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Lymphocyte kinetics in
HTLV-1 infection
Charles Bangham
Department of Immunology
Wright-Fleming Institute
Human T-lymphotropic virus
              type 1 (HTLV-1)

• infects 10-20 million people worldwide.

• endemic (1-20% of adults) in South America,
  Caribbean, Central Africa, southern Japan.

• 2-3% develop an aggressive T-cell
  leukaemia/lymphoma

• 2-3% develop a chronic inflammatory disease either of
  CNS, eyes, muscles, joints, lungs or skin.

• 95% remain healthy carriers of HTLV-1.
HTLV-1 persistence and inflammatory disease


Three main questions:


1.      How does HTLV-1 persist?

2.      How does it spread?

3.      Why do some develop HAM/TSP, whereas
        most remain healthy carriers?
The proviral load of HTLV-1 is high and
 correlates with the risk of HAM/TSP

                             median proviral load
                             (copies/100 PBMCs)


                             HAM/TSP:               5.4


                             asymptomatic: 0.34




                            Nagai et al 1998
                            J. Neurovirol. 4, 586
How is the high proviral load maintained?

 Retroviruses replicate by two routes:


                      host cell          - provirus latent
mitotic
                      polymerase         - little sequence
                                           variation in virus




                      reverse            - provirus
infectious                                 expressed
                      transcriptase      - sequence
                                           variation
Evidence for latency of HTLV-1

                             variability (Kabat-Wu)                         Env

1. HTLV-1 varies little in                                                  HIV-1
   sequence:
                                                                            HTLV-1

                                          amino acid position
                                               Daenke et al. 1990: J. Virol. 64, 1278


2. HTLV-1 mRNA and proteins are usually undetectable
   in PBMCs.
3. Virions are absent and plasma is non-infectious.
‘Standard model’ of HTLV-1 persistence

HTLV-1 is maintained by passive proliferation of provirus-
  containing lymphocytes.

A fraction of cells express HTLV-1, but too few to allow the
    immune response to make an impact on proviral load.

Supported by observation of
large clones of HTLV-1+
lymphocytes in vivo:
                                                 Wattel et al. 1995:
                                                 J. Virol.69, 2863
What is wrong with the ‘standard model’?

There is a strong T-cell and antibody response to HTLV-1.

Anti-HTLV-1 cytotoxic T lymphocytes (CTLs) are
  chronically activated; virus-specific IgM is produced.

Passively proliferating HTLV-1+ cells would be outgrown if
  any start to express HTLV-1: 1%/day        40-fold drop in
  load over 1 year.

      - does the CTL response make any impact?
Anti-HTLV-1 CTLs are -


      • abundant




      • chronically activated

      • chiefly directed against the HTLV-1 Tax protein
but    CTL frequency, specificity and activation do not differ
       between HAM/TSP and asymptomatics
                                  Bangham 2000 Curr Opin Immunol 12, 397
HTLV-1-specific CTL frequency is positively
       correlated with proviral load




                                                 Kubota et al. 2000
                                                 Wodarz et al. 2001




- so do CTLs determine load, or passively reflect the load?
CTLs exert selection on HTLV-1 in vivo

1. The tax gene is under positive selection in
   asymptomatic carriers but not in HAM/TSP patients:
                                           AC (N=4)   HAM (N=4)
                     DN / DS =              1.15          0.42

                                                      % specific lysis

2. Naturally occurring Tax variants
   escape CTL recognition:


 Niewiesk et al 1994: J. Virol. 68, 6778
 Niewiesk et al 1995: J. Virol. 69, 2649
Positive selection at individual Tax residues




                                    HLA-A2-
                                    restricted CTL
                                    epitopes

                                    Positive
                                    selection at
                                    individual
                                    residues
9 genes were overexpressed in CD8+ cells from
    individuals with a low HTLV-1 proviral load
                                                A
AC1 CD8L                        AC2 CD8L        1 (AJ001687): NKG2D
cluster:                        cluster:        2 (M57888): Granzyme B
                                                3 (U20350): CX3CR1
33 genes                        16 genes        4 (M30894): TCR-gamma
                                                5 (M12824): CD8 A
           20       3       2                   6 (AF031824): Leukocystatin
                                                7 (M18737): Granzyme A
                                                8 (M85276): Granulysin (NKG5)
                                                9 (S69115): NKG7


