HIV AID

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Acquired Immunodeficiency Syndrome(AIDS)

History 1950s: Blood samples from Africa have HIV

antibodies.

1976: irst knownAI!" patient died.

19#0: irst h$man retrovir$s isolated%H&'V(1).

19#1: irst reports of *Ac+$ired Imm$no(de,cienc- "-ndrome in 'os An/eles.

19#: Vir$s ,rst isolated in rance %'AV).

19#: Vir$s isolated in the 2.". %calledH&'V(III and AI!"(3elated Vir$s4 A3V).

19#5: !evelopment and implementation ofantibod- test to screen blood donors.

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Acquired Immunodeficiency Syndrome(AIDS)

History (Continued) 19#6: onsens$s name H$man

Imm$node,cienc- Vir$s %HIV(1).

3elated vir$s %HIV() identi,ed.

199: AI!" becomes the leadin/ ca$se ofdeath amon/ ad$lts a/es 5( in the2.".

1997: ortalit- rates of AI!" starts to

decline d$e to the introd$ction of ne8dr$/ coctails.

001: orld Health ;r/ani

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AI!": A 'eadin/ a$se of !eathAmon/ =eople A/ed 5( -ears in

2.".

Deaths per 100,000 people aged !"## years

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$%er%ie& of HI'

-Infect and ills CD# lymphocytes

-oss cell mediated immunity opportunistic infect*

-$ther (macrofag , monosit) that ha%e protein CD#

on their surface can +e infected also

" HI'"1 and HI'" cause AID

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5

Viral-host Dynamics

About 1010 (10 billion) virions are produceddaily

Average life-span of an HIV virion in plasmais ! hours

Average life-span of an HIV-infected "D#lymphocytes is 1$! days

HIV can lie dormant %ithin a cell for manyyears& especially in resting (memory) "D#cells& unli'e other retroviruses

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"lassification of HIV

HIV class entivirus *etrovirus single stranded *+A transcribed to double

stranded D+A by reverse transcriptase Integrates into host genome High potential for genetic diversity "an lie dormant %ithin a cell for many years&

especially in resting (memory) "D#, # lymphocytes

HIV type (distinguished genetically)

HIV-1 -. %orld%ide pandemic (current #0 /people) HIV- -. isolated in est Africa2 causes AID3 much

more slo%ly than HIV-1 but other%ise clinicallysimilar

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7

HIV at Surfaceof CD4Lymphocyte

Courtesy of CDC

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'irulogy of HI'

-Is of one the t%o HV-%o identical ss (,)*+A surrounded by envelop (lipid

bilayer) containing viirus-specifict glycoprotein

(gp 10 and gp #1)-4enom comple5

1$ encode structural protein gag , pol, env

2. tat , rev (replication) 2 nef , vif , vpr and vpu

(as accessory gene)

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5 3* *

gag pol env

P24, PR! PL HI"!

gp#2$ gp4#

VI% !&! VP' R(V "(%

gag internal core protein as group-specifict antigen

pol polymerase protein ( riverse transriptase)env envelope glycoprotein

VI6 viral infectivity factor

A transactivating protein

V78 viral protein 8*9V regulator of e5pression of virion protein

+96 negtive regulatory factor

* long terminal repeat

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gene protein encode by gene 6ungtion of protein

gag p# & p: nucleocapsid p1: matri5 protein

pol riverse trancriptase transcribec *+AD+A

protease (7*;) cleaves precursor polipeptide

integrase (I+) integrates viral D+A host D+A

env gp 10 attachment to "D# protein

gp #1 fussion %ith host cell

tat A activation of transcription v$ gene

rev *9V transport m*+A from nucleus

to cytplamanef +ef decrease "D# < /H" I protein

on surface infected cellls& induce

death of uninfected "& I impor-

tand for pathogenesis 3IV

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gene protein encode +y gene ungtion of protein

vif Vif 9nhance infectivity by inhibit

A7;=9">4 &en?yme that

cause hypermutation of

retroviral D+A

vpr Vpr transport viral core from cytplasma in nondividing cells

Vpu Vpu enhance virion release from

cells

+otes - Apolipoprotein = *+A editing en?ymes

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"tr$ct$re of the H$manImm$node,cienc- Vir$s HIV is a

3etrovir$s

gp#2$gp #1

gp#

ipid bilayer

71: /atri5

protein

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Se%eral important antigen of HI'

