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Global Epidemiology of HIV: Risk Factors, Social Networks and Inter-Subtype Recombinant Strains in Vaccine Trial Sites

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Global Epidemiology of HIV: Risk Factors, Social Networks and Inter-Subtype Recombinant Strains in Vaccine Trial Sites FE McCutchan1, GH Kijak1., S Tovanabutra1., E ... – PowerPoint PPT presentation

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Title: Global Epidemiology of HIV: Risk Factors, Social Networks and Inter-Subtype Recombinant Strains in Vaccine Trial Sites


1
Global Epidemiology of HIV Risk Factors, Social
Networks and Inter-Subtype Recombinant Strains in
Vaccine Trial Sites
FE McCutchan1, GH Kijak1., S Tovanabutra1., E
Sanders-Buell1., C Beyrer2., M deSouza3., M
Arroyo1.,3., M Robb1., D. Birx1., N Michael1.
  • US Military HIV Research Program, Rockville, MD,
    USA with joint sponsorship by the Division of
    AIDS, NIAID, NIH, Bethesda, MD, USA
  • Johns Hopkins University Bloomberg School of
    Public Health, Baltimore, MD, USA
  • Armed Forces Research Institute of Medical
    Sciences, Bangkok, Thailand
  • Current address Centers for Disease Control
    and Prevention, Atlanta, GA, USA

2
Background
  • The genetic diversity of HIV-1, comprised of
    multiple subtypes (clades) and inter-subtype
    recombinant forms, poses a significant challenge
    to vaccine design and evaluation
  • The rapid replication rate of HIV-1, coupled with
    a high mutation rate and recombination, are the
    underlying forces driving diversity
  • In the infected individual, a swarm of highly
    related but non-identical strains, termed a
    quasispecies, exists
  • At the population level, multiple subtypes often
    co-circulate, leading to the generation of
    inter-subtype recombinant forms
  • The geographic distribution of subtypes and
    recombinant forms is complex and highly uneven
    across the globe

3
HIV-1 diversity impacts vaccine development at
several stages
  • Identification of prevalent strains in the
    pandemic and their geographic distribution
  • Incorporation of prevalent strains into candidate
    vaccines
  • Establishment of vaccine trail cohorts where
    prevalent strains circulate, and obtaining a
    detailed description of the strains that will
    challenge vaccinees
  • Evaluation of breakthrough infections -
    relationship of infecting strains to those in the
    vaccine, as a measure of cross-clade immunity

4
A complex pandemic
Subtypes A B C D F G H J K
CRF CRF01_AE CRF02_AG - - - - - - CRF35_AD URF
Six Globally Prevalent Strains
5
  • Current candidate vaccines are based on one or
    more of the six globally prevalent strains
  • Vaccine trials are taking place or planned in
    populations where these strains are circulating
  • Many vaccine trial sites have a complex molecular
    epidemiology, with multiple subtypes and
    recombinant forms co-circulating

6
Vaccine cohorts in East Africa and Asia
CRF01_AE, B, C
A, C, D
7
Preparation for vaccine trials in East Africa and
Asia
8
HIV-1 Strains in East Africa
Kenya
Uganda
Tanzania
CRF02
120 complete genomes
9
Origin and Detection of Recombinant Forms
10
HIV-1 is a diploid virus, with two copies of
the RNA genome packaged in the viral particle
  • At each replication cycle, RT switches several
    times between RNA templates during generation of
    the DNA provirus, which is the source of new
    viral RNA genomes
  • Usually, the two RNAs are nearly identical, so
    the recombination process does not generate much
    new diversity
  • Some individuals become infected with more than
    one subtype of HIV-1, leading to co-packaging of
    RNAs from different subtypes into viral
    particles now strand switching generates highly
    divergent strains with segments from different
    subtypes alternating across the genome
  • Dual infections with more than one subtype are
    thought to be the source of inter-subtype
    recombinant strains in the pandemic

11
A
Detection of Recombination
D
Resolution 300 bp
Bootstrap Value
Position in Genome
12
  • When more that one HIV-1 subtype circulates in a
    population, inter-subtype recombinant forms are
    usually present as well
  • Some recombinant forms begin to spread widely in
    populations, and can be recovered from many
    individuals widely separated locations - two of
    these Circulating recombinant Forms (CRF) are
    among the most prevalent globally
  • Still more recombinants have been recovered only
    from a single individual, and are termed Unique
    Recombinant Forms (URF)
  • Little is known about the factors that lead to
    the emergence of CRF

