HIV Lecture
31
A global view of HIV infection 38.6 million people [33.4 !46.0 million] living with HIV, 2008 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. 2.4 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. About 1.1 million in the U.S. are HIV-positive! About 56,000 new HIV infections in the US per year! About one-quarter of infected people don t realize they are infecte !
Transcript of HIV Lecture
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A global view of HIV infection38.6 million people [33.4 !46.0 million] living with HIV, 2008
The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete theimage and then insert it again.
2.4
The image cannot be displayed. Your computermay not have enough memory to open theimage, or the image may have been corrupted.Restart your computer, and then open the fileagain. If the red x still appears, you may have todelete the image and then insert it again.
The image cannot be displayed. Your computer may not have enough memory to open theimage, or the image may have been corrupted. Restart your computer, and then open the fileagain. If the red x still appears, you may have to delete the image and then insert it again.
About 1.1 million in the U.S. are HIV-positive!About 56,000 new HIV infections in the US per year!About one-quarter of infected people don!t realize they are infecte !
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How virus load and CD4 counts change over time
in a typical infection
1200
1000
800
600
400
200
0
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11+
0
1/21/4
1/8
1/16
1/32
1/64
1/1281/256
1/512
C D 4 + T
- c e l l s , c e l l s /µ L P
l a s
m aV i r emi a ( Di l u t i on al T i t er )
Clinical latency
Opportunisticdiseases
Constitutionalsymptoms
Death± Acute HIV syndromewide dissemination of virus
seeding of lymphoid organs
Primaryinfection
Weeks Years
Acute!
Phase! Clinical latency!
AIDS!
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HIV infected persons with CD4 < 200or
HIV-infected and have had an AIDS defining illness:Candidiasis of bronchi, trachea, or lungs ! ! !Candidiasis, esophageal!Cervical cancer, invasive ! ! ! !Encephalopathy, HIV-related!
Coccidioidomycosis, disseminated or extrapulmonary!Toxoplasmosis of brain
!
Cryptococcosis, extrapulmonary ! ! !Pneumonia, recurrent!Cryptosporidiosis, chronic intestinal (>1 month's duration) ! Lymphoma, primary, of brain!
Cytomegalovirus disease (other than liver, spleen, or nodes) !Wasting syndrome due to HIV!
Cytomegalovirus retinitis (with loss of vision)!Herpes simplex: chronic ulcers (>1 month's duration); or bronchitis, pneumonitis, or esophagitis!
Histoplasmosis, disseminated or extrapulmonary!
Isosporiasis, chronic intestinal (>1 month's duration)*Kaposi's sarcoma!
*Lymphoma, Burkitt's (or equivalent term)!
Lymphoma, immunoblastic (or equivalent term)!Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary!
Mycobacterium tuberculosis, any site (pulmonary** or extrapulmonary)!Mycobacterium, other species or unidentified species, disseminated or extrapulmonary!
Pneumocystis carinii pneumonia!
Progressive multifocal leukoencephalopathy!
Salmonella septicemia, recurrent!
Definition of AIDS:!
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Single stranded, RNA viral genome!
Double stranded, DNA copy!
Viral Reverse!
Transcriptase!
enzyme (RT for short)!
What makes retroviruses unique?!
Feature 1: Retroviruses make DNA out of RNA!
Why is this important?1. RT is a drug target!2. RT makes mistakes - high error rate gives rise to
drug resistance!
5!! 3!!
5!!
3!! 5!!
3!!
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Viral Integrase enzyme!
What makes retroviruses unique?Feature 2: Retroviruses integrate their DNA
into the host chromosome
Why is this important?1.Integrase is a drug target!
2.Once integrated, the viral DNA becomes a permanent part
of the cell - it can only be eradicated by killing the cell.
Makes HIV a life-long infection. But, good for gene therapy!
5!!
3!! 5!!
3!!Viral DNA!
Host cell DNA!
+!
Integrated viral DNA!
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Science, October 4, 2002!
Nature, October 10, 2002!
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Where does integration occur?!
Retroviruses preferentially integrate at active genes!
From: Schroder et al. Cell 110, 521-529; 2002!
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Virus Strain E
Virus Strain C
Virus Strain D
Percent SequenceDivergence
46810 2 0
When and from where did HIV come from?!
Constructing a phylogenetic tree!
Virus Strain A
Virus Strain B
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!
Timing the origin of the HIV pandemic
A. Phylogenetic tree of env sequences obtained over past 20 yrs.!B. Branch lengths from each leaf to the root of the tree plotted
against time. Linear fit to the data is shown (bold turquoise line).!C. Enlarged version of inset in part B!!
HIV has evolved into multiple clades, or subtypes!
Common!
ancestor!
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HIV and SIV are closely related!
Virutally all old-world primates have their own strain of SIV!Infected animals don
!
t get sick - a perfect host-parasite relationshi!
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SIV Chimpanzee!
Strains!
SIV Sooty Mangabey!
Strains!
HIV-1!
HIV-2!
