ad an ages o en i onmen al s abili y may ha e d i en he e o-
lu ion o occlusion, his does no explain why mos baculo i-
uses ansmi om hos - o-hos in an agg ega ed manne . One
possibili y is ha sha ing he OBs educes he cos s o p oduc-
ing hese in e -hos ansmission s uc u es. Al e na i ely, dis-
pe sing in g oups migh pe se ha e a di ec i ness e ec .
Inc eased i ion s abili y has also been demons a ed in
en e o i uses bound o polysaccha ides a he su ace o gu
bac e ia, as shown by e alua ing esis ance o hea and chlo ine
(Robinson, Jesudhasan, and P ei e 2014). Ye , again, his does
no show o disp o e ha a achmen o bac e ia e ol ed as a
means o inc easing s abili y. Vesicle-cloaked o a i uses we e
ound o be mo e in ec ious in mouse pups han equal numbe s
o ee i ions de i ed om b oken esicles (San iana e al.
2018). Al hough he eason o his highe in ec i i y is s ill
unclea , i was sugges ed ha encapsula ion in esicles may
p o ec i ions om deg ada ion by p o eases and/o bile acids
p esen in he gas oin es inal ac . In he case o HAV,
memb ane-w apped i al pa icles we e indeed shown o be
sensi i e o he ac ion o bile acids, leading o he elease o ully
in ec ious naked i ions ha a e mo e s able in he en i on-
men and could be op imized o ansmission be ween hos s
(Hi ai-Yuki e al. 2016).
2.2 A oidance o ci cula ing an ibodies
An ibody neu aliza ion con ibu es o educing i al loads a e
he acu e phase o he in ec ion and hence imposes a selec i e
p essu e o he ex e nal i al p o eins, as shown amply in well-
s udied i uses such as HIV-1 (Wei e al. 2003) and HCV (Dowd
e al. 2009), among o he s. The ole played by cell- o-cell sp ead
in HIV-1 neu aliza ion has been s udied in de ail and, albei i
allows he i us o a oid neu aliza ion in many cases (Abela
e al. 2012), some an ibodies emain e icien a blocking cell- o-
cell sp ead (Zhong e al. 2013a;Agos o, Uchil, and Mo hes 2015;
Reh e al. 2015).
In p inciple, some o he mechanisms media ing i al dis-
pe sal in he o m o clus e s, such as i al bio ilms o encapsu-
la ion in esicles, may also hinde i ions om an ibodies. This
has been p oposed, o ins ance, o HTLV-1 i al bio ilms
(Thoulouze and Alco e 2011). In he case o HAV and HCV,
memb ane-w apped i al clus e s ci cula ing in blood du ing
acu e in ec ion we e shown o be mo e esis an o neu alizing
an ibodies, likely acili a ing HAV dissemina ion wi hin he
hos . Cloaking o i ions inside esicles should also p o ec
o he en e ic i uses (polio i us, o a i uses, and no o i uses)
om neu aliza ion, bu his emains o be conclusi ely shown
because i al pa icle neu aliza ion migh s ill be possible i
esicles become ansi o ily pe meable, o ins ance du ing cell
en y. Fu he mo e, an ibody p essu e would no explain why
esicles con ain mul iple i ions ins ead o single i ions.
Finally, i ion agg ega es may hinde an ibody neu aliza ion,
bu agg ega ion may also p omo e neu aliza ion i an ibody
sensi i i y is dominan o e esis ance in he clus e s, as
epo ed o VSV (Cue as, Du a´n-Mo eno and Sanjua´n 2017).
The causal associa ions be ween collec i e dispe sal and
an ibody-media ed neu aliza ion hus emain unce ain.
2.3 Inc ease in ec i i y h ough a ‘mass e ec ’
The speci ic in ec i i y o a gi en i us, de ined as he p obabil-
i y ha a i al pa icle ini ia es a p oduc i e in ec ion, shows
ample a ia ion among cell ypes. Typically, umo al cells a e
mo e pe missi e o in ec ion han no mal cells, ei he because
hey a e me abolically mo e ac i e and hence p o ide mo e
esou ces o i uses, o because hey su e om inna e immu-
ni y de ec s. One possibili y is ha he in ec ion ba ie s en-
coun e ed in less pe missi e cells a e mo e easily o e come by
he i us i he cell ecei es mul iple i al pa icles simul a-
neously. Fo ins ance, HIV-1 showed simila in ec i i y by he
ee i us and he cell- o-cell ou es in highly pe missi e cells
such as HEK293 o MT4 leukemia T cells, bu in ec i i y was su-
pe io by he cell- o-cell ou e in p ima y CD4 cells (Zhong e al.
2013a). Cell- o-cell sp ead was also ound o aid in ec ion unde
ad e se condi ions such as an i e o i al he apy (Sigal e al.
2011;Agos o, Uchil, and Mo hes 2015). Cell- o-cell sp ead accel-
e a es HIV-1 gene exp ession, and his e ec is mo e ma ked in
p ima y pe iphe al blood mononuclea cells han in a
leukemia-de i ed cell line (Boulle e al. 2016). This accele a ion
was ecapi ula ed by inocula ing cells wi h ee i ions a high
MOI, sugges ing ha he ad an age o cell- o-cell sp ead indeed
esided in in ec ing cells wi h mul iple i al genome copies a
once. In he case o ma seille i us, in ec ion by esicle-
encapsula ed i uses was also shown o accele a e ini ia ion o
he i al eplica ion in ameba (A an es e al. 2016). Whe he his
esul s om he en y o mul iple genomes pe cell o om he
al e na i e en y ou e used o collec i e in ec ion emains
unclea .
Howe e , hese s udies did no assess whe he a gi en num-
be o i ions sp eading om cell- o-cell we e o e all mo e in-
ec ious han he same numbe o ee-dispe sing i ions,
which is he ele an ques ion o add essing whe he sp ead-
ing in g oups is selec i ely ad an ageous. This was mo e di-
ec ly add essed in ano he s udy, which used mic o luidics o
place single accinia i ions a he su ace o HeLa cells and
ound ha mos cells ecei ing single i al pa icles emained
unin ec ed, whe eas in ec ion p obabili y inc eased disp opo -
iona ely wi h he numbe o i ions deposi ed pe cell (S ie el
e al. 2012). HeLa a e highly pe missi e cells, and his e ec
migh hus e en be mo e ma ked in o he cell ypes. A simila
esul has been ob ained ecen ly using VSV by compa ing equal
numbe s o ee e sus sali a-agg ega ed i ions (And eu-
Mo eno and Sanjua´n 2018). I was ound ha i ion agg ega ion
4|Vi us E olu ion, 052019, Vol. 5, No. 1
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
ended o accele a e he in ec ion cycle in a cell ype-dependen
manne , he e ec being s onge in less pe missi e cells.
This mass e ec is akin o he Allee e ec in ecology, which
is de ined as a posi i e ela ionship be ween popula ion size
and pe -capi a g ow h a e. The Allee e ec es ic s he abili y
o a small ounde popula ions o become es ablished (in asion
p obabili y) and is ele an o o he p ocesses such as ex inc ion
(Taylo and Has ings 2005;K ame e al. 2009). Allee e ec s ha e
been documen ed in many species including mic oo ganisms
(Kaul e al. 2016), bu emained la gely unexplo ed in i uses
un il ecen ly (And eu-Mo eno and Sanjua´n 2018). In he con-
ex o a mass e ec ac ing on in ec i i y, he ele an scale a
which he i us ounde popula ion size should be e alua ed is
he indi idual cell (i.e. he cellula MOI). Simila o he Allee e -
ec in animals, which can esul om coope a i e b eeding, co-
ope a i e hun ing o p eda ion a oidance, among o he
p ocesses, he inc eased in ec i i y o g oups o i ions could e-
sul om a ious mechanisms. Fo ins ance, by accele a ing in-
ec ion, he i us migh be be e able o cope wi h an i i al
ba ie s such as CRISPR immuni y in bac e ia, in e e on-sig-
naled inna e immune esponses and o he es ic ion ac o s.
Al e na i ely, by ini ia ing he in ec ion wi h mul iple genome
copies, he i us migh educe he changes o ea ly s ochas ic
loss, which may occu i some essen ial and limi ing ac o s
(e.g. he polyme ase) a e deg aded, dilu ed, seques e ed, o
exp essed a insu icien le els a he ea lies s ages o cellula
in ec ion. P esumably, all hese s ochas ic p ocesses should be
less likely o cu ail he in ec ion cycle i he numbe o copies
o each i al p oduc is highe .
2.4 Di e si y-based bene i s
Vi uses, pa icula ly RNA i uses and i oids, display highe
mu a ion a es pe base han any o he biological en i y
(Sanjua´n and Domingo-Calap 2016), meaning ha a la ge ac-
ion o RNA i us genomes con ain mu a ions, mos o which
a e dele e ious. This has subs an ia ed he no ion ha high
MOIs may acili a e ans-complemen a ion o i al gene ic
de ec s, allowing indi idually non-in ec ious i ions o be ‘ eac-
i a ed’ a high MOIs (Andino and Domingo 2015). Ano he pos-
sible eason o combining di e en genomes in a cell,
po en ially bene icial o he i us, is ela ed o he ac ha
many i uses ha e compac genomes encoding mul i unc ional
p o eins, esul ing in i ness adeo s o pleio opic e ec s ha
hampe e olu iona y op imiza ion (Belshaw e al. 2008). In such
compac genomes, bene icial mu a ions end o display nega-
i e epis asis ha is, genomes combining di e en bene icial
mu a ions end o be less i han expec ed om single-
mu a ion e ec s (Sanjua´n and Elena 2006). As sugges ed
p e iously, hese limi s o adap abili y could be o e come i
bene icial mu a ions in a pa icula gene a e p o ided om di -
e en copies o genomes co-in ec ing he same cell (Bo de ı´a
e al. 2015;Sanjua´n 2017).
The e is some empi ical e idence suppo ing di e si y-
based bene i s associa ed o high MOIs. In he case o seg-
men ed i uses such as in luenza and Ri Valley i uses, a
likely eason why indi idual i ions a e o en non-in ec ious is
ha hey miss one essen ial genome segmen (B ooke e al.
2013;Wichge s Sch eu , and Ko ekaas 2016). These i ions,
named ‘semi-in ec ious pa icles’ o in luenza i uses, a e bio-
logically ac i e and can egain in ec i i y a high MOIs h ough
complemen a ion upon co-in ec ion (B ooke 2017). Mul ipa i e
i uses cons i u e he mos ex eme case, because hei seg-
men s a e encapsida ed sepa a ely and he e o e high MOIs a e
c i ical o in ec i i y, as discussed p e iously (Sica d e al. 2016;
Lucı´a-Sanz and Man ubia 2017). Di e en in luenza i us s ains
o isola es can also in e ac syne gis ically. This was shown us-
ing one a ian ca ying a mu a ion in he a ian encoding o
a neu aminidase ha changed i al pa icle elease om
in ec ed cells (Xue 2016). Howe e , i emains o be cla i ied
whe he gene ic complemen a ion o in luenza i us simply
elies on andom co-in ec ion by ee i ions o is p omo ed by
some o he o m o co-dispe sal. In measles i us, his is
achie ed by capsids ha accommoda e mo e han one copy o
he genome. Co-encapsida ion o i al genomes can p omo e
gene ic complemen a ion, bu also he eme gence o new phe-
no ypes esul ing om he combina ion o di e en gene ic a -
ian s in he same cell (Shi ogane, Wa anabe, and Yanagi 2012).
A simila s a egy could be used by he espi a o y syncy ial i-
us (RSV), which o ms long ilamen ous pa icles con aining
se e al i al genomes (Lilje oos e al. 2013). These we e ecen ly
shown o be highly in ec ious o ms o RSV (Ke e al. 2018). The
di e si y-based ene has also been pu o wa d o baculo i us
OBs. Despi e being la ge DNA i uses wi h p esumably low mu-
a ion a es, baculo i uses exhibi high popula ion mu a ion
equencies, including la ge dele ions ha should abolish in ec-
i i y (Cha eigne e al. 2015). OBs may p omo e gene ic comple-
men a ion among hese mu an s and hence con ibu e o he
main enance o di e si y (Cla ijo e al. 2010;Simon e al. 2013).
An impo an conside a ion, hough, is ha gene ic comple-
men a ion is only one o se e al possible ypes o in e ac ions
ha could ake place be ween gene ically di e se, co-in ec ing
i uses. Ano he such in e ac ion is nega i e dominance, which
akes place when he i ness o one i us a ian is diminished
in cells co-in ec ed by ano he , dele e ious a ian , while he
dele e ious a ian does no bene i om he i e i us. In
cases whe e he e is no mu ual bene i , co-dispe sal educes he
abili y o he i es a ian o be a o ed by na u al selec ion
(Miyashi a and Kishino 2010). Nega i e dominance is pa icu-
la ly likely in oligome ic s uc u es such as i al capsids wi h
he abili y o o m chime a, bu can also occu in monome ic
s uc u es i he mu an p oduc is oxic (C owde and
Ki kegaa d 2005). A compelling demons a ion o nega i e dom-
inance and i s e olu iona ily implica ions was made using a
d ug ha educes he lexibili y o polio i us capsids and p e-
en s uncoa ing (Tanne e al. 2014). A newly a isen esis ance
mu a ion agains his d ug will end o pseudo ype wi h wild-
ype, d ug-sensi i e capsids, o o o m chime ic capsids ha
a e sensi i e o he d ug. Hence, d ug- esis an i uses we e
supp essed by d ug-sensi i e i uses in ec ing he same cell,
e a ding he e olu ion o esis ance. Whe he he d ug-
esis an a ian will ul ima ely e ol e depends on he MOI
because high a es o co-in ec ion inc ease he chances ha
nega i e dominance p e en s he selec ion o esis an s ains.
The e o e, in his case, dispe sal in g oups should ha e a nega-
i e impac on i al i ness.
3. Collec i e dispe sal and coope a ion
Fo clus e ed dispe sal o be conside ed a coope a i e ai , i
should ha e e ol ed in esponse o he bene i s o sha ing he
dispe sal ehicle o he ecipien cell wi h o he membe s o he
i al popula ion. A basic ques ion o be add essed he e is
whe he he mode o dispe sal a play has a gene ic basis. This
is unknown in mos cases, including i al agg ega ion in sali a
o semen, en e ic i us esicle o ma ion, p oduc ion o i al
bio ilms, mos ypes o cell- o-cell sp ead, and bac e ial binding.
The baculo i us genes in ol ed in OB o ma ion a e known ( he
R. Sanjua´n and M.-I. Thoulouze |5
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023

polyhed in gene), bu he gene ic basis o he o ma ion o mul-
iple e sus simple occlusion-de i ed bodies is no (Roh mann
2014). In addi ion o es ablishing he he i abili y o i ion
clus e ing, he bene i s o dispe sing in g oups should be dem-
ons a ed and could in p inciple s em om any o he
abo e-discussed p ocesses, i.e. inc eased s abili y, immune
a oidance, inc eased in ec i i y due o mass e ec s, o posi i e
in e ac ions among gene ic a ian s.
Ano he impo an aspec o be conside ed is ha e e y co-
ope a i e ai isks in asion by chea e s, which a e in p inciple
a o ed by selec ion because hey bene i om coope a o s
wi hou ecip oca ing. A clea example o chea ing in i uses is
p o ided by de ec i e in e e ing pa icles (DIPs), which ca y
la ge dele ions and can only eplica e in he p esence o an-
o he , iable copy o he i us, some imes called ‘helpe ’
(Ma io and Dimmock 2010;Dı´az-Munoz, Sanjuan and Wes
2017). Classical wo k es ablished ha passaging a i us epea -
edly a a high a io o o al in ec ious pa icles o cells (i.e. high
i al densi y) inc eases he cellula MOI and ends o selec o
DIPs, which ake o e he popula ion because hei sho e
genomes a e eplica ed as e (Ma io and Dimmock 2010).
Inside he cell, he machine y equi ed o i al eplica ion,
gene exp ession, and encapsida ion is, a leas o some ex en , a
public good and, a high MOIs, DIPs, o o he ypes o chea e i-
uses bene i om ‘helpe ’ i uses wi hou con ibu ing o he
public goods (Chao and Elena 2017).
The e o e, by inc easing he cellula MOI, i al sp ead in
g oups should in p inciple a o chea e s, in u n selec ing
agains collec i e sp ead and coope a ion. Howe e , he s uc-
u es used o collec i e sp ead may no p oduce an e ec on
he MOI equi alen o ha o passaging i uses a high densi y.
Fi s , dispe sing in g oups does no necessa ily imply ha he e
is un es ic ed mixing be ween indi iduals. Upon cell- o-cell
sp ead, i al bio ilm o ma ion, OB p oduc ion, o sp ead in
esicles, g oup membe s a e de i ed om he same dono cell
and hence a e highly ela ed gene ically. As shown in he social
e olu ion li e a u e, gene ic ela edness is a key de e minan o
he e olu ion o coope a ion and diminishes he likelihood o
chea e in asion (Wes e al. 2006;Ga dne , Wes , and Wild
2011;Dı´az-Munoz, Sanjuan and Wes 2017). Mo e gene ally,
chea e s should no e ol e i he popula ion is asso ed in a
way ha coope a o s in e ac p e e en ially wi h o he coope a-
o s (Nowak 2006;Ga dne , Wes , and Wild 2011).
Howe e , i he main enance o coope a ion elies on ex-
cluding gene ically un ela ed indi iduals, he e olu ion o
di e si y-based coope a ion seems di icul a p io i. We hus
may expec ha he bene i s o collec i e dispe sal modes ha e
o do wi h inc easing s abili y in he ex acellula milieu, a oid-
ing ci cula ing an ibodies, o inc easing in ec i i y h ough a
mass e ec , a he han wi h gene ic complemen a ion o o he
di e si y-based ypes o coope a ion. The la e would equi e
mechanisms o disc imina ing among coope a o and non-
coope a o a ian s, o ha di e si y-based coope a ion is so
c i ical o su i al ha he p esence o chea e s is less de i-
men al o i ness han ailu e o complemen . Hence, al hough
ins ances o gene ic complemen a ion and o he ypes o
di e si y-associa ed bene i s ha e been desc ibed in i uses
(see abo e), we cu en ly lack solid e olu iona y models ha
help us in e p e such bene i s in e ms o i al coope a ion.
A second eason why dispe sal in g oups is no e olu ion-
a ily equi alen o high i al popula ion densi ies is ha hese
wo p ocesses may inc ease he cellula MOI a di e en s ages
o in ec ion. Fo ins ance, i ion agg ega ion in ex acellula lu-
ids such as sali a in VSV o semen in HIV-1 should ac only a
he le el o in e -hos ansmission, as well as baculo i us clus-
e ing in OBs o bac e ia-media ed clus e ing o en e o i uses.
In con as , high i al densi ies equi e ex ensi e i al eplica-
ion and hence should occu a la e in ec ion s ages. The selec-
i e p essu es ac ing du ing in e -hos ansmission o in he
i s cellula in ec ion cycles ollowing ansmission migh di e
om hose ac ing la e on. Fo ins ance, inc easing pa icle s a-
bili y is expec ed o be pa icula ly impo an o success ul
in e -hos ansmission in i uses ha s ay in he en i onmen
o long pe iods. Al e na i ely, du ing he i s in ec ion s ages
o a new hos , i may be c i ical o boos in ec i i y o accele a e
he in ec ion cycle o o e come ea ly in ec ion ba ie s, as dis-
cussed abo e. Finally, i is also possible ha di e si y-d i en i -
ness bene i s could be e olu iona ily s able i i ion clus e ing is
episodic, since his may limi he oppo uni ies o chea e
in asion.
4. Conclusions
Dispe sal in g oups has been now documen ed in widely di e -
en i uses including en eloped and non-en eloped i uses,
segmen ed and non-segmen ed i uses, and i uses wi h di e -
en ypes o genome, such as (þ)ssRNA, ()ssRNA, dsRNA, and
dsDNA i uses, as well as e o i uses. The ehicles media ing
collec i e sp ead also a y widely and include lipid esicles,
p o ein ma ices, di e en o ms o agg ega ion, and binding o
he su ace o hos o non-hos cells. Fu he mo e, hese can ac
a he le el o in a o in e hos sp ead/ ansmission. The p op-
e ies o di e en modes o i al dispe sal in g oups a e summa-
ized in Table 1.
A majo open ques ion is why collec i e dispe sal is used by
i uses. The answe may a y depending on he i us, he scale
o ansmission (in a- o in e hos ), he ansmission ehicle
used, he na u e and a chi ec u e o he physiological compa -
men in ol ed, and so on. In e es ingly, collec i e dispe sal al-
ways coexis s wi h he s anda d ee i ion sp ead mode. In
some cases, i ion clus e ing occu s only episodically, such as
o ins ance du ing agg ega ion o HIV-1 in semen amyloid
ib ils. In o he cases, collec i e and indi idual sp ead occu
nea ly simul aneously, such as o ins ance upon elease o
en e o i uses om cells inside esicles e sus ee i ions.
O e all, i al cycles appea o combine indi idual i ions and
clus e s, en eloped and non-en eloped o ms, he shi om
one sp ead mode o ano he depending on he biology o he i-
us. This has been pa ially illus a ed by ecen li e a u e on
en e ic i uses and opens up new a enues o esea ch.
Reasonably, dispe sal in g oups o he combina ion o ee
i ions and collec i e sp ead should p o ide a i ness ad an age
o i uses, bu e y ew s udies ha e add essed his ques ion di-
ec ly. Al e na i ely, dispe sal in g oups migh be a by-p oduc
o o he p ocesses, such as i us associa ion wi h cellula mem-
b anes, o ins ance. To cla i y his, i would be help ul o es ab-
lish whe he collec i e i al sp ead has a gene ic basis by
iden i ying mu an s ha modi y his ai . Rela ed o his, we
may conside wo possible scena ios: i s , ce ain sp ead mech-
anisms could con e a gain in i ness hemsel es, collec i e in-
ec ion being a consequence o such sp ead modes. Inc easing
en i onmen al s abili y o a oiding an ibodies would all in he
i s ca ego y. Howe e , one should show why such p o ec i e
s uc u es a e sha ed by mul iple i ions. Second, he i ness
ad an age could eside speci ically in in ec ing cells wi h mul i-
ple genomes. Mass e ec s and gene ic complemen a ion would
all in his second ca ego y. I so, such bene i s should, in p inci-
ple, be ecapi ula ed by ee i ions in ec ing cells a high MOI.
6|Vi us E olu ion, 052019, Vol. 5, No. 1
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
Acknowledgemen s
We hank E nes o Seg edo-O e o o help ul discussions.
Funding
This wo k was suppo ed by he Eu opean Resea ch Council
(g an 724519 Vis-a-Vis).
Con lic o in e es : None decla ed.
Re e ences
Abela, I. A. e al. (2012) ‘Cell-Cell T ansmission Enables HIV-1 o
E ade Inhibi ion by Po en CD4bs Di ec ed An ibodies’, PLoS
Pa hogens, 8: e1002634.
Agos o, L. M., Uchil, P. D., and Mo hes, W. (2015) ‘HIV Cell- o-Cell
T ansmission: E ec s on Pa hogenesis and An i e o i al
The apy’, T ends in Mic obiology, 23: 289–95.
Allen, S. A. e al. (2015) ‘Cha ac e iza ion o he In luence o
Semen-De i ed Enhance o Vi us In ec ion on he In e ac ion
o HIV-1 Wi h Female Rep oduc i e T ac Tissues’, Jou nal o
Vi ology, 89: 5569–80.
Andino, R., and Domingo, E. (2015) ‘Vi al Quasispecies’, Vi ology,
479–480: 46–51.
And eu-Mo eno, I., and Sanjua´n, R. (2018) ‘Collec i e In ec ion o
Cells by Vi al Agg ega es P omo es Ea ly Vi al P oli e a ion
and Re eals a Cellula -Le el Allee E ec ’, Cu en Biology, 28:
3212–9.
A an es, T. S. e al. (2016) ‘The La ge Ma seille i us Explo es
Di e en En y Pa hways by Fo ming Gian In ec ious
Vesicles’, Jou nal o Vi ology, 90: 5246–55.
Bald, J. G., and B iggs, G. E. (1937) ‘Agg ega ion o Vi us Pa icles’,
Na u e, 140: 111.
Belshaw, R. e al. (2008) ‘Pacing a Small Cage: Mu a ion and RNA
Vi uses’, T ends in Ecology & E olu ion, 23: 188–93.
Bi d, S. W. e al. (2014) ‘Nonly ic Vi al Sp ead Enhanced by
Au ophagy Componen s’, P oceedings o he Na ional Academy o
Sciences o he Uni ed S a es o Ame ica, 111: 13081–6.
Bo de ı´a, A. V. e al. (2015) ‘G oup Selec ion and Con ibu ion o
Mino i y Va ian s Du ing Vi us Adap a ion De e mines Vi us
Fi ness and Pheno ype’, PLoS Pa hogens, 11: e1004838.
Boulle, M. e al. (2016) ‘HIV Cell- o-Cell Sp ead Resul s in Ea lie
Onse o Vi al Gene Exp ession by Mul iple In ec ions pe Cell’,
PLoS Pa hogens, 12: e1005964.
B ooke, C. B. (2017) ‘Popula ion Di e si y and Collec i e
In e ac ions du ing In luenza Vi us In ec ion’, Jou nal o
Vi ology, 91: e01164–1.
e al. (2013) ‘Mos In luenza a Vi ions Fail o Exp ess a
Leas One Essen ial Vi al P o ein’, Jou nal o Vi ology, 87:
3155–62.
Chao, L., and Elena, S. F. (2017) ‘Nonlinea T ade-O s Allow he
Coope a ion Game o E ol e om P isone ’s Dilemma o
Snowd i ’, P oceedings o he Royal Socie y B: Biological Sciences,
284: 20170228.
Cha eigne , A. e al. (2015) ‘Ul a Deep Sequencing o a
Baculo i us Popula ion Re eals Widesp ead Genomic
Va ia ions’, Vi uses, 7: 3625–46.
Chen, Y. H. e al. (2015) ‘Phospha idylse ine Vesicles Enable
E icien en Bloc T ansmission o En e o i uses’, Cell, 160:
619–30.