                    9                           B
                                                1 (X57352): IFITM3 (I-8U)
                1       2
                                                C
                                                1 (U26174): Granzyme K
                                                2 (M28393): Perforin
                    5
                                HAM CD8L        D
                                cluster:        1 (M17016): Granzyme B precursor
                                                2 (M1121): RANTES (1)
                                17 genes        3 (M1121): RANTES (2)


                                    Vine, Heaps et al., 2004: J Immunol 173, 5121
Protective role of HLA class 1 indicates
 that CTLs limit HTLV-1 expression in vivo

1. Possession of either HLA-A*02 or HLA-Cw*08 :

 •       reduced proviral load by 3-fold                               HLA-A2 and HLA-Cw8
                                                                       prevent 36% of
                                                                       potential HAM/TSP
 •       halved the odds of HAM/TSP                                    cases.


2. HLA class 1 heterozygosity was associated with a
     lower proviral load.

     Jeffery et al: PNAS (1999) 96, 3848; J Immunol (2000) 165, 7278
     Vine et al: J Infect Dis (2002) 186, 932
Alternative scheme of HTLV-1 persistence



                                                                          CTL




Spontaneously expressed Tax protein drives proliferation of provirus+ cells.
CTLs kill virus-expressing cells.
A fraction of daughter cells survive by shutting down expression (how?)
Proviral load is determined by an equilibrium between virus and CTLs : the
chief determinant of load is the rate – the ‘efficiency’ – of CTL killing.
Nowak and Bangham 1996: Science 272, 74-79; Bangham and Osame 2005: Oncogene 24, 6035–6046.
Predictions of model 2
1. Proviral load is determined by a) CTL efficiency &
                                  b) rate of Tax expression.

2. Mean lymphocyte turnover rate a) is abnormally high in
   HTLV-1 infection, especially in HAM/TSP patients, and
                                  b) correlates with [Tax].

3. Proviral load correlates with Tax protein expression.

4. The advantage to the virus conferred by Tax expression
   diminishes as the CTL lysis rate increases.
Quantification of anti-viral CTL efficiency

                              dy
                                 = c − εyz
                 HAM          dt
                 patient

                           y = freq. of infected cells
                           z = freq. of CTLs
                           ε = lysis rate constant - ‘CTL efficiency’
             carrier
                           c = constant




                               Asquith, Mosley et al., 2005:
                               J Gen Virol 86, 1515
Quantification of anti-viral CTL efficiency
                                 6
     % T a x + C D 4 + c e lls                                     repeat 1: observed data
                                 5
                                                                   repeat 1: best theoretical fit
          a fte r 1 8 h rs
                                 4
                                 3                                 repeat 2: observed data

                                 2
                                                                   repeat 2: best theoretical fit
                                 1
                                 0
                                     0   10   20    30     40        50           60          70
                                                   % CD8+ cells

ε is reduced:
          80% by block of perforin
          29% by partial HLA mismatch                             Asquith, Mosley et al., 2005
     100% by full HLA mismatch                                    J Gen Virol 86, 1515
Prediction 1: CTL lytic efficiency determines
           HTLV-1 proviral load in vivo
  proviral load (copies/100 PBMC)

                                                                         Asquith, Mosley et al.
                                                                         2005: J Gen Virol 86,
                                                                         1515




                                            lytic efficiency ε
                                    (%Tax+ cells killed/CD8+ cell/day)

Conclusion: 30% to 50% of observed variation in HTLV-1
            proviral load is accounted for by variation in ε.
Impact of CTL activity in HTLV-1 infection


1. The rate of CD8+ cell-mediated lysis is an important
determinant - perhaps the largest single determinant - of
variation in HTLV-1 load between individuals.


