AIDS CLINICAL ROUNDS

The UC San Diego AntiViral Research Center sponsors weekly

presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.

The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
!Molecular!Epidemiology!of!HIV!in!!San!
Diego!and!Tijuana!
Tracking!HIV!

Sanjay!Mehta!MD!
Assistant!Professor!
February!2015!
How!Does!an!InternaGonal!Border!
Affect!the!Spread!of!InfecGous!
Diseases!

www.globecartoon.com!
 Ebola!and!Air!Travel!

•  An!esGmated!2.8!travelers!with!Ebola!board!an!
internaGonal!plane!each!month!
Bogoch,!Lancet!Jan!2015!
www.darrinbell.com!
SARS:!The!Metropole!Hotel!

US!Central!Intelligence!Agency!
 San!DiegoTTijuana!Border!
San!Diego!County!
!pop!3.1!million!
San!Diego!City!
!pop!1.3!million!
Tijuana!
! !pop!1.3!million!
 San!DiegoTTijuana!Border!

•  Worlds!busiest!
land!border!
•  Over!50!million!
border!crossings!
each!year!

CityTdata.com!
Inthedf.com!
 San!Diego!Tijuana!Border!

•  How!likely!is!this!going!to!stop!the!spread!of!infecGous!
diseases!across!the!border?!
Lest!We!Forget!

faculty.catawba.edu!
 2009!H1N1!Influenza!Epidemic!

•  From!a!small!town!in!
Veracruz,!Mexico!the!
2009!H1N1!epidemic!
spread!into!Imperial!and!
San!Diego!counGes!first!
in!the!US.!

Scienceblog.com!
Cameron!et!al!JIDC!2009!
 Dengue!
•  14!confirmed!
cases!of!Dengue!
in!Baja!California!
•  A.!aegypG!found!at!
32nd!st!Naval!StaGon!
and!in!a!home!in!
Chula!Vista!
Aedes%aegyp*%has!arrived!!
•  Transmits!Dengue,! !
Chikungunya!and!
Yellow!Fever!
 HIV!in!Mexico!
•  In!1980s,!most!HIV!cases!in!
Mexico!were!in!individuals!who!
previously!lived!in!the!US.!
•  By!1991,!44.3%!of!cases!were!in!
previous!US!residents.!
•  In!2000!the!rate!dropped!to!
~12%,!but!was!higher!in!rural!
areas,!with!over!20%!of!HIV!
cases!in!Michoacán!and!
Zacatecas!acquired!in!the!US.!

MagisTRodriguez!JAIDS!2004!
! Strathdee!et!al!!JAMA!2008!
 MigraGon!to!US!

Zacatecas!

Michoacán!
 QuesGons!
1)  Can!we!demonstrate!that!San!Diego!and!Tijuana!
HIV!epidemics!are!connected?!
2)  Is!there!direcGonality!to!viral!migraGon!across!the!
border?!
3)  What!risk!factors!are!driving!the!border!HIV!
epidemic?!
!
 Molecular!Epidemiology!
Using!the!relaGonships!between!viral!sequence!data!
sampled!from!infected!individuals!to!characterize!the!
spread!of!HIV!!

1)  AACTGATCGC
2)  AACAGATCGC
 HIV!Diversity!
Low!fidelity! High!fidelity!
HSV!
HIV!
HCV! HIV!

Duffy,!Shackleton,!Holmes!2008!
 HIV!Diversity!
•  Results!in!a!unique!HIV!sequence!for!each!infected!
individual!
•  This!unique!sequence!signature!conGnues!to!evolve!
over!Gme!(~1%/yr!for!HIVT1!pol)!
•  This!can!be!used!to!
•  Study%intra1individual%viral%spread%
•  Study%inter1individual%viral%spread%
•  Study%epidemics%in%*me%and%space%
The!HIV!Diaspora!

From!Tebit!and!Arts!Lancet!ID,!2011!
 Establishing!RelaGonships!
Phylogenetic Trees Network Maps

B!

1)  AACTGATCGC 1)  AACTGATCGC

2)  AACAGATCGT 2)  AACAGATCGT

Evolutionary Difference at Overall difference

each site
 Networks!
•  Clusters!can!be!represented!as!networks!!
–  Data!is!resolved!into!putaGve!linked!pairs!
–  Linkage!structure!emerges!
Terminology!T!Networks!
Cluster(

Network(
 Understanding(HIV(Transmission(Networks(

A B C A(Sexual(Network:!Real(World(Network(
•  Dashed!lines!indicate!sexual!contact!

D E F

An(HIV(Transmission(Network:(What(we(see(
A C
•  Solid!lines!indicate!very!similar!viruses!
•  Red!circles!indicate!HIV!infected!persons!
D F •  Other!individuals!are!HIV!negaGve!so!don’t!appear!

