is t-cell immune system able to protect itself? a query by hiv

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A"Query"by"HIV�

Tetsuo'Tsukamoto'CEA/Fontenay2aux2Roses'

'(Presented'on'2012203224'at'Maison'du'Japon'in'Paris)'

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HIV"asks:"Is"the"immune"system"able"to"protect"itself?�

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To"immunologists…"

I'would'like'to'beg'your'understanding'on'inaccuracy'and'oversimplificaKon'in'the'following'stories.'

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Concepts"

• 'recursive'process'

• 'the'immune'system'

• 'HIV'infecKon'

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What"is"recursion?�

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Recursive"ini@alism"

TTP'='The'TTP'Project'

'

…'It'never'ends!'

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Recursive"func@on"

f ≡ g( f )

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An"integer"sequence"

an = an−1 + 1, a0 = 1 (recurrence'relaKon)

an = n + 1

↓ solve'

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Why"do"we"solve"recurrence"rela@ons?"

In'a'recurrence'relaKon,'recursive'call'starts'before'the'end'of'the'previous'

call'(i.e.'within'the'previous'call).'

So'it'consumes'a'lot'of'memory.'

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an = an−1 + 1, a0 = 1 (recurrence'relaKon)

a1 = 1+1"

a2 = (1+1)+1

….

a1,000,000,000 = ((((……………+1)+1)+1)+1)+1

↓ calculate'without'solving'

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Solve'a'recurrence'relaKon'

='

'Convert'it'into'a'more'efficient'form'

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If'we'have'a'fast'computer'equipped'

with'a'lot'of'memory'(RAM),'then'we'

may'not'need'to'solve'recurrence'relaKons.'

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Recurrence'relaKons'will'be'endless'without'an'end"condi@on.'

(e.g.'''a0 = 1 for an = an−1 + 1)'

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Recursion"in"our"life?"

…..'

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Summary"

• 'To'understand'recursion,'we'must'first'

understand'recursion.'

• 'A'recursive'process'requires'an'end'condiKon.'

• A'recursive'process'can'be'memory2

consuming'dependent'on'its'depth.'

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What"is""the"immune"system?�

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Immunology:"a"brief"look"

Our'bodies'are'used'for'decades.'

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Our'bodies'must'be'maintained'in'

steady'states'for'decades.'

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Virus2infected'cells'and'cancer'cells'have'different'genes'(DNA/RNAs)'from'other'cells.'

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Virus2infected'cells'and'cancer'cells'produce'unexpected'proteins.'

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Virus2infected'cells'and'cancer'cells'have'unexpected'func@ons,'which'can'threat'integrity'of'our'bodies.''

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Cellular"immunity"(T"lymphocytes)"is'designed'to'detect'abnormal'cells'with'

unexpected'(and'potenKally'risky)'proteins'(funcKons)'in'order'to'maintain'

integrity'of'our'bodies.''

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How"to"do"it?"

1. Cells'produce'proteins'and'put'them'on'

the'cell'surfaces'so'that'T'lymphocytes'

can'detect'unexpected'proteins.'

2. T'lymphocytes'circulate'in'our'bodies'

to'test'proteins'on'the'cells'referring'to'

their'“unexpected"protein"database”.'

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1."Major"histocompa@bility"complex"(MHC)"

http://upload.wikimedia.org/wikipedia/commons/thumb/d/d4/MHC_expression.svg/729px-MHC_expression.svg.png

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MHC'molecules'present'processed'

proteins'(about'10'amino'acids'in'length;'

called'pep@des)'to'T'lymphocytes.'


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http://upload.wikimedia.org/wikipedia/commons/thumb/d/d7/MHC_Class_I_processing.svg/493px-MHC_Class_I_processing.svg.png

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2:"T"lymphocytes"

There'are'about'1011'T'lymphocytes'

in'a'human'body.'

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Lymphocytes"

http://upload.wikimedia.org/wikipedia/commons/8/82/SEM_blood_cells.jpg

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2:"T"lymphocytes"

Every'single"T"lymphocyte'is'designed'to'recognize'only'a'single'unexpected'pep@de'(amino'acid'sequence).'

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2:"T"lymphocytes"

If'we'assume'that'104'T'lymphocytes'

recognize'the'same'unexpected'

pepKde,''this'means'that'the'whole'T'

lymphocyte'database'contains'data'for"107"different"pep@des.'

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2:"T"lymphocytes"

T'lymphocytes'surveys'all'body'cells'

using'molecules'called'T"cell"recepters'(TCR).'

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T"cell"recepter"(TCR)"

http://http://upload.wikimedia.org/wikipedia/commons/c/c3/TCRComplex.png

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2:"T"lymphocytes"

Every"T"lymphocyte'expresses'only'a'single"TCR"clone'and'thus'recognizes'only'a'single'unexpected'pepKde.'

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TCRWMHC"interac@on"

Janeway et al. Immunobiology, 5th edition, 2001 (Garland Science).

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Summary"

• 'Every'single'cell'present'millions'of'

different'passphrases'to'T'lymphocytes.'

• 'If'one'or'more'passphrases'match'

their'“unexpected"pep@de"database”,'this'cell'could'be'marked'as'risky'and'be'purged.'

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HIV"infec@on�

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HIV"infec@on"

• 'HIV'infects'T'cells'(lymphocytes).'

• 'HIV'infecKon'results'in'AIDS.'

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http://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/Symptoms_of_AIDS.svg/496px-Symptoms_of_AIDS.svg.png

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HIV"infec@on"

However,'AIDS'progression'takes'5210'

years'acer'infecKon.'