2. In a typical infected individual, each CD8+ cell kills
     ~5 HTLV-1-infected cells/day.
          turnover rate of Tax+ cells of ~7% per day.
        i.e. total of ~2 x 109 infected CD4+ cells killed/day.
Measurement of lymphocyte turnover
          rates in vivo

• infuse 2H-labelled glucose (5% ) i.v. overnight


• carbon ring is incorporated into newly synthesized
nucleosides          genomic DNA of newly divided cells


• decay of 2H/1H in DNA        direct estimate of t½ of
specific (sorted) lymphocyte subsets
                            Macallan et al (1998) PNAS 95, 708
                            Asquith et al (2002) Trends Immunol. 23, 596
2H-glucose
                     kinetics in vivo:
 CD45RO+ cells turn over faster than CD45RA+
                                                                        CD45RO+

0.15                                                     0.15
                                  L01-HS                                                L07-TBI
                              AC 1                                                    HAM 1
 0.1                                                     0.10



0.05                                                     0.05



  0                                                      0.00
       0   2      4      6        8         10                  0   2     4       6     8         10


                                                                              CD45RA+
0.15                                             2H   incorporation
                                  L10-HBO
                              AC 2
0.10



0.05



0.00
       0   2      4      6        8         10



 Asquith et al. 2006: submitted                                          time (d)
Prediction 2a: mean proliferation rate of CD4+ T
  cells in HAM/TSP > asymptomatic carriers


            C D 4 + C D 4 5 R O + T ly m p h o cy te
                                                   5
               p ro life ra tio n ra te (d a y-1 )
                                                   4                                   p = 0.01
                                                                                       (Mann-Whitney,
                                                   3
                                                                                               2-tailed)
                                                   2

                                                   1

                                                   0
                                                       Asymptomatic   HAM/TSP
                                                       carriers       patients



                                                                                 Asquith et al. 2007
                                                                                 PNAS 104, 8035-8040
In vivo turnover rate of CD4+CD45RO+ cells
   correlates with Tax expression ex vivo


         CD4 CD45RO proliferation rate in
                                            5

                                            4
                vivo (% per day)



                                            3

                                            2                                                      P = 0.016
        +




                                                                                                   (Spearman rank
                                            1                                                      correlation)
        +




                                            0
                                                0   2         4         6         8     10
                                                         Tax expression ex vivo
                                                    (Tax CD4+/CD4+ after 18h culture)
                                                        +




                                                                                             Asquith et al. 2007
                                                                                             PNAS 104, 8035-8040
Prediction 2b:
Tax-expressing cells turn over faster
      than Tax – cells in vivo
     0.07
                                       L02-HAY
     0.06               Tax+                       turnover rate:
     0.05
     0.04
     0.03                                           7% per day
     0.02       Tax –
     0.01
        0
            0      2       4   6   8         10



     0.14
                                       L07-TBI
     0.12         Tax+
      0.1
     0.08                                           13% per day
     0.06
     0.04       Tax –
     0.02
                                                  Asquith et al. 2007
        0
            0      2       4   6   8         10   PNAS 104, 8035-8040
Prediction 3: proviral load correlates
        with Tax expression

                   25


                   20
(Tax+CD4+/CD4+)
% Tax expression




                            y = 0.86x + 3.08
                                 2
                               R = 0.71
                   15
                                                                                  HAM/TSP
                                                                                  AC
                   10


                    5
                                                          y = 0.61x + 0.56
                                                               2
                                                             R = 0.82
                    0
                        0   5                  10         15                 20
                                       Proviral load
                                   (% of PBMC infected)



                                                               Asquith et al. 2005: Retrovirology 2, 75
Prediction 4: advantage conferred by Tax
expression falls as CTL lysis rate increases
    Increase in proviral load caused by



                                                                model prediction
       increase in % Tax expression




                                                                experimental
                                                                results


                                   Rate of CTL lysis            Asquith et al. 2005: Retrovirology 2, 75
                            (Tax+ cells killed/day/CD8+ cell)
Quantification of HTLV-1 infection dynamics
                   in vivo
        cytokines (Il-2, IL-15)
                                                       1d (70d)
        antigen



(30d)
         0.05 – 5%
         per day
                          1d         1d
                                          X               CTL




resting
HTLV-1+
                       HTLV-1-      1d
cell
                       expressing
               ?       cell                   Asquith and
                                              Bangham 2008:
                                              Trends Immunol.
                                              29, 4-11
Tax expression in HAM/TSP > carriers
              at a given proviral load


                                     Asquith et al.
                                     2005:
                                     Retrovirology
                                     2, 75-83




- and a given
FoxP3+                                Toulza et al.
frequency                             2008: Blood
                                      111, 5047-5053
What determines the rate of HTLV-1
      proviral expression in vivo?
- strain (sequence) of virus?                 No.

