Virus dynamics. How fast does HIV reproduce in vivo? Collaborators. HIV is a retrovirus. Treatment leads to a rapid decline in virus load

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1 Vrus dyamcs Mart Nowak Isttute for Advaced Study Prceto Collaborators Robert May (Oxford) Sebasta Bohoeffer (Zurch) Domk Wodarz (Seattle) Marc Lpstch (Harvard) Alu Lloyd (Prceto) George Shaw (Brmgham, Alabama) Adrew McMchael (Oxford) Charles Bagham (Lodo) Jeff Lfso (Washgto) HIV s a retrovrus Vrus RNA How fast does HIV reproduce vvo? Reverse trascrpto mrna Provrus DNA 994: protease hbtors ad quattatve PCR Treatmet leads to a rapd decle vrus load At-vral treatmet Vrus load HIV T/-3 days Tme George Shaw

2 Vrus dyamcs Vrus dyamcs wth treatmet λ + k β λ k d u a d u a Ufected target cell Vrus Ifected target cell Ufected target cell Vrus Ifected target cell The basc model of vrus dyamcs At-vral treatmet Ufected cells λ dx β xv Ufected cells λ dx β xv Ifected cells β xv ay Ifected cells β xv ay Free vrus v& ky uv Free vrus v& ky uv Mcro-epdemology wth fected host Vrus decles as Latetly fected cells At-vral treatmet Vrus load Free vrus half-lfe v( t) v * Ifected cell half-lfe: -3 days at ue ae u a ut Vrus load At-vral treatmet T/-3 days T/0 days Tme Tme

3 A exteded model of vrus dyamcs HIV- half-lves Ufected cells Productvely fected cells Latetly fected cell Cells wth defectve provrus Free vrus v& λ dx β xv 3 q q q ky β xv 3 a β xv a β xv a uv 3 y y y 3 + α y α y Productvely fected cells : -3 days Latetly fected cells : 0 days Defectve provrus : 00 days Free vrus : hours HIV- half-lves Productvely fected cells : -3 days Latetly fected cells : 0 days Defectve provrus : 00 days Free vrus : hours HIV- half-lves Productvely fected cells : -3 days Latetly fected cells : 0-00 days Defectve provrus : 00 days Free vrus : hours HIV eradcato requres -3 years of effectve therapy. HIV eradcato requres >0 years of effectve therapy ad s most lkely mpossble. What klls productvely fected cells? vral cytopathcty CTL resposes Comparg HIV ad HBV dyamcs: Half-lfe of productvely fected cells: HIV: -3 days HBV: 0-00 days Note that all patets have very smlar decay slopes correspodg to half-lfes of -3 days. 3

4 Vral cytopathcty leads to a costat half-lfe despte dfferet CTL actvty Ifecto Cell becomes a target for CTL Cell produces ew vros ad des What s the mechasm of HIV dsease progresso? The expermet s based toward those cells that produce plasma vrus. CTL ca greatly reduce vrus producto wthout affectg the half-lfe. Evoluto of vrulece HIV-: clcal profle The closest relatves of HIV- ad HIV- are SIVs. All SIVs appear to be apathogec ther atural hosts. SIV ca be trasferred to other speces, where t duces AIDS. CD4 000 Vrus < to >5 years 0 Prmary phase Asymptomatc phase AIDS Tme HIV-: clcal profle CD4 000 Vrus < to >5 years Why s there such a log ad varable asymptomatc phase? Prmary phase Asymptomatc phase AIDS 0 A mechasm of dsease progresso.. has to expla why the steady state of vrus dyamcs (wth a tmescale of days) shfts over may years. possbltes: the mmue system chages the vrus chages Tme 4

5 HIV s a quasspeces Vral replcato s error proe. HIV reverse trascrptase ad RNA polymerase have error rates of about 0 4 The vrus populato ay oe patet s extremely heterogeeous. HIV ca escape from mmue resposes. Evoluto toward dsease Escape from mmue resposes Faster replcatg, more aggressve stras Broader cell tropsm Vrus load Dversty threshold Tme Atgec varato vrus mutat mmue respose agast mutat v& Each mutat goes to equlbrum: rv px v cv bx,..., br v x cp r p Atgec varato Total vrus load s proportoal to atgec dversty. v : v br cp Add ew mutats over tme. Atgec varato Atgec varato of HIV vrus mutat specfc mmue respose cross reactve mmue respose v& v ( r px qz) cv bx z& kv bz,..., vrus mutat specfc mmue respose cross reactve mmue respose v& v ( r px qz) cv bx uvx z& kv bz uvz,..., Vrus load: v br cp + kq Vrus load: v br cp ( ru kq) 5