Relationships between HIV and SIV: HIV as a zoonosis
This genetic evidence argues thatHIV-1 arose from transmission ofSIV from chimpanzees to humans!
!
It also argues that HIV-2 arosefrom transmission of SIV from
sooty mangabeys to humans!
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RNAlater
Non-Invasive SIVcpz Detection!
Slide from Beatrice Hahn, UAB!
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Extended Survey of Wild Apesin Cameroon
!
MB! LB!BB!EK!
DP!BQ!WE!
MT!DG!
CP!
TK!MG!MP!MF!
SL!BM!
NK!
KG!
* !
SIVcpzTAN3SIVcpzTAN2
SIVcpzTAN1
100
SIVcpzAnt
100
SIVcpzGAB2SIVcpzMT117
SIVcpzMT145
SIVcpzDP995
100
SIVcpzDP22SIVcpzDP23 SIVcpzDP24SIVcpzCAM155
100
SIVcpzCAM13SIVcpzGAB199
SIVcpzCAM3
SIVcpzDP933
SIVcpzDP942100SIVcpzCAM5
SIVcpzUS
SIVcpzEK505 SIVcpzEK502SIVcpzEK519
SIVcpzEK516SIVcpzBM1034
100
100
91
98
97
94
SIVcpzMB189
SIVcpzMB802SIVcpzMB23
100
SIVcpzMB771SIVcpzMB803SIVcpzLB7
100
SIVcpzLB714SIVcpzLB715100
SIVcpzLB730SIVcpzMB317
SIVcpzMB751
SIVcpzMB749100
SIVcpzMB248
SIVcpzMB245SIVcpzMB66
99
SIVcpzMB897
100
99
6
96
100
0.05
HIV-1/N
HIV-1/N
HIV-1/MHIV-1/M
HIV-1/M
HIV-1/M
HIV-1/O
HIV-1/O
gp41!
Slide from Beatrice Hahn UAB
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a, Map of west-central Africa showing major rivers, and cities with explosive population growthin the twentieth century. Chimpanzees carrying the SIV strains most closely related to theviruses of HIV-1 group M, such as that described by Worobey et al.2, have been found insoutheast Cameroon (red ring). b, Léopoldville in 1896 (view from Mount Léopold) and c,around 1955 (the commercial centre).(Photos F. L. Michel (b) and C. Lamote (c), collection of
the Royal Museum for Central Africa, Tervuren, Belgium.)!
Sharp and Hahn, Nature 455:605 (2008)!
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HIV-1: A Class I Fusion System
Cryoelectron micrographsof virions with artificially
high numbers of spikes
Zanetti et al, PLoS Pathog. 2006
Reverse transcriptase (RT)!Protease!Integrase
!
HAART!
Perhaps only 10"
spike!
trimers per virion
High cost
(getting better)
Side-effects(getting better)
Difficult regimens(rapidly changing)
Multi-drug
resistant viruses(getting worse)
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Selective Pressure of Therapy
V i r a l l o a d
Time
Drug-susceptible quasispeciesDrug-resistant quasispecies
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Selective Pressure of TherapyTreatment begins
V i r a l l o a d
Time
Drug-susceptible quasispeciesDrug-resistant quasispecies
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Selective Pressure of Therapy
Incomplete suppression
•" Inadequate potency
•" Inadequate drug levels
•" Inadequate adherence
•" Pre-existing resistance
V i r a l l o a d
Time
Drug-susceptible quasispeciesDrug-resistant quasispecies
Treatment begins
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Genotypic analysis of plasma HIV from
patients on therapy with ritonavir
Weeks
P l a s m a R N A
( b D N A )
104
105
106
104
105
48444036322824201612840
104
105
V82V/A
V82V/A
WT
V82AI54VA71V
V82AI54VA71V
M36M/IK20K/R
V82AI54VA71VM36IK20R
V82AI54VA71VM36IK20R
Patient 235
Patient 203
WT
V82AI54VA71V
V82AI54VA71V
M46I/M
WT WT WT WT WT
Patient 124
600 mg bid
no drug
V82AI54I/V
A71A/V
600 mgBID
400 mg
BID
500 mg
BID
Molla, et al., Nature Medicine, 1996
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Protease inhibitors! RT Inhibitors (Nucs)!
RT and PI resistance is now well understood - viralgenotyping is highly predictive of phenotype
Dark: causes phenotypic resistance; Orange: contributes to resistance; Light Orange: accessory
resistance mutation; IS - increased susceptibility to drug.!
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H+
Endosome
Enveloped Virus Entry:1. !Attachment2. Receptor engagement
3. !Trigger Event! !pH-dependent! !pH-independent4. !Conformational Change5. !Membrane Fusion
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2!1!
3!
Huang et al. Sci. 310:1025 (2005)!
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Coreceptor
Helical Region 1! Helical Region 2!
NH2!Fusion peptide!
T20!
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Provided by Trimeris, Inc.!
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Targets for HIV Entry Inhibitors
maraviroc (2007) enfuvirtide (2003)Licensed entry inhibitors:
