HIV and AIDS HIV and AIDS

Acquired Immunodeficiency
Syndrome
Disease caused by an infectious
agent:
a retrovirus
HIV and AIDS HIV and AIDS
History of an infectious agent History of an infectious agent
1979 - 5 cases of !30:24.898.,73
pneumon|a
0ot-||ke |ntracyst|c
bod|es of !30:24.898
.,73 |n |ung
6yto|og|c preparat|on from a
bronchoa|veo|ar |avage -
C|emsa sta|n
|n Los Ange|es 197-1978: on|y two cases of
!30:24.898.,73 pneumon|a
A|| homosexua|
HIV and AIDS HIV and AIDS
|th d|ssem|nat|on to extrapu|monary s|tes, !30:24.898.,73
tends to produce foc| w|th prom|nent ca|c|f|cat|on, as seen |n the
k|dney
HIV and AIDS HIV and AIDS
an infectious agent an infectious agent - - Kaposi's Sarcoma Kaposi's Sarcoma
EarIy 1981: 5 cases of
Kaposi's sarcoma
Hitherto: rare
(immunocompromization)
EIderIy - Non-aggressive
1981 - 2 cases of Kapos|'s sarcoma
Young
Ha|e
8an Franc|sco and New
York
AIDS Definition AIDS Definition
A|08 |s current|y def|ned as the presence of one of 25
cond|t|ons |nd|cat|ve of severe |mmunosuppress|on
0R
h|V |nfect|on |n an |nd|v|dua| w|th a 604+ ce|| count of <200
ce||s per cub|c mm of b|ood
A|08 |s therefore the end po|nt of an |nfect|on that |s
cont|nuous, progress|ve and pathogen|c
|th the preva|ence of h|V |n the deve|op|ng wor|d, h|V and
|ts comp||cat|ons w||| be w|th us for generat|ons
AIDS Statistics AIDS Statistics
Approx|mate|y 44,000,000 peop|e |n the wor|d are h|V-|nfected
Approx|mate|y 14,000 new h|V |nfect|ons occur da||y around
the wor|d
0ver 907 of these are |n deve|op|ng countr|es
1000 are |n ch||dren |ess than 15 years of age.
0f adu|t |nfect|ons, 487 are |n women and 157 |n |nd|v|dua|s
15-25 years
As of 0ecember 2003, 929,985 Amer|cans reported w|th A|08.
At |east 501,9 of them have d|ed (2002 f|gures}
5,315 ch||dren under 15
HIV and AIDS HIV and AIDS
AIDS Statistics AIDS Statistics
8ub-8aharan Afr|ca
About 1 m||||on new cases of A|08 per year
30 m||||on peop|e w|th h|V |nfect|on
A|08 |s respons|b|e for a decrease |n ||fe expectancy and |ncrease |n
ch||d morta||ty. 6h||d morta||ty rates |n East Afr|ca w||| doub|e by 2010 and
adu|t ||fe expectancy has dec||ned |n that reg|on
8evera| countr|es |n sub-8aharan Afr|ca report |nfect|on rates of 20-257,
espec|a||y urban areas
Z|mbabwe: 33.77 of adu|t popu|at|on |nfected
|n Zamb|a, 1 |n 5 urban g|r|s |s h|V-pos|t|ve by the age of 20
Important Properties Important Properties
human |mmunodef|c|ency v|ra| part|c|es are
seen at med|um magn|f|cat|on |n th|s e|ectron
m|crograph (606}
The virus onIy grows on
T4 ceIIs that are
proIiferating in
response to an immune
stimuIus -- Therefore
difficuIt to grow in
cuIture
HIV HIV - - The Virus The Virus HIV HIV - - The Virus The Virus
Retrovirus Retrovirus
Three genes
GAG - POL - ENV
Three poIyproteins
Six reguIatory genes
TAT - REV - NEF - VIF - VPR - VPU
HIV HIV - - The Virus The Virus HIV HIV - - The Virus The Virus
Retrovirus Retrovirus
%wo g|ycoprote|ns: gp10 gp120 and gp41
gp41 |s fusogen that spans the membrane
ENV gene
HIV HIV - - The Virus The Virus HIV HIV - - The Virus The Virus
Croup-8pec|f|c Ant|gens
p17: |nner surface
p24: nuc|eocaps|d
p9: nuc|eocaps|d assoc|ated w|th RNA
CAC gene
Polyprotein
Retrovirus Retrovirus
HIV HIV - - The Virus The Virus
Retrovirus Retrovirus
Enzymes
!o|ymerase (reverse transcr|ptase -
RNA dependent 0NA po|ymerase}
|ntegrase
!rotease (cuts po|yprote|ns}
!0L gene
Polyprotein
The Genome of HIV The Genome of HIV
%hree structura| genes
L%Rs
Extra open read|ng frames are c|ue to |atency
%hese 0RFs code for sma|| prote|ns - ant|bod|es |n A|08 pat|ents
Viruses simiIar to HIV Viruses simiIar to HIV
HV HV- -2: was isolated from ADS patients in 2: was isolated from ADS patients in
West Africa 1986 West Africa 1986
Simian immunodeficiency virus (SV): was Simian immunodeficiency virus (SV): was
isolated from monkeys with an ADS isolated from monkeys with an ADS- -like like
illness illness
Human T Human T- -cell lymphotropic virus (HTLV cell lymphotropic virus (HTLV- -4): 4):
infect T cells, no kill, no disease infect T cells, no kill, no disease
Summary of RepIicative cycIe Summary of RepIicative cycIe
TypicaI retrovirus cycIe TypicaI retrovirus cycIe
ntry: ntry: (gp120, binding ; gp41, fusion) (gp120, binding ; gp41, fusion)
- - Chemokine receptors ( Chemokine receptors (CXCR4, CCR5 CXCR4, CCR5) )
- - Mutation Mutation in these receptors (infection??) in these receptors (infection??)
Uncoating, Transcription of viral RNA genome Uncoating, Transcription of viral RNA genome
,RNA ,RNA- -dependent DNA polymerase" dependent DNA polymerase"
Transcription of viral mRNA from proviral DNA Transcription of viral mRNA from proviral DNA
by by host cell RNA polymerase host cell RNA polymerase
Translation to several large polyproteins Translation to several large polyproteins
Released by budding from the cell membrane Released by budding from the cell membrane
HIV HIV - - Life History Life History HIV HIV - - Life History Life History
Entry |nto the ce||
%4 (604+} ce||s are major target
human heLa
6e||
human heLa 6e||
transfected w|th 604
ant|gen
N0% |NFE6%E0 |NFE6%E0
HIV HIV - - Life History Life History HIV HIV - - Life History Life History
604
604
604
llv
66R5
66R5
crero||re
Hutant
66R5
racroprage
Chemokine receptors are necessary co-receptors along with CD4 antigen
Transmission & EpidemioIogy Transmission & EpidemioIogy
SexuaI contact SexuaI contact
BIood transfusion BIood transfusion
From infected mother to neonate From infected mother to neonate
or via breast feeding or via breast feeding
Infection occurs by transfer of either HIV Infection occurs by transfer of either HIV- -
infected ceIIs or free HIV infected ceIIs or free HIV
2/3 2/3 of AIDS victims Iiving in Africa, Asia, & of AIDS victims Iiving in Africa, Asia, &
Latin america Latin america
AIDS is the AIDS is the 4th 4th Ieading cause of death Ieading cause of death
worIdwide worIdwide
Pathogenesis & Immunity Pathogenesis & Immunity
%he ce||u|ar and |mmuno|og|ca| p|cture - %he course of the d|sease
%he ce||u|ar and |mmuno|og|ca| p|cture - %he course of the d|sease
10 b||||on h|V part|c|es per day
V|rus ha|f ||fe 5.7 hours
100-10 m||||on v|r|ons per m| b|ood (set po|nt}
8ma|| m|nor|ty of %4 ce||s are |nfected
V|rus found |n |ymph nodes
InexorabIe decIine of CD4+ InexorabIe decIine of CD4+
T4 ceIIs T4 ceIIs
InexorabIe decIine of CD4+ InexorabIe decIine of CD4+
T4 ceIIs T4 ceIIs
hy do a|| of
the %4 ce||s
d|sappear?
At ear|y stages
of |nfect|on
on|y 1 |n 10,000
ce||s |s |nfected
Late 1 |n 40
ut few ce||s are |nfected:
Ear|y stage of |nfect|on 1:10,000
Late 1:40
hy do a|| %4 hy do a|| %4
ce||s ce||s
d|sappear? d|sappear?
1. !&N6%&RE0
HEHRANE
V|rus destroys the ce|| as a resu|t of
budd|ng
ut syncyt|a not
common
Host %4 ce||s are
not h|V+
6ou|d "sweep
up" un|nfected
ce||s
Uninfected
CD4 ceII
Gp120
negative
CeIIs Fuse
KiIIing of CD4 ceIIs
2. Syncytium
Formation
Infected CD4
ceII
Gp120 positive
Why do aII T4 ceIIs disappear? Why do aII T4 ceIIs disappear?
Cytotoxi
c T ceII
KiIIing of CD4 ceIIs
3. Cytotoxic T ceII-mediated
Iysis
hy do a|| %4 hy do a|| %4
ce||s ce||s
d|sappear? d|sappear?
UT: Most cells
are not infected
KiIIing of CD4+ ceIIs
4. |nd|ng of free Cp120
to 604 ant|gen makes
un|nfected %4 ce|| |ook
||ke an |nfected ce||
6omp|ement-med|ated
|ys|s
6ou|d account for the
|oss of un|nfected %4
ce||s
KiIIing of CD4+ ceIIs
4. |nd|ng of free Cp120
to 604 ant|gen makes
un|nfected %4 ce|| |ook
||ke an |nfected ce||
6omp|ement-med|ated
|ys|s
6ou|d account for the
|oss of un|nfected %4
ce||s
CIinicaI Findings CIinicaI Findings
ErIy, acute stage ErIy, acute stage
MiddIe, Iatent stage MiddIe, Iatent stage
Late, immunodeficiency stage Late, immunodeficiency stage
%he ce||u|ar and |mmuno|og|ca| p|cture
%he course of the d|sease
1. Acute |nfect|on
l|gr v|rus l|ler
V||d syrplors
Fa|| |r C01 ce||s oul recovers
R|se |r C08 ce||s oul recovers
A r|gr v|rus l|ler (up lo 10 r||||or v|ruses per r|
o|ood)
Hacrophages |nfected
Macrophages bring HIV into the body if sexuaIIy
transmitted
2. A strong |mmune response
V|rus a|most d|sappears from c|rcu|at|on
Cood cytox|c % ce|| response
8o|ub|e ant|bod|es appear |ater aga|nst both
surface and |nterna| prote|ns
Host v|rus at th|s stage comes from recent|y
act|vated (d|v|d|ng} and |nfected 604+ ce||s
604+ ce|| product|on compensates for |oss due to
|ys|s of ce||s by v|rus product|on and destruct|on
of |nfected ce||s by 6%Ls
3. A |atent state
Latency of v|rus and of symptoms
V|rus pers|sts |n extra-vascu|ar t|ssues
Lymph node dendr|t|c ce||s
Rest|ng 604+ memory ce||s (|ast a very
|ong t|me - a very stab|e popu|at|on of
ce||s} carry prov|rus
4. %he beg|nn|ng of d|sease
Hass|ve |oss of 604+ ce||s
C01 ce||s are lre largels ol lre v|rus
Ce||s lral pro||lerale lo respord lo lre
v|rus are ||||ed oy |l
0erdr|l|c ce||s preserl arl|ger ard v|rus
lo C01 ce||s
Ep|lope var|al|or a||oWs rore ard rore llv lo
escape lror |rrure resporse jusl as resporse Wares
Apoplos|s ol C01 ce||s
h|V pat|ents w|th h|gh %4 ce|| counts h|V pat|ents w|th h|gh %4 ce|| counts
do not deve|op A|08 do not deve|op A|08
5. Advanced d|sease - A|08
608+ ce||s destroy more 604+ ce||s
C01 ce|| |oss rears v|rus ard |rlecled
ce||s ro |orger corlro||ed
As C01 ce||s la|| oe|oW 200 per cu rr
v|rus l|ler r|ses rap|d|y ard rera|r|rg
|rrure resporse co||apses
C08 ce|| ruroer co||apses
0pportun|st|c |nfect|ons
0ealr |r ~2 years W|lroul |rlerverl|or
HIV and AIDS HIV and AIDS
Cood corre|at|on between
number of h|V part|c|es
measured by !6R and
progress|on to d|sease
HIV and AIDS HIV and AIDS
V|ra| |oad pred|cts
surv|va| t|me
HIV and AIDS HIV and AIDS
604 ce|| count |s not a
good pred|ctor of
progress|on to d|sease
Laboratory Diagnosis Laboratory Diagnosis
ELISA ELISA
Western BIot AnaIysis (gp41, p24) Western BIot AnaIysis (gp41, p24)
OraQuick (rapid screening immunoassay) OraQuick (rapid screening immunoassay)
PCR PCR (very sensitive and specific method) (very sensitive and specific method)
Anti Anti- -HIV Strategies HIV Strategies Anti Anti- -HIV Strategies HIV Strategies
hh|gr|y
AAcl|ve
AArl|-
RRelrov|ra|
%%rerapy
hAAR%: %wo nuc|eos|de ana|og R% |nh|b|tors and 1 protease |nh|b|tor
Now a|so: %wo nuc|eos|de ana|og R% |nh|b|tors and 1 non nuc|eos|de
Remember! Remember!
Educat|on |ed to |eve||ng off of rate of |ncrease |n
A|08
hAAR% has great|y s|owed death rate
%he fact that fewer peop|e are dy|ng per year from
the |nfect|on means that the number of h|V-|nfected
peop|e |n the popu|at|on |s r|s|ng!
&n|ess educat|on cont|nues to be successfu| and
un|ess we can cure |nfected peop|e of v|rus, the
prob|em of v|rus spread |s, and w||| cont|nue to be,
w|th us