13
Implications of Recombination for Vaccine Trials
  • Dual infection with more than one subtype of
    HIV-1 can occur
  • Participants in vaccine trials may be
    challenged simultaneously with multiple
    subtypes
  • Protection from infection or disease progression
    may occur when challenged with a single subtype,
    but not when challenged with the more diverse
    mixture of strains in a dual infected individual
  • Over time, individuals initially protected from a
    single-clade challenge could later succumb to a
    multi-clade challenge, obscuring vaccine efficacy
  • The overall efficacy of vaccines could be blunted
    in high risk populations, where dual infections
    may be more common, making extrapolation of
    results between population sectors with different
    risk levels more difficult
  • The social networks of vaccine trial volunteers
    may be important to consider the higher
    incidence in high-risk networks may be
    counterbalanced by other factors that could
    complicate vaccine evaluation

14
  • For Molecular Epidemiology, recombination poses
    new challenges
  • Need complete sequencing of each HIV-1 strain, or
    the use of genotyping tools that evaluate the
    subtype in many different regions of each strain
  • The possibility of dual infection needs to be
    accommodated in genotyping approaches
  • Large populations need to be genotyped to capture
    the diversity in mixed-subtype epidemics

15
The Epidemiologic Link Between High-risk Groups,
Dual Infection, and Recombinant Strains
16
  • Fluorescent Multiregion Hybridization Assays for
    Regional Application

17
Comparative Epidemiology in East Africa
MHAacd assay
MHA
Population High risk females Urban and rural
communities Rural communities Agricultural
Plantation
Country Tanzania Tanzania Uganda Kenya
Cohort HISIS CODE MER Kericho
Genotypes (N) 238 487 329 366 1420

18
Comparative Epidemiology in Thailand
MHAbce assay
MHA Genotypes (N) 336 177 293 806
Population Injecting Drug Users Antenatal
Clinic Vaccine Trial Volunteers
Province Chiang Mai Lampang Rayong-Chon Buri
19
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20
  • High risk cohorts with multiple HIV-1 exposures
    have higher rates of dual infection and
    recombinant strains
  • Many different inter-subtype recombinant HIV-1
    can emerge in a single dual infected individual,
    who may transmit them to others
  • Many recombinant strains are generated within
    high risk social networks, with high rates of
    transmission

21
Recombinant Strains and Social Networks
22
Describing a Recombinant Strain Subtypes and
Breakpoints
1
9200
Subtype A
380
4600
5700
1900
AC Recombinant
1
9200
Subtype C
23
  • Through recombination, parts of the parental
    strains are lost, and cannot be regained until
    another dual infection provides opportunity to
    recombine again
  • Irreversibility lends stability
  • Could recombination breakpoints serve as stable
    markers through many cycles of transmission,
    permitting mapping of the social networks in
    which HIV spreads?

380
4600
1900
5700
A
A
A
C
C
Lost Genetic Material
C
C
C
A
A
24
Hypotheses
  • Mapping of shared breakpoints among recombinant
    strains could provide a new dimension to the
    molecular epidemiology of HIV-1
  • The structure and relationships of recombinant
    strains may provide information about the social
    networks in which they spread

25
Recombinant Strains and Risk Groups
26
Recombinant Strains in Low Risk Groups
Transmission
Sampling
single
single
single
single
single
Complete sharing of breakpoints
27
Recombinant Strains in High Risk Groups
Transmission
single
dual
single
single
Partial sharing of breakpoints
dual
single
28
Complete Genome Sequences of Recombinant Strains
Risk Groups
N
Region
Subtypes
Countries
17 21 26
Uganda Kenya Tanzania
HeterosexualPerinatal
East Africa
A, C, D
42 6 13
Thailand Myanmar China
HeterosexualIDU Unknown
CRF01_AE, B, C
Asia
125
29
Fine-mapping of 125 recombinant strains
  • Each alignment is 9000 bp
  • Inspect alignment base-by-base (600 person-hours)
  • Map breakpoint locations onto reference strain
    HXB2
  • Create database of recombination breakpoints
  • A to C at 380
  • C to A at 1900
  • A to C at 4600
  • C to A at 5700
  • 896 breakpoints determined
  • 521 in strains from East Africa
  • 375 in strains from Asia

30
  • Numerous closely spaced shifts in subtype were
    mapped, many of which were too closely spaced to
    be efficiently detected and mapped by sliding
    window techniques
  • Overall, the recombinant strains were more
    complex than first appreciated

40 of breakpoints are spaced less than 300 nt
apart
Spacing (nt)
Adjacent Breakpoint Pair
31
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32
Recombinant HIV Networks and Risk Groups in Asia
  • 24 CRF01_AE/B recombinants from Thailand and
    Myanmar
  • 11 from IDU
  • 13 from heterosexual transmission

33
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34
Expanding the Analysis to 125 Recombinant Strains
from Asia and E. Africa
35
Network Visualization Software
  • Each strain is a node
  • Each shared breakpoint is a connection,
    represented by a line
  • Highly interconnected strains form dense
    clusters, with less connected strains at the
    periphery