1* gp 10 and gp #1 (type specific glycoprotein) gp10 interact %ith "D# protein second protein

chemo'ine reseptors$ gp #1 mediates fussion of

viral envelope and cell membrane$

Ab against gp10 neutrali?e innfectivity of HIV

* -roup specific antigen gp#

located in the core is not 'no%$ Ab against this

antigent not neutrali?e of HIV infectivity

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ife Cycle of HI'

1* Attachment. 'irus +inds to surface

molecule (CD#) of / helper cells and

macrophages*

Coreceptors. equired for HI' infection*

CC# and CC! mutants are resistant to

infection*

* usion. 'iral en%elope fuses &ith cell

mem+rane, releasing contents into the

cell*

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HIV 'ife -cle: Attachment3e+$ires ! 3eceptor pl$s a

oreceptor

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ife Cycle of HI'2* e%erse /ranscription. 'iral 3A is

con%erted into D3A +y unique en4yme reversetranscriptase*

e%erse transcriptase

3A """""""""""""""""""""5 D3Ae%erse transcriptase is the target of se%eral

HI' drugs. A6/, ddI, and ddC*

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HIV 'ife -cle: 3everse&ranscriptase onverts 3>A into

!>A

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ife Cycle of HI'

#* Integration. 'iral D3A is inserted into host cell

chromosome +y unique en4yme integrase*Integrated %iral D3A may remain latent for years

and is called aprovirus*

!* eplication. 'iral D3A is transcri+ed and 3Ais translated, maing %iral proteins*

'iral genome is replicated*

7* Assem+ly.3e& %iruses are made*8* elease.3e& %iruses +ud through the cell

mem+rane*

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HIV 'ife -cle: 'atent vers$sActive Infection

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HIV 'ife -cle: 'atent vers$sActive Infection in acropha/es

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HIV Immu)o*ogy

; i f Ad ti

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I)trace**u*ar

+)fect+o)

>a?ve B(ell

>a?ve cell

>a?ve &helpercell

HC Ipre-e)tat+o) ofe).oge)ou-a)t+ge)

HC IIpre-e)tat+o) ofe/oge)ou-

a)t+ge)

ell(mediated%&'s)

H$moral%plasma cells @antibodies)

%ree a)t+ge)

&h1 &h

;vervie8 of AdaptiveImm$ne 3esponse (/trace**u*ar

+)fect+o)A=

Diagram courtesy of Dr. Samuel Anderson

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Ce**u*ar Immu)e Re-po)-e-to HIV

CD0 Cytoto/+c ! *ymphocyte 1C!L

Cr+t+ca* for co)ta+)me)t of HIV

Der+e. from )ae !0 ce**-, h+chrecog)+e +ra* a)t+ge)- +) co)te/t ofHC c*a-- I pre-e)tat+o)

D+rect*y .e-troy +)fecte. ce**

&ct++ty augme)te. y !h# re-po)-e

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Ce**u*ar Immu)e Re-po)-e-to HIV

CD4 He*per ! Lymphocyte 1!h P*ay- a) +mporta)t ro*e +) ce**8me.+ate.

re-po)-e

Recog)+e- +ra* a)t+ge)- y a) a)t+ge)pre-e)t+)g ce** 1&PC 't+*+e- ma9or h+-tocompat++*+ty comp*e/ 1HC

c*a-- II

D+:ere)t+ate. accor.+)g to the type of ;he*p

ce**8me.+ate. +mmu)+ty

!h2 8 act+ate = *ymphocyte-, promot+)g a)t+o.yme.+ate. +mmu)+ty

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Humora* Immu)e Re-po)-eto HIV

"eutra*+at+o)

&)t+o.+e- +). to -urface of +ru- topree)t attachme)t to target ce**

&)t+o.y8.epe).e)t ce**8me.+ate.cytoto/+c+ty 1&DCC

%c port+o) of a)t+o.y +).- to "> ce**

St+mu*ate- "> ce** to .e-troy +)fecte.ce**

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HIV (a-+o) etho.-

a?e- #$ +**+o) [email protected] 8A rap+.mutat+o) of HIV a)t+ge)-

I)tegrate- +)to ho-t D"&

Dep*ete- CD4 *ymphocyte- Do)8regu*at+o) of HC8I proce-- Impa+r- !h# re-po)-e of CD4 he*per !

*ymphocyte I)fect- ce**- +) reg+o)- of the o.y

here a)t+o.+e- pe)etrate poor*y,eBgB, the ce)tra* )erou- -y-tem

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Pathoge)e-+- of HIV

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2F

Ge)era* echa)+-m- of HIVPathoge)e-+-

D+rect +)9ury

"erou- 1e)cepha*opathy a). per+phera*)europathy

>+.)ey 1HIV&" HIV8a--oc+ate. )ephropathy Car.+ac 1HIV car.+omyopathy

().ocr+)e 1hypogo)a.+-m +) oth -e/e-

GI tract 1.y-mot+*+ty a). ma*a-orpt+o)

I).+rect +)9ury pportu)+-t+c +)fect+o)- a). tumor- a- a

co)-eue)ce of +mmu)o-uppre--+o)

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3$

Ge)era* Pr+)c+p*e- ofImmu)e Dy-fu)ct+o) +) HIV

&** e*eme)t- of +mmu)e -y-tem area:ecte.

&.a)ce. -tage- of HIV are a--oc+ate.

+th -u-ta)t+a* .+-rupt+o) of *ympho+.t+--ue

Impa+re. a+*+ty to mou)t +mmu)e re-po)-e to)e a)t+ge)

Impa+re. a+*+ty to ma+)ta+) memory re-po)-e-

Lo-- of co)ta+)me)t of HIV rep*+cat+o)

Su-cept++*+ty to opportu)+-t+c +)fect+o)-

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3#

Ro*e of Cyto?+)e Dy-regu*at+o)+) Pathoge)e-+- of HIV

HIV +- a--oc+ate. +th +)crea-e.e/pre--+o) of pro8+)ammatory cyto?+)e-!"%8a*pha, IL8#,IL86, IL8#$, I%"8gamma

&--oc+ate. +th up8regu*at+o) of HIVrep*+cat+o)

HIV re-u*t- +) .+-rupt+o) a). *o-- of+mmu)oregu*atory cyto?+)e-

IL82, IL8#2 "ece--ary for mo.u*at+)g e:ect+e ce**8

me.+ate. +mmu)e re-po)-e- 1C!L- a). ">ce**-

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Ro*e of Cyto?+)e Dy-regu*at+o)+) Pathoge)e-+- of HIV

HIV +- a--oc+ate. +th +)crea-e.e/pre--+o) of pro8+)ammatory cyto?+)e-!"%8a*pha, IL8#,IL86, IL8#$, I%"8gamma

&--oc+ate. +th up8regu*at+o) of HIVrep*+cat+o)

HIV re-u*t- +) .+-rupt+o) a). *o-- of+mmu)oregu*atory cyto?+)e-

IL82, IL8#2 "ece--ary for mo.u*at+)g e:ect+e ce**8

me.+ate. +mmu)e re-po)-e- 1C!L- a). ">ce**-

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Co)-eue)ce of Ce**8me.+ate.Immu)e Dy-fu)ct+o)

I)a+*+ty to re-po). to +)trace**u*ar+)fect+o)- a). ma*+g)a)cy

ycoacter+a, Sa*mo)e**a, Leg+o)e**a Le+-hma)+a, !o/op*ama,

Crypto-por+.+um, +cro-por+.+um

PCP, H+-top*amo-+-

HSV, VJV, KC +ru-, po/ +ru-e-

(=V8re*ate. *ymphoma-

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PCP, H+-top*amo-+-



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PCP, H+-top*amo-+-



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!ra)-m+--+o)

o.e- of +)fect+o) Se/ua* tra)-m+--+o) at ge)+ta* or co*o)+c muco-a =*oo. tra)-fu-+o) other to +)fa)t &cc+.e)ta* occupat+o)a* e/po-ure

V+ra* trop+-m!ra)-m+tte. +ru-e- +- u-ua**y macrophage8trop+c!yp+ca**y ut+*+e- the chemo?+)e receptor CCR5 to

ga+) ce** e)try Pat+e)t- homoygou- for the CCR5 mutat+o) arere*at+e*y re-+-ta)t to tra)-m+--+o)

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ell free

HIV

"in orm$cosa

ho$rs

# ho$rs

#B HIV co8receptor-,CD4 chemo?+)ereceptor CC5

Immat$re!endritic cell

3B ature De).r+t+cce** +) reg+o)a* L"u).ergoe- a -+)g*erep*+cat+o), h+ch

tra)-fer- HIV to !8ce**

Via l-mphatics orcirc$lation

&(cell

==

B$rst of HIVreplication

2B Se*ect+e ofmacrophage8trop+c HIV

(ar*y Pha-e- of HIV I)fect+o) ofuco-a* Surface-

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Laoratory ar?er- of HIVI)fect+o)

V+ra* *oa.

ar?er of HIV rep*+cat+o) rate

"umer of HIV R"& cop+e-@mm3 p*a-ma

CD4 cou)t

ar?er of +mmu)o*og+c .amage

"umer of CD4 !8*ymphocyte-

ce**-@mm3 p*a-ma

AI!" Associated !isease

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AI!" Associated !iseaseate/ories

1* -astrointestinal. Cause most of illness and deathof late AIDS*

Symptoms.

Diarrhea

9asting (e:treme &eight loss)

A+dominal pain

Infections of the mouth and esophagus*

;athogens. Candidaalbicans, cytomegalo%irus,

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AIDS Associated Disease Categories

* espiratory. 80= of AIDS patients de%elop

serious respiratory pro+lems*

;artial list of respiratory pro+lems associated &ith AIDS.

>ronchitis

;neumonia

/u+erculosis

ung cancer

Sinusitis

;neumonitis

AIDS A i t d Di C t i

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AIDS Associated Disease Categories

2* 3eurological. $pportunistic diseases andtumors of central ner%ous system*

Symptoms many include. Headaches, peripheral

ner%e pro+lems, andAIDS dementia complex

(

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AIDS Associated Disease Categories#* Sin Disorders. ?0= of AIDS patients de%elop

sin or mucous mem+rane disorders*

@aposis sarcoma 1B2 male AIDS patients de%elop @S

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Drugs Against HI' e%erse /ranscriptase Inhi+itors. Competiti%e

en4yme inhi+itors* :ample. A6/, ddI, ddC*

;rotease Inhi+itors. Inhi+it the %iral proteases*;re%ent %iral maturation*

;ro+lem &ith indi%idual drug treatments.

esistance* Drug Coctails. A com+ination of.

$ne or t&o re%erse transcriptase inhi+itors

$ne or t&o protease inhi+itors*

Drug coctails ha%e +een %ery effecti%e insuppressing HI' replication and prolonging thelife of HI' infected indi%iduals, +ut long termeffecti%eness is not clear*

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/ransmission of AIDS (9orld&ide)

1*Se:ual contact &ith infected indi%idual. All

forms of se:ual intercourse (homose:ual andheterose:ual)* 8!= of transmission*

* Sharing of unsterili4ed needles +yintra%enous drug users and unsafe medical

practices. !"10= of transmission*2* /ransfusions and >lood ;roducts.

Hemophiliac population &as decimated in1?E0s* is is lo& today* 2"!= of

transmission*#*

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>ey Po+)t-

HIV +- a retro+ru-, capa*e of +)tegrat+)g +)toho-t ge)ome a). e-ta*+-h+)g chro)+c +)fect+o)

HIV ca) e c*a--+Me. +)to -ugroup- 1c*a.e-h+ch hae character+-t+c geograph+c .+-tr+ut+o)

!he +mporta)t -tep- +) the *+fecyc*e of HIV +)c*u.ece** e)try, reer-e tra)-cr+pt+o), +)tegrat+o), a).maturat+o)@a--em*y

Ce**8me.+ate. +mmu)+ty +- cr+t+ca* for co)ta+)me)t

of HIV +)fect+o) a). other +)trace**u*ar +)fect+o)-

HIV ea.e- ho-t +mmu)+ty y a ar+ety ofmecha)+-m-

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>ey Po+)t- 12

HIV act+ate- the +mmu)e -y-tem to+)crea-e +t- o) rep*+cat+o)

CD4 cou)t .ec*+)e- y oth .+rect

a). +).+rect mecha)+-m- HIV R"& -et po+)t pre.+ct- rate of

progre--+o) to &IDS

CD4 cou)t .ec*+)e +- a--oc+ate. +tha pre.+cta*e -eue)ce ofopportu)+-t+c +)fect+o)-

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>ey Po+)t- 12




progre--+o) to &IDS


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>ey Po+)t- 12




progre--+o) to &IDS


HIV AID

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