Cla ijo, G. e al. (2010) ‘Mixed Geno ype T ansmission Bodies
and Vi ions Con ibu e o he Main enance o Di e si y in an
Insec Vi us’, P oceedings o he Royal Socie y B: Biological Sciences,
277: 943–51.
C owde , S., and Ki kegaa d, K. (2005) ‘T ans-Dominan
Inhibi ion o RNA Vi al Replica ion Can Slow G ow h o
D ug-Resis an Vi uses’, Na u e Gene ics, 37: 701–9.
Cue as, J. M., Du a´n-Mo eno, M., and Sanjua´n, R. (2017)
‘Mul i-Vi ion In ec ious Uni s A ise F om F ee Vi al Pa icles in
an En eloped Vi us’, Na u e Mic obiology, 2: 17078.
Del Po illo, A. e al. (2011) ‘Mul iploid Inhe i ance o
HIV-1 Du ing Cell- o-Cell In ec ion’, Jou nal o Vi ology, 85:
7169–76.
Dı´az-Mu~
noz, S. L., Sanjua´n, R., and Wes , S. (2017) ‘Socio i ology:
Con lic , Coope a ion, and Communica ion among Vi uses’,
Cell Hos Mic obe, 22: 437–41.
Table 1. Types o collec i e dispe sal in i uses and some o hei ea u es.
Vehicle Scale o i al sp ead Scale o mixing Possible ad an ages
Many i uses Cell- o-cell junc ions Mainly in ahos Unique cell Immuni y a oidance, p omo e sp ead by
p e en ing dilu ion, o he
HTLV-1 Ex acellula ma ix In ahos , blood Unique cell Immuni y a oidance, p omo e sp ead by
p e en ing dilu ion
HIV-1 DC su ace In ahos , in ec ed issues Mul iple cells P omo e sp ead by a oiding dilu ion
En e o i uses Bac e ial su ace In e hos Mul iple cells Inc ease s abili y, enhance cell
a achmen
HAV Ex acellula esicles In ahos , blood Unique cell Immuni y a oidance
En e o i uses Ex acellula esicles In a/in e hos Unique cell Inc ease in ec i i y
Ro a i uses Ex acellula esicles In e hos , s ool Unique cell P o ec om deg ada ion, inc ease
in ec i i y
No o i uses Ex acellula esicles In e hos , s ool Unique cell P o ec om deg ada ion, inc ease
in ec i i y
Ma seille i uses Ex acellula esicles In e hos Unique cell Inc ease empe a u e s abili y, inc ease
in ec i i y by p omo ing en y
Baculo i uses OBs In e hos , la a cada e s Unique cell En i onmen al s abili y, gene ic
complemen a ion
HIV-1 SEVI In e hos , semen Mul iple cells Inc eased in ec i i y
VSV Sali a compounds In e hos , sali a Mul iple cells Inc eased in ec i i y in poo ly pe missi e
cells
R. Sanjua´n and M.-I. Thoulouze |7
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
Dowd, K. A. e al. (2009) ‘Selec ion P essu e om Neu alizing
An ibodies D i es Sequence E olu ion du ing Acu e In ec ion
Wi h Hepa i is C Vi us’, Gas oen e ology, 136: 2377–86.
Duncan, C. J. e al. (2014) ‘High-Mul iplici y HIV-1 In ec ion and
Neu alizing An ibody E asion Media ed by he mac ophage-T
Cell Vi ological Synapse’, Jou nal o Vi ology, 88: 2025–34.
E ickson, A. K. e al. (2018) ‘Bac e ia Facili a e En e ic Vi us
co-In ec ion o Mammalian Cells and P omo e Gene ic
Recombina ion’, Cell Hos Mic obe, 23: 77–88.e75.
Feng, Z. e al. (2013) ‘A Pa hogenic Pico na i us Acqui es an
En elope by Hijacking Cellula Memb anes’, Na u e, 496:
367–71.
Floyd, R. (1979) ‘Vi al Agg ega ion: Mixed Suspensions o
Polio i us and Reo i us’, Applied En i onmen al Mic obiology, 38:
980–6.
Galasso, G. J. (1967) ‘Quan i a i e S udies on he Quali y, E ec s
o Agg ega ion and The mal Inac i a ion o Vesicula
S oma i is Vi us’, A chi u¨ die gesam e Vi us o schung, 21:
437–46.
, and Sha p, D. G. (1962) ‘Vi us Pa icle Agg ega ion and he
Plaque-Fo ming Uni ’, Jou nal o Immunology (Bal imo e, MD:
1950), 88: 339–47.
Ga dne , A., Wes , S. A., and Wild, G. (2011) ‘The Gene ical
Theo y o Kin Selec ion’, Jou nal o E olu iona y Biology, 24:
1020–43.
G aw, F., and Pe elson, A. S. (2016) ‘Modeling Vi al Sp ead’,
Annual Re iew o Vi ology, 3: 555–72.
Hi ai-Yuki, A. e al. (2016) ‘Bilia y Sec e ion o Quasi-En eloped
Human Hepa i is A Vi us’, MBio, 7: e01998–16.
Jones, M. K. e al. (2014) ‘En e ic Bac e ia P omo e Human and
Mouse No o i us In ec ion o B Cells’, Science, 346: 755–9.
Jose sson, L. e al. (2013) ‘Single Cell Analysis o Lymph Node
Tissue F om HIV-1 In ec ed Pa ien s Re eals Tha he Majo i y
o CD4þT-Cells Con ain One HIV-1 DNA Molecule’, PLoS
Pa hogens, 9: e1003432.