- proportion of defective proviruses?         Unknown.

- T cell activation (ag, cytokines)?
    Unlikely to explain observed between-individual variation.

- HTLV-1 regulatory products (p30II, Rex, HBZ)
    Limit existing proviral expression, but do not control onset.

- epigenetic changes?

- genomic integration site?
Is HTLV-1 integration random?

Linker-mediated PCR

PBMCs taken from 10 HAM patients + 10 ACs

311 genomic integration sites mapped

Observed integration sites compared with random NlaIII
  sites in genome

Kiran Meekings, 2008: PLoS Pathogens 4(3): e1000027 .
Statistical analysis carried out in collaboration with Rick Bushman,
Jeremy Leipzig, Chuck Berry
HTLV-1 integration frequency in vivo
   correlates with gene density

                    10
Observed/Expected




                    8

                    6                                                    in vitro
                    4                                                    in vivo

                    2

                    0
                           1       2      3       4       5      6
                            Gene density (number genes within 25kb)

                                                                      Meekings et al. 2008:
                         p = 1.8 x 10-5 (logistic regression)         PLoS Pathogens
                                                                      4(3): e1000027
HTLV-1 proviral integration in vivo predominates:




                                                                                                                             Observed / Expected
                                                                                                                                                    3
  Observed / Expected



                                                                                                                                                   2.5
                                    4
                                                                                                                                                    2
                                    3
                                                                                                                 In Vitro                          1.5
                                    2                                                                                                               1
                                                                                                                 In Vivo
                                    1                                                                                                              0.5
                                    0                                                                                                               0
                                                     1            2       5       10         25                                                                1               2        5                  10   25

                                                     Distance from integration site (kb)                                                                 Distance from Integration site (kb)

                                              - near CpG islands                                                            - near transcription start sites


- and is associated with                                                                                                                                                 50%
                                                                                                                                                                         40%




                                                                                                                                                          % in g e n e
                                               0.4                                                                                                                       30%
                        Proportion of sites




                                              0.35
                                               0.3
                                                                                                                                                                         20%
                                              0.25                                                                                                                       10%
                                                                                                  Tax Positive
                                               0.2
                                              0.15                                                Tax Negative                                                           0%
                                               0.1                                                                                                                                                              Meekings et al.




                                                                                                                                                                                   AC


                                                                                                                                                                                            H A M /T S P
                                              0.05
                                                0                                                                                                                                                               2008: PLoS
                                                         1         2      5      10     25

                                                             Integration Site Window (kb)
                                                                                                                                                                                                                Pathogens
                                                                                                                                                                                                                4(3): e1000027

                                               - Tax expression                                                                                          - and with HAM-TSP
Rate of proviral expression & rate of
  CTL lysis determine HTLV-1 load and
            risk of HAM/TSP
proviral expression



                             HAM              HAM
                      fast   moderate load    high load
      HTLV-1




                             AC               AC
                      slow
                             low load         moderate load


                                  fast             slow

                                         CTL lysis
Conclusion: persistence of HTLV-1 in vivo
                                         p12I                   CD4+FoxP3+
                                                                cells
                      histone
                    deacetylation
                                                 CTLs

integration into                proviral          infectious spread
transcriptionally               expression        (viral synapse)
active units
                                                T-cell
                                                proliferation
                               p30, Rex, HBZ

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Lymphocyte kinetics in HTLV-1 infection

  • 1. Lymphocyte kinetics in HTLV-1 infection Charles Bangham Department of Immunology Wright-Fleming Institute
  • 2. Human T-lymphotropic virus type 1 (HTLV-1) • infects 10-20 million people worldwide. • endemic (1-20% of adults) in South America, Caribbean, Central Africa, southern Japan. • 2-3% develop an aggressive T-cell leukaemia/lymphoma • 2-3% develop a chronic inflammatory disease either of CNS, eyes, muscles, joints, lungs or skin. • 95% remain healthy carriers of HTLV-1.
  • 3. HTLV-1 persistence and inflammatory disease Three main questions: 1. How does HTLV-1 persist? 2. How does it spread? 3. Why do some develop HAM/TSP, whereas most remain healthy carriers?
  • 4. The proviral load of HTLV-1 is high and correlates with the risk of HAM/TSP median proviral load (copies/100 PBMCs) HAM/TSP: 5.4 asymptomatic: 0.34 Nagai et al 1998 J. Neurovirol. 4, 586
  • 5. How is the high proviral load maintained? Retroviruses replicate by two routes: host cell - provirus latent mitotic polymerase - little sequence variation in virus reverse - provirus infectious expressed transcriptase - sequence variation
  • 6. Evidence for latency of HTLV-1 variability (Kabat-Wu) Env 1. HTLV-1 varies little in HIV-1 sequence: HTLV-1 amino acid position Daenke et al. 1990: J. Virol. 64, 1278 2. HTLV-1 mRNA and proteins are usually undetectable in PBMCs. 3. Virions are absent and plasma is non-infectious.
  • 7. ‘Standard model’ of HTLV-1 persistence HTLV-1 is maintained by passive proliferation of provirus- containing lymphocytes. A fraction of cells express HTLV-1, but too few to allow the immune response to make an impact on proviral load. Supported by observation of large clones of HTLV-1+ lymphocytes in vivo: Wattel et al. 1995: J. Virol.69, 2863
  • 8. What is wrong with the ‘standard model’? There is a strong T-cell and antibody response to HTLV-1. Anti-HTLV-1 cytotoxic T lymphocytes (CTLs) are chronically activated; virus-specific IgM is produced. Passively proliferating HTLV-1+ cells would be outgrown if any start to express HTLV-1: 1%/day 40-fold drop in load over 1 year. - does the CTL response make any impact?
  • 9. Anti-HTLV-1 CTLs are - • abundant • chronically activated • chiefly directed against the HTLV-1 Tax protein but CTL frequency, specificity and activation do not differ between HAM/TSP and asymptomatics Bangham 2000 Curr Opin Immunol 12, 397
  • 10. HTLV-1-specific CTL frequency is positively correlated with proviral load Kubota et al. 2000 Wodarz et al. 2001 - so do CTLs determine load, or passively reflect the load?
  • 11. CTLs exert selection on HTLV-1 in vivo 1. The tax gene is under positive selection in asymptomatic carriers but not in HAM/TSP patients: AC (N=4) HAM (N=4) DN / DS = 1.15 0.42 % specific lysis 2. Naturally occurring Tax variants escape CTL recognition: Niewiesk et al 1994: J. Virol. 68, 6778 Niewiesk et al 1995: J. Virol. 69, 2649
  • 12. Positive selection at individual Tax residues HLA-A2- restricted CTL epitopes Positive selection at individual residues
  • 13. 9 genes were overexpressed in CD8+ cells from individuals with a low HTLV-1 proviral load A AC1 CD8L AC2 CD8L 1 (AJ001687): NKG2D cluster: cluster: 2 (M57888): Granzyme B 3 (U20350): CX3CR1 33 genes 16 genes 4 (M30894): TCR-gamma 5 (M12824): CD8 A 20 3 2 6 (AF031824): Leukocystatin 7 (M18737): Granzyme A 8 (M85276): Granulysin (NKG5) 9 (S69115): NKG7 9 B 1 (X57352): IFITM3 (I-8U) 1 2 C 1 (U26174): Granzyme K 2 (M28393): Perforin 5 HAM CD8L D cluster: 1 (M17016): Granzyme B precursor 2 (M1121): RANTES (1) 17 genes 3 (M1121): RANTES (2) Vine, Heaps et al., 2004: J Immunol 173, 5121
  • 14. Protective role of HLA class 1 indicates that CTLs limit HTLV-1 expression in vivo 1. Possession of either HLA-A*02 or HLA-Cw*08 : • reduced proviral load by 3-fold HLA-A2 and HLA-Cw8 prevent 36% of potential HAM/TSP • halved the odds of HAM/TSP cases. 2. HLA class 1 heterozygosity was associated with a lower proviral load. Jeffery et al: PNAS (1999) 96, 3848; J Immunol (2000) 165, 7278 Vine et al: J Infect Dis (2002) 186, 932
  • 15. Alternative scheme of HTLV-1 persistence CTL Spontaneously expressed Tax protein drives proliferation of provirus+ cells. CTLs kill virus-expressing cells. A fraction of daughter cells survive by shutting down expression (how?) Proviral load is determined by an equilibrium between virus and CTLs : the chief determinant of load is the rate – the ‘efficiency’ – of CTL killing. Nowak and Bangham 1996: Science 272, 74-79; Bangham and Osame 2005: Oncogene 24, 6035–6046.
  • 16. Predictions of model 2 1. Proviral load is determined by a) CTL efficiency & b) rate of Tax expression. 2. Mean lymphocyte turnover rate a) is abnormally high in HTLV-1 infection, especially in HAM/TSP patients, and b) correlates with [Tax]. 3. Proviral load correlates with Tax protein expression. 4. The advantage to the virus conferred by Tax expression diminishes as the CTL lysis rate increases.
  • 17. Quantification of anti-viral CTL efficiency dy = c − εyz HAM dt patient y = freq. of infected cells z = freq. of CTLs ε = lysis rate constant - ‘CTL efficiency’ carrier c = constant Asquith, Mosley et al., 2005: J Gen Virol 86, 1515
  • 18. Quantification of anti-viral CTL efficiency 6 % T a x + C D 4 + c e lls repeat 1: observed data 5 repeat 1: best theoretical fit a fte r 1 8 h rs 4 3 repeat 2: observed data 2 repeat 2: best theoretical fit 1 0 0 10 20 30 40 50 60 70 % CD8+ cells ε is reduced: 80% by block of perforin 29% by partial HLA mismatch Asquith, Mosley et al., 2005 100% by full HLA mismatch J Gen Virol 86, 1515
  • 19. Prediction 1: CTL lytic efficiency determines HTLV-1 proviral load in vivo proviral load (copies/100 PBMC) Asquith, Mosley et al. 2005: J Gen Virol 86, 1515 lytic efficiency ε (%Tax+ cells killed/CD8+ cell/day) Conclusion: 30% to 50% of observed variation in HTLV-1 proviral load is accounted for by variation in ε.
  • 20. Impact of CTL activity in HTLV-1 infection 1. The rate of CD8+ cell-mediated lysis is an important determinant - perhaps the largest single determinant - of variation in HTLV-1 load between individuals. 2. In a typical infected individual, each CD8+ cell kills ~5 HTLV-1-infected cells/day. turnover rate of Tax+ cells of ~7% per day. i.e. total of ~2 x 109 infected CD4+ cells killed/day.
  • 21. Measurement of lymphocyte turnover rates in vivo • infuse 2H-labelled glucose (5% ) i.v. overnight • carbon ring is incorporated into newly synthesized nucleosides genomic DNA of newly divided cells • decay of 2H/1H in DNA direct estimate of t½ of specific (sorted) lymphocyte subsets Macallan et al (1998) PNAS 95, 708 Asquith et al (2002) Trends Immunol. 23, 596
  • 22. 2H-glucose kinetics in vivo: CD45RO+ cells turn over faster than CD45RA+ CD45RO+ 0.15 0.15 L01-HS L07-TBI AC 1 HAM 1 0.1 0.10 0.05 0.05 0 0.00 0 2 4 6 8 10 0 2 4 6 8 10 CD45RA+ 0.15 2H incorporation L10-HBO AC 2 0.10 0.05 0.00 0 2 4 6 8 10 Asquith et al. 2006: submitted time (d)
  • 23. Prediction 2a: mean proliferation rate of CD4+ T cells in HAM/TSP > asymptomatic carriers C D 4 + C D 4 5 R O + T ly m p h o cy te 5 p ro life ra tio n ra te (d a y-1 ) 4 p = 0.01 (Mann-Whitney, 3 2-tailed) 2 1 0 Asymptomatic HAM/TSP carriers patients Asquith et al. 2007 PNAS 104, 8035-8040