I
An(Transmission(Network:(Limita?ons(of(our(
A
knowledge(
C
•  Dates!of!infecGon!are!used!to!assign!direcGon!of!
transmission!
H D F •  New!HIV!infected!persons!already!in!care!appear!
•  Other!potenGal!“sources”!of!HIV!transmission!
J! K! idenGfied!
G
•  What!we!don’t!see!remains!missing!
Courtesy!of!Susan!Liple!
 Why!use!Network!Analysis!!
•  PhylogeneGc!analysis!cannot!esGmate!the!direcGon!of!
transmission!with!certainty.!
•  Similar!strains!may!be!found!in!many!more!than!two!individuals,!
especially!if!they!are!part!of!the!same!transmission!network.!
•  A!network!map!beper!represents!similariGes!between!
sequences! ?
D
? E

A B C F

G
H

23! 11/07/14!
Courtesy!of!Susan!Liple!
 Terminology!–!PhylogeneGc!Trees!

Trees!allow!us!to!
1)  infer!characterisGcs! Node!
about!ancestors!!
2)  Beper!understand!
the!role!of!Gme!
(Tips)

Time!or!GeneGc!Difference!!!
San!Diego!–!Tijuana!Molecular!Epidemiology!
Project!
 CollaboraGng!Projects!Across!the!
Border!Region!
•  Tijuana!
•  Persons!who!inject!drugs!(PWID)!!T!Proyecto!El!Cuete!
•  Female!sex!workers!(FSW)!and!Clients!!T!Mujer!Segura,!Mujer!Mas!
Segura,!Proyecto!Parejas,!Hombre!Seguro,!!Amigos!
•  Truck!Drivers!–!Crossing!Borders!–!Proyecto!Mapa!
•  Community!HIV!clinic!–!CAPACITS!clinic!Tfuture!
•  Prenatal!HIV!clinic!–!IMPAACT!T!future!
•  MSM!in!Tijuana!Tfuture!
•  San!Diego!
•  MSM!T!Primary!InfecGon!Research!ConsorGum!!
•  PWID!T!STAHR!study!and!STAHR!II!study!
•  MSM,!Heterosexuals!TSouth!Bay!Primary!InfecGon!Surveillance!
•  MSM,!PWID,!Heterosexuals!–!CHARTER!cohort!T!future!
•  MSM,!PWID,!Heterosexuals!T!CNICS!Cohort!T!future!
!
 San!Diego!–!Tijuana!Molecular!
Epidemiology!Project!
•  Projects!used!various!sampling!methods!
–  Respondent!Driven!Sampling!
–  Convenience!Sampling!
–  VenueTbased!Sampling!
–  Targeted!Sampling!
 San!Diego!–!Tijuana!Molecular!
Epidemiology!Project!
•  Data!collecGon!!
–  HIVT1!pol!genotype!(sequence!data)!
–  SocioTdemographic!data!(Age,!Sex,!Race,!etc…)!
–  Clinical!data!(HIV!VL,!CD4,!STI!infecGon,!etc…)!
–  !Risk!Factor!Data!(IDU,!sexual!RF,!etc…!
!

!!!!!TT!Geographic!Data!
 San!DiegoTTijuana!Molecular!
Epidemiology!Study!
•  1111!HIV!sequences!were!collected!from!the!
collaboraGng!studies!(including!263!
background!sequences)!
•  4!sequences!were!removed!due!to!lab!
contaminaGon!or!duplicaGon!
•  The!remaining!1107!sequences!included!!
–  76!from!subjects!residing!in!Tijuana!
–  768!from!subjects!residing!in!San!Diego!
–  263!background!sequences!from!San!Diego!
 Clustering!
•  Using!a!network!approach,!we!inferred!the!presence!
of!transmission!clusters!by!inferring!linkages!when!
two!sequences!were!≤!1.5%!different!
•  We!idenGfied!164!transmission!clusters!(2T33!
individuals)!
•  17!included!sequences!from!Tijuana,!and!5!included!
sequences!from!both!Tijuana!and!San!Diego!
 Data!VisualizaGon!
hpp://Gcino.ucsd.edu/avantgarde/dev_hua/
demo2.html!
!
!
hpp://54.69.246.216/avant_data/
circle_packing!
 Clustering!
•  8!Clusters!made!up!of!predominantly!PWID!
–  InteresGngly,!bisexual!individuals!were!significantly!more!common!in!
these!clusters!than!others!
•  16!Clusters!were!made!up!predominantly!of!heterosexuals!
–  All!of!these!that!had!3!or!more!individuals!were!predominantly!made!
up!of!females!
•  89!clusters!were!made!up!predominantly!of!MSM!
Map(of(the(Observed(San(Diego(–(Tijuana(Transmission(Network(
 Tijuana!Clusters!
•  17!clusters!indenGfied!in!subjects!residing!in!
Tijuana!
–  Predominantly!involved!sex!workers!and!injecGon!drug!
users!
–  In!6!individuals!who!seroconverted!over!the!course!of!the!
study,!4!were!linked!to!another!individual!
–  In!two!idenGfied!epidemiologically!linked!pairs!who!
seroconverted!over!the!course!of!!the!study,!only!one!was!
geneGcally!linked!
San!DiegoTTijuana!CrossTBorder!
Clusters!
 CrossTBorder!Clusters!
•  5!idenGfied!clusters!including!sequences!from!
San!Diego!and!Tijuana!
–  Significantly!higher!proporGon!of!
•  Females!(p=0.02)!
•  Heterosexuals!(p=0.0003)!
–  Consistent!with!our!sampling!
•  Suggests!the!heterosexualTPWID!HIV!epidemic!
in!Tijuana!is!linked!to!the!San!Diego!MSM!HIV!
epidemic!
 CrossTborder!Clusters!