Kaul, R. B. e al. (2016) ‘Expe imen al Demons a ion o an Allee
E ec in Mic obial Popula ions’, Biology Le e s, 12: 20160070.
Ke, Z. e al. (2018) ‘The Mo phology and Assembly o Respi a o y
Syncy ial Vi us Re ealed by C yo-Elec on Tomog aphy’,
Vi uses, 10: 446.
Klasse, P. J. (2015) ‘Molecula De e minan s o he Ra io o Ine
o In ec ious Vi us Pa icles’, P og ess in Molecula Biology and
T ansla ional Science, 129: 285–326.
K ame , A.M. e al., (2009) ‘The E idence o Allee E ec s’,
Popula ion Ecology, 51:
Kuss, S. K. e al. (2011) ‘In es inal Mic obio a P omo e En e ic
Vi us Replica ion and Sys emic Pa hogenesis’, Science, 334:
249–52.
Law, K. M. e al. (2016) ‘In Vi o HIV-1 Cell- o-Cell T ansmission
P omo es Mul icopy Mic o-Compa men alized In ec ion’, Cell
Repo , 15: 2771–83.
Lilje oos, L. e al. (2013) ‘A chi ec u e o Respi a o y Syncy ial
Vi us Re ealed by Elec on C yo omog aphy’, P oceedings o he
Na ional Academy o Sciences o he Uni ed S a es Ame ica, 110:
11133–8.
Lucı´a-Sanz, A., and Man ubia, S. (2017) ‘Mul ipa i e Vi uses:
Adap i e T ick o E olu iona y T ea ?’, NPJ Sys ems Biology and
Applica ions, 3: 34.
Ma io , A. C., and Dimmock, N. J. (2010) ‘De ec i e In e e ing
Vi uses and Thei Po en ial as An i i al Agen s’, Re iews in
Medical Vi ology, 20: 51–62.
McDonald, D. (2010) ‘Dend i ic Cells and HIV-1 T ans-In ec ion’,
Vi uses, 2: 1704–17.
Miyashi a, S. e al. (2015) ‘Vi uses Roll he Dice: The S ochas ic
Beha io o Vi al Genome Molecules Accele a es Vi al
Adap a ion a he Cell and Tissue Le els’, PLoS Biology, 13:
e1002094.
, and Kishino, H. (2010) ‘Es ima ion o he Size o Gene ic
Bo lenecks in Cell- o-Cell Mo emen o Soil-Bo ne Whea
Mosaic Vi us and he Possible Role o he Bo lenecks in
Speeding up Selec ion o Va ia ions in T ans-Ac ing Genes o
Elemen s’, Jou nal o Vi ology, 84: 1828–37.
Mo hes, W. e al. (2010) ‘Vi us Cell- o-Cell T ansmission’, Jou nal
o Vi ology, 84: 8360–8.
Munch, J. e al. (2007) ‘Semen-De i ed Amyloid Fib ils D as ically
Enhance HIV In ec ion’, Cell, 131: 1059–71.
Mu ooka, T. T. e al. (2012) ‘HIV-In ec ed T Cells A e Mig a o y
Vehicles o Vi al Dissemina ion’, Na u e, 490: 283–7.
Nowak, M. A. (2006) ‘Fi e Rules o he E olu ion o Coope a ion’,
Science (New Yo k, N.Y.), 314: 1560–3.
Pais-Co eia, A. M. e al. (2010) ‘Bio ilm-like Ex acellula Vi al
Assemblies Media e HTLV-1 Cell- o-Cell T ansmission a
Vi ological Synapses’, Na u e Medicine, 16: 83–9.
Ramak ishnaiah, V. e al. (2013) ‘Exosome-Media ed
T ansmission o Hepa i is C Vi us Be ween Human Hepa oma
Huh7.5 Cells’, P oceedings o he Na ional Academy o Sciences o
he Uni ed S a es o Ame ica, 110: 13109–13.
Real, F. e al. (2018) ‘Li e Imaging o HIV-1 T ans e ac oss T Cell
Vi ological Synapse o Epi helial Cells Tha P omo es S omal
Mac ophage In ec ion’, Cell Repo , 23: 1794–805.
Reh, L. e al. (2015) ‘Capaci y o B oadly Neu alizing An ibodies
o Inhibi HIV-1 Cell-Cell T ansmission Is S ain- and
Epi ope-Dependen ’, PLoS Pa hogens, 11: e1004966.
Robinson, C. M., Jesudhasan, P. R., and P ei e , J. K. (2014)
‘Bac e ial Lipopolysaccha ide Binding Enhances Vi ion
S abili y and P omo es En i onmen al Fi ness o an En e ic
Vi us’, Cell Hos & Mic obe, 15: 36–46.
Robinson, S. M. e al. (2014) ‘Coxsackie i us B Exi s he Hos Cell
in Shed Mic o esicles Displaying Au ophagosomal Ma ke s’,
PLoS Pa hogens, 10: e1004045.
Roh mann, G. F. (2014) ‘Baculo i us Nucleocapsid Agg ega ion
(MNPV s SNPV): An E olu iona y S a egy, o a P oduc o
Replica ion Condi ions?’, Vi us Genes, 49: 351–7.