6 Atgec varato of HIV The dversty threshold model has 3 possble outcomes Vrus load: v br cp ( ru kq). Dsease after log asymptomatc perod. kq < ru < kq + cp Dversty threshold: c cp ru kq. Idefte vrus cotrol. ru < kq 3. Immedate dsease. kq + cp < ru Immue resposes to multple eptopes Immue resposes to multple eptopes Immuodomace Multple eptope theory Atgec varato presece of multple eptopes v& v η η ( r c v k * v p x + x ( c v * q * y + y ( k v ) b) * b) 6

7 Atgec varato presece of multple eptopes Atgec varato presece of multple eptopes a ew mutat arses Dversfcato the mmuodomat eptope Atgec varato presece of multple eptopes Atgec varato presece of multple eptopes Partal shft mmuodomace, o respose to ew varat Partal shft mmuodomace, respose to ew varat loss of respose to old varat Atgec varato presece of multple eptopes Atgec varato presece of multple eptopes Complete shft mmuodomace loss of old varat Immue respose agast varable eptope selects for vral dversty. 7

8 Atgec varato presece of multple eptopes Immue resposes to multple eptopes Immue respose agast coserved eptope selects agast vral dversty. Immuodomace breadth of the respose s related to mmue memory Domk Wodarz HIV dsease progresso accordg to ths model The vrus wll retur f therapy s wthdraw There s a hghly dyamc balace betwee the vrus ad the mmue system wth rapd vrus turover. The evolutoary adaptato of the vrus dvdual patets s the mechasm of dsease progresso. Vrus load Detecto lmt At-vral treatmet Tme A ew theory of CTL memory Is t possble to treat ad help the patet s mmue system to ga cotrol of the vrus? Log lved CTL resposes ca elmate vrus fectos or reduce vrus load to low levels. 8

9 Cytotoxc T lymphocytes CTL CTL memory s characterzed by hghly resposve, log-lved cells CD4 help Helper cells CD8 kll Kller cells CTL HIV HIV klls CD4 cells whch are eeded for CTL memory. Falure to establsh a CTL memory respose leads to persstet fecto, hgh vrus load ad rapd dsease progresso A good CTL memory respose leads to vrus elmato (rare?) or low vrus load ad slow dsease progresso Ifected cell HIV: rate of dsease progresso HIV replcato ad establshmet of memory Fast progressors: hgh vrus load No CTL Memory CTL memory makes the dfferece. CTL Memory CTL Memory No CTL Memory Slow progressors: low vrus load Ital rate of vral spread HIV replcato ad establshmet of memory Treatmet durg prmary fecto No CTL Memory No treatmet Treatmet CTL Memory CTL Memory No CTL Memory Vaccato or early treatmet Ital rate of vral spread CTLp SIV: Jeff Lfso Vrus HIV: Bruce Walker 9

10 SIV fecto, o treatmet 4 weeks of treatmet ; re-challege Vrus CD4 respose CD4 respose Vrus Tme (weeks) Tme (weeks) SIV prmary fecto wthout treatmet Treatmet durg chroc HIV fecto Vrus set-pot Vrus load the frst week of fecto s correlated wth set-pot s correlated wth survval. Treatmet Treatmet wth drug holday(s) Tme Jeff Lfso: mokeys, authors CTLp Vrus At-vral treatmet ad mmuotherapy HIV therapy CTLp Immuotherapy Vrus For prmary fecto: Use vaccato ad early treatmet to reduce the tal vral growth rate ad brg patets to a state of log term o-progresso. For chroc fecto: Use treatmet ad mmuotherapy to swtch patets to a state of log term o-progresso. 0

11 Summary HIV dyamcs Dsease progresso CTL memory / vrus cotrol Collaborators Robert May (Oxford) Sebasta Bohoeffer (Zurch) Domk Wodarz (Seattle) Marc Lpstch (Harvard) Alu Lloyd (Prceto) George Shaw (Brmgham, Alabama) Adrew McMchael (Oxford) Charles Bagham (Lodo) Jeff Lfso (Washgto) Three possble mechasms of HIV dsease progresso Evoluto of the vrus Slow break-dow of the mmue system Accumulato of opportustc fectos