–  3/5!clusters!included!PWID!and!heterosexuals!in!Tijuana,!
and!MSM!in!US!(i.e.!bridging!of!risk!groups!across!the!
border)!

PWID
MSM

Heterosexuals
(sex workers)
 Bridging!PopulaGons!

•  Very!important!in!the!Southeast!Asian!epidemic!
Is!there!direcGonality!to!viral!migraGon?!

Faria!et!al,!Science!2014!
MigraGon!Across!the!San!DiegoTTijuana!Border!
Region!

Time scaled phylogenetic tree

 Viral!MigraGon!

TransiGon!from! !1)San!Diego!to!Tijuana!(Blue!to!Red)!
! ! ! ! !2)!Tijuana!to!San!Diego!(Red!to!Blue)!
 How!Much!Viral!MigraGon!
0.25
From SD toTJ
From TJ to SD
Total

0.2
Probability!

0.15
Density

0.1

5E-2

0
-10 0 10 20 30 40 50 60
Viral Movement Counts

Increasing Amount !
When!did!Viral!MigraGon!Occur!

Timing!of!Viral!MigraGon!between!San!Diego!and!Tijuana!
 US!is!sGll!exporGng!HIV!to!Mexico!
•  What!is!the!role!of!deportaGon!
–  In!Tijuana!
•  HIV!prevalence!of!deportees!esGmated!1.23%!
•  77%!of!male!HIV!+!IDUs!are!deportees!
•  Deportees!report!feeling!that!IDU!and!
transacGonal!sex!more!acceptable!in!their!new!
environment!
–  8!deportees!involved!in!transmission!clusters!
•  4!likely!acquired!infecGon!in!TJ!
•  Other!4!deported!with!HIV?!

Pinedo!et!al.!2014!
Ojeda,!et!al!2011!
What!risk!factors!are!driving!the!border!HIV!
epidemic?!!
A!Focus!of!the!nonTMSM!Epidemic!in!San!Diego!
lies!just!across!the!Border!
 Conclusions!based!on!our!Sample!
•  The!San!Diego!and!Tijuana!epidemics!are!connected!
bridging!risk!groups!across!the!border!
•  There!is!evidence!of!biTdirecGonal!viral!migraGon!
across!the!border!
–  1990s!–!More!migraGon!from!SD!to!TJ!
–  2000s!–!More!migraGon!from!TJ!to!SD!
•  The!demographics!of!the!border!epidemic!likely!
differs!from!that!of!the!overall!San!Diego!epidemic!
Does the disparity in resources between
Mexico and the US affect HIV prevention
efforts in the border region?!
Treatment!as!PrevenGon!

•  Test!and!Treat!
strategies!rely!on!
frequent!tesGng!of!
high!risk!individuals!
and!early!treatment!!
Viral!IntroducGons!can!Help!Sustain!an!Epidemic!

Rakai Cohort, Uganda

69% of non-household transmissions were from outside the community

Grabowski,!PloSMed!2015!
 One!Epidemic!

Which!country!
has!universal!
access!to!HIV!

For!prevenGon!of!new!infecGons,!we!need!aggressive!screening!
for!HIV!infecGon!on!both!sides!of!the!border,!followed!by!linkage!
to!care.!!
 Acknowledgements!
UCSD SDPIRC and CFAR
UCSD GPH
Susan Little
Doug Richman Steffanie Strathdee
Tom Patterson
Davey Smith Kimberly Brouwer
Christy Anderson Rich Garfein
Gina Osorio Maria Rangel
Karole Ignacio Karla Wagner
Lab! Alicia Vera
Millenka Vargas
Deyna Arellano
GIS Daniela Abramovitz
Hayden Lowenstein

Bioinformatics Team
Lorri Freitas
Antoine Chaillon
Funding(Sources( Ben Murrell
Sergei L Kosakovsky Pond
Konrad Scheffler
Joel Wertheim
Jason Young