  • 24. In vivo turnover rate of CD4+CD45RO+ cells correlates with Tax expression ex vivo CD4 CD45RO proliferation rate in 5 4 vivo (% per day) 3 2 P = 0.016 + (Spearman rank 1 correlation) + 0 0 2 4 6 8 10 Tax expression ex vivo (Tax CD4+/CD4+ after 18h culture) + Asquith et al. 2007 PNAS 104, 8035-8040
  • 25. Prediction 2b: Tax-expressing cells turn over faster than Tax – cells in vivo 0.07 L02-HAY 0.06 Tax+ turnover rate: 0.05 0.04 0.03 7% per day 0.02 Tax – 0.01 0 0 2 4 6 8 10 0.14 L07-TBI 0.12 Tax+ 0.1 0.08 13% per day 0.06 0.04 Tax – 0.02 Asquith et al. 2007 0 0 2 4 6 8 10 PNAS 104, 8035-8040
  • 26. Prediction 3: proviral load correlates with Tax expression 25 20 (Tax+CD4+/CD4+) % Tax expression y = 0.86x + 3.08 2 R = 0.71 15 HAM/TSP AC 10 5 y = 0.61x + 0.56 2 R = 0.82 0 0 5 10 15 20 Proviral load (% of PBMC infected) Asquith et al. 2005: Retrovirology 2, 75
  • 27. Prediction 4: advantage conferred by Tax expression falls as CTL lysis rate increases Increase in proviral load caused by model prediction increase in % Tax expression experimental results Rate of CTL lysis Asquith et al. 2005: Retrovirology 2, 75 (Tax+ cells killed/day/CD8+ cell)
  • 28. Quantification of HTLV-1 infection dynamics in vivo cytokines (Il-2, IL-15) 1d (70d) antigen (30d) 0.05 – 5% per day 1d 1d X CTL resting HTLV-1+ HTLV-1- 1d cell expressing ? cell Asquith and Bangham 2008: Trends Immunol. 29, 4-11
  • 29. Tax expression in HAM/TSP > carriers at a given proviral load Asquith et al. 2005: Retrovirology 2, 75-83 - and a given FoxP3+ Toulza et al. frequency 2008: Blood 111, 5047-5053
  • 30. What determines the rate of HTLV-1 proviral expression in vivo? - strain (sequence) of virus? No. - proportion of defective proviruses? Unknown. - T cell activation (ag, cytokines)? Unlikely to explain observed between-individual variation. - HTLV-1 regulatory products (p30II, Rex, HBZ) Limit existing proviral expression, but do not control onset. - epigenetic changes? - genomic integration site?
  • 31. Is HTLV-1 integration random? Linker-mediated PCR PBMCs taken from 10 HAM patients + 10 ACs 311 genomic integration sites mapped Observed integration sites compared with random NlaIII sites in genome Kiran Meekings, 2008: PLoS Pathogens 4(3): e1000027 . Statistical analysis carried out in collaboration with Rick Bushman, Jeremy Leipzig, Chuck Berry
  • 32. HTLV-1 integration frequency in vivo correlates with gene density 10 Observed/Expected 8 6 in vitro 4 in vivo 2 0 1 2 3 4 5 6 Gene density (number genes within 25kb) Meekings et al. 2008: p = 1.8 x 10-5 (logistic regression) PLoS Pathogens 4(3): e1000027
  • 33. HTLV-1 proviral integration in vivo predominates: Observed / Expected 3 Observed / Expected 2.5 4 2 3 In Vitro 1.5 2 1 In Vivo 1 0.5 0 0 1 2 5 10 25 1 2 5 10 25 Distance from integration site (kb) Distance from Integration site (kb) - near CpG islands - near transcription start sites - and is associated with 50% 40% % in g e n e 0.4 30% Proportion of sites 0.35 0.3 20% 0.25 10% Tax Positive 0.2 0.15 Tax Negative 0% 0.1 Meekings et al. AC H A M /T S P 0.05 0 2008: PLoS 1 2 5 10 25 Integration Site Window (kb) Pathogens 4(3): e1000027 - Tax expression - and with HAM-TSP
  • 34. Rate of proviral expression & rate of CTL lysis determine HTLV-1 load and risk of HAM/TSP proviral expression HAM HAM fast moderate load high load HTLV-1 AC AC slow low load moderate load fast slow CTL lysis
  • 35. Conclusion: persistence of HTLV-1 in vivo p12I CD4+FoxP3+ cells histone deacetylation CTLs integration into proviral infectious spread transcriptionally expression (viral synapse) active units T-cell proliferation p30, Rex, HBZ