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The"immune"system"fails"in"the"early"phase"

http://upload.wikimedia.org/wikipedia/commons/a/a4/Hiv-timecourse.png

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What"is"the"problem?"

Persistent'HIV'infecKon'

='

The'immune'system'fails'to'control'

HIV'replicaKon'in"the"early"phase"

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What"causes"the"failure"in"the"early"phase?"

HIV'does'not'evenly'adack'all'T'cells.'

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HIV'has'a'genome'(in'the'form'of'an'RNA).'

Thus,'HIV2infected'cells'synthesize'HIV'

proteins'and'produce'HIV'parKcles.'

What"happens"aXer"HIV"infec@on?"

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An"HIV"par@cle"contains"a"gene"(RNA)"

http://upload.wikimedia.org/wikipedia/commons/6/63/HIV_Virion-en.png

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HIV"infects"T"lymphocytes"expressing"proteins"called"CD4"and"CCR5"

http://upload.wikimedia.org/wikipedia/commons/c/c7/HIV_attachment.gif

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HIV"genome"is"integrated"into"the"genome"of"an"

infected"cell"

http://upload.wikimedia.org/wikipedia/commons/3/35/HIV_gross_cycle_only.png

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HIV"pep@des"are"also"placed"on"MHC"molecules"

http://upload.wikimedia.org/wikipedia/commons/thumb/d/d7/MHC_Class_I_processing.svg/493px-MHC_Class_I_processing.svg.png

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HIV'prefers'those'T'cells'which'have'

been'ac@vated'by'pep@de"s@mula@on"and'express"CCR5.'

HIV"preference"(1)"

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HIV'prefers'T'cells'which'recognize'

HIV'pepKdes.''These'are'called'

HIVWspecific"T"cells.'

HIV"preference"(2)"

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HIV'best'prefers'ac@vated"HIVWspecific"T"cells,'and'destroys'a'fracKon'of'these'T'cells'in'the'early'phase.'

Taken"together,"

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HIVWs@mulated"T"cells"begin"to"express"CCR5"and"are"targeted"by"HIV"

http://upload.wikimedia.org/wikipedia/commons/c/c7/HIV_attachment.gif

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HIV2specific'T'cells'try'to'protect""T"cells.'

What"do"HIVWspecific"T"cells"do?"

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HIV'selecKvely'a_acks'those'T"cells'which'are'protec@ng"T"cells.'

What"does"HIV"do?"

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HIV"targets"T"cells"protec@ng"T"cells"

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Immune"surveyrance"could"be"regarded""as"a"recursive"process"

(defun T.detect? (organ)...) (defun T.proliferate (organ)...) (defun T.kill (organ)...) (defun T.survey (organ) (when (T.detect? organ) ;; yes (T.proliferate organ) (T.kill organ) (T.survey organ)))

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A"recursive"process"requires""an"end"condi@on"

(T.survey "lung") -> (T.survey "lung") -> O.K. (T.survey "T") -> (T.survey "T") ->> (T.survey "T") ->>> (T.survey "T") ....

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Summary"

The"immune"system"must"protect"itself,'while'other'organs'are'protected'by'the'

immune'system.'

This'could'be'regarded'as'a'vulnerability'

(security"hole)'hard2coded'in'our'body.'

Indeed,'HIV'seems'to'adack'the'

vulnerability.'

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HIVWspecific"T"cells"could"be"lost""aXer"recursive"a_acks"by"HIV"

Mean'count'of'single'pep@deWspecific"T"cells'in'a'human'body'is'esKmated'

to'be'around'104"～"105"(0.00001%'of"

total'T'cell'count).'

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Lung"epithelium"can"be"repaired"aXer"injury"

Crosby LM and Waters CM. Am J Physiol Lung Cell Mol Physiol. 2010;298:L715-31.

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Selec@vely"a_acked"TWcell"popula@ons"cannot"be"easily"recovered"

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The"immune"system"is"already"broken"in"the"early"phase"


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Summary"

Once'destroyed,'pepKde2specific'T2cell'

populaKons'cannot'be'recovered.'

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Conclusion"

HIV'infecKon'is'extremely'difficult'to'be'

controlled'because'of'its'mechanism'as'

well'as'limitaKons'with'the'design'of'the'

immune'system.'

We'are'searching'for'methods'to'protect'

HIV2specific'T'cells.'

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Acknowledgements"

Wikimedia'contributors'

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Thank"you""for"your"a_en@on"

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Appendix:"es@mated"number"of"uns@mulated"(naïve)"T"cells"per"epitope"per"capita"

weight' no'T'cells/epitope' latency'before'AIDS'

Human' 50,000'g' 10,000'~'100,000' 5'~'10'years'

Monkey' 5,000'g' 1,000'~'10,000' 1'~'5'years'

Mouse' 25'g' 10'~'100' ???'

Q.'What'happens'if'HIV2like'immunodeficiency'virus'infects'mice?'

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Appendix:"CD4+"and"CD8+"T"cells"

nickname' evoluKonarily' interact'with' HIV'infecKvity'

CD4+'T'cells' helper' advanced' MHC'class'II'

(expressed'in'immune'

cells)'

yes'

CD8+'T'cells' cytotoxic'

(killer)'

primiKve' MHC'class'I'

(expressed'in'all'cells)'

no'

HIV'adacks'HIV2specific'CD4+'T'cells'which'will'

otherwise'help'HIV2specific'CD8+'T2cell'funcKon.'

is t-cell immune system able to protect itself? a query by hiv

Health & Medicine

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