UCiNET and NetDraw by S. Borgatti Boston
College/Analytic Technologies
36
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37
  • Within these regional epidemics, virtually all of
    the recombinant strains analyzed shared at least
    one of their breakpoints, and often each of their
    breakpoints, with at least one other strain in
    the region
  • Observed a highly connected network of related,
    but non-identical recombinants
  • Degree of networking appeared greater among
    Asia vs. E. Africa strains

38
How do CRF relate to other strains in their
geographic region?
Criterion 100 bp
CRF07_BC
CRF10_CD
CRF08_BC
CRF34_01B
CRF15_01B
CRF16_A2D
Asia
East Africa
CRF21_A2D
39
  • CRF share some of their breakpoints with unique
    recombinant forms (URF) in their respective
    regional epidemics
  • Distinction between Circulating and Unique
    Recombinant forms may be a reflection, not of any
    intrinsic property of the virus, but rather a
    result of their relative abundance, and
    therefore, the probability of re-sampling them,
    and their potential for stabilization in
    lower-risk networks where dual infection is less
    common

40
What can be learned about social networks from
the relationships among recombinant strains
circulating within them?
41
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42
In Asia
  • Heterosexual and IDU Networks in Thailand are
    strongly interconnected and these connections
    were already established during the first decade
    of the Thailand epidemic
  • Fewer connections across national borders
  • Strains from Myanmar bridge China and Thailand
    epidemics

43
Recombinant Networks in E. Africa
AC
AD
TZ UG KE
CD
ACD A2D
By Subtype
By Country
44
In East Africa
  • Recombinant strains share some of their
    breakpoints even when isolated in different
    countries
  • Given the distances involved, long chains of
    transmission undoubtedly separate the sampled
    strains, yet breakpoints mark them as part of a
    recombinant lineage

45
Connections Across National Borders
CD
B/C
AC
AD
Tanzania Uganda Kenya
CRF01_AE/B
China Myanmar Thailand
A2D
Asia
E. Africa
46
  • Highly interconnected networks of related strains
    were observed, both in E. Africa and in Asia
  • Networks of recombinant strains were more
    tightly interconnected in higher risk groups,
    like IDU, than in general population cohorts
  • Dual infection in high-risk groups, which is
    required to generate the recombinant strain
    networks that we observe is occurring to a
    considerable degree
  • CRF may represent recombinant strains that have
    entered much lower-risk networks, where the
    opportunity for dual infection and further
    recombination is limited - reproductive isolation

47
Conclusion
  • HIV-1 strains reflect the social networks in
    which they are spreading
  • Recombinant strains can be useful for delineating
    the boundaries and dynamics of the social
    networks in which they spread
  • High-risk groups may contribute
    disproportionately to the overall diversity of
    the pandemic, because of increased dual infection
    and recombination
  • Testing candidate vaccines in many types of
    social networks, with different levels of risk,
    may be an optimal strategy in the quest for an
    HIV-1 vaccine

48
Contributors
  • Participants in cohort development and other
    studies in Tanzania, Uganda, Kenya, Thailand,
    China, Myanmar
  • Oliver Hoffmann, Steffan Geis, Leonard Maboko,
    Donan Mmbando, Eluter Samky, Michael Hoelscher,
    and other members of the Mbeya Medical Research
    Programme, Tanzania
  • David Serwadda, Nelson Sewankambo, Maria Wawer,
    Ron Gray Makerere University and Uganda Virus
    Research Institute, Uganda,Columbia University
    and Johns Hopkins University, USA and other
    members of the Rakai Project, Uganda
  • Carl Mason, USAMRU-K, Monique Wassuna, KEMRI, and
    other contributors to the Kenya Blood Bank Study
  • David Celentano, Chris Beyrer, Vinai Suriyanon,
    Jaroon Jittiwutikarn, Thira Sirisanthana, Myat
    Htoo Razak and other contributors to the Opiate
    Users Research Study, Thailand
  • Vilaiwan Gulgolgarn, Manu Wera-arpachai, Chirasak
    Khamboonrueng, Kenrad Nelson, Nakorn Dabbhasuta
    and others from the Lampang perinatal
    transmission cohort study, Thailand
  • Supachai Rerks-Ngarm, Sonchai Wattana, Wiwat
    Wiriyakijja, Sorachai Nitayaphan, Chirapa
    Eamsila, Jerome Kim, Michael Benenson, Arthur
    Brown and others for samples from volunteers
    deferred from enrollment in the Phase III
    prime-boost vaccine trial in Rayong-Chonburi
    Provinces, Thailand
  • Special thanks to Jocelyn Chiu and her mentors,
    Sodsai Tovanabutra, and Eric Sanders-Buell, for
    inspection and analysis of 1,125,000 nucleotides
    of sequence alignment

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