Sajjan, D. B., and Hinchige i, S. B. (2016) ‘S uc u al O ganiza ion
o Baculo i us Occlusion Bodies and P o ec i e Role o
Mul ilaye ed Polyhed on En elope P o ein’, Food and
En i onmen al Vi ology, 8: 86–100.
Sanjua´n, R. (2017) ‘Collec i e In ec ious Uni s in Vi uses’, T ends
in Mic obiology, 22: 402–12.
(2018) ‘Collec i e P ope ies o Vi al In ec i i y’, Cu en
Opinion in Vi ology, 33: 1–6.
, and Domingo-Calap, P. (2016) ‘Mechanisms o Vi al
Mu a ion’, Cellula and Molecula Li e Sciences, 73: 4433–48.
, and Elena, S. F. (2006) ‘Epis asis Co ela es o Genomic
Complexi y’, P oceedings o he Na ional Academy o Sciences o he
Uni ed S a es o Ame ica, 103: 14402–5.
San iana, M. e al. (2018) ‘Vesicle-Cloaked Vi us Clus e s A e
Op imal Uni s o In e -O ganismal Vi al T ansmission’, Cell
Hos & Mic obe, 24: 208–20.
Sa en au, Q. J. (2011) ‘The Di ec Passage o Animal Vi uses
Be ween Cells’, Cu en Opinion in Vi ology, 1: 396–402.
Shi ogane, Y., Wa anabe, S., and Yanagi, Y. (2012) ‘Coope a ion
Be ween Di e en RNA Vi us Genomes P oduces a New
Pheno ype’, Na u e Communica ion, 3: 1235.
Sica d, A. e al. (2016) ‘The S ange Li es yle o Mul ipa i e
Vi uses’, PLoS Pa hogens, 12: e1005819.
8|Vi us E olu ion, 052019, Vol. 5, No. 1
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023
Sigal, A. e al. (2011) ‘Cell- o-Cell Sp ead o HIV Pe mi s Ongoing
Replica ion despi e An i e o i al The apy’, Na u e, 477: 95–8.
Simon, O. e al. (2013) ‘Exp ession o a Pe o al In ec ion Fac o
De e mines Pa hogenici y and Popula ion S uc u e in an
Insec Vi us’, PLoS One, 8: e78834.
Slack, J., and A i , B. M. (2007) ‘The Baculo i uses
Occlusion-De i ed Vi us: Vi ion S uc u e and Func ion’,
Ad ances in Vi us Resea ch, 69: 99–165.
S ie el, P. e al. (2012) ‘Coope a i e Vaccinia In ec ion
Demons a ed a he Single-Cell Le el Using FluidFM’, Nano
Le e s, 12: 4219–27.
Symeonides, M. e al. (2015) ‘HIV-1-Induced Small T Cell
Syncy ia Can T ans e Vi us Pa icles o Ta ge Cells Th ough
T ansien Con ac s’, Vi uses, 7: 6590–603.
Tanne , E. J. e al. (2014) ‘Dominan D ug Ta ge s Supp ess he
Eme gence o An i i al Resis ance’, Eli e, 3: e03830, doi:
10.7554/eLi e.03830.
Taylo , C. M., and Has ings, A. (2005) ‘Allee E ec s in Biological
In asions’, Ecology Le e s, 8: 895–908.
Thoulouze, M. I., and Alco e , A. (2011) ‘Can Vi uses Fo m
Bio ilms?’, T ends in Mic obiology, 19: 257–62.
Usmani, S. M. e al. (2014) ‘Di ec Visualiza ion o HIV-Enhancing
Endogenous Amyloid Fib ils in Human Semen’, Na u e
Communica ions, 5: 3508.
Van Dis, E. S. e al. (2016) ‘No SEVI-Media ed Enhancemen o
Rec al HIV-1 T ansmission o HIV-1 in Two Humanized Mouse
Coho s’, Vi ology, 488: 88–95.
Wallis, C., and Melnick, J. L. (1967) ‘Vi us Agg ega ion as he
Cause o he Non-Neu alizable Pe sis en F ac ion’, Jou nal o
Vi ology, 1: 478–88.
Wei, X. e al. (2003) ‘An ibody Neu aliza ion and Escape by
HIV-1’, Na u e, 422: 307–12.
Wes , S. A. e al. (2006) ‘Social E olu ion Theo y
o Mic oo ganisms’, Na u e Re iews. Mic obiology,4:
597–607.
Wichge s Sch eu , P. J., and Ko ekaas, J. (2016)
‘Single-Molecule FISH Re eals Non-Selec i e Packaging o
Ri Valley Fe e Vi us Genome Segmen s’, PLoS Pa hogens,
12: e1005800.
Xue, K. S. e al. (2016) ‘Coope a ion Be ween Dis inc Vi al
Va ian s P omo es G ow h o H3N2 In luenza in Cell Cul u e’,
Eli e, 5: e13974.
Zhong, P. e al. (2013a) ‘Cell- o-Cell T ansmission Can O e come
Mul iple Dono and Ta ge Cell Ba ie s Imposed on Cell-F ee
HIV’, PLoS One, 8: e53138.
e al. (2013b) ‘Cell- o-Cell T ansmission o Vi uses’, Cu en
Opinion in Vi ology, 3: 44–50.
R. Sanjua´n and M.-I. Thoulouze |9
Downloaded om h ps://academic.oup.com/ e/a icle/5/1/ ez014/5522199 by Red de Biblio ecas del CSIC use on 01 Decembe 2023