introduction to pathophysiologyof hiv and viral hepatitis · 2019-10-05 · • resume art if two...
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I N T R O D U C T I O N T O H I V
P A T H O P H Y S I O L O G Y
R O G E R PA R E D E S
M D, P H D
I N F E C T I O U S D I S E A S E S S E R V I C E & I R S I C A I X A A I D S R E S E A R C H I N S T I T U T E
H O S P I T A L U N I V E R S I T A R I G E R M A N S T R I A S I P U J O L
B A D A L O N A , C A T A L O N I A , S P A I N
DISCLOSURES
• I have received research grants from MSD, ViiV and Gilead
• I have participated in advisory boards for MSD and ViiV
• I don’t have stock options
Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations Published June 27, 2014 11
Figure 1. Sequence of appearance of laboratory markers for HIV-1 infection
Note. Units for vertical axis are not noted because their magnitude differs for RNA, p24 antigen, and antibody.
Modified from MP Busch, GA Satten (1997)50 with updated data from Fiebig (2003),48 Owen (2008),49 and
Masciotra (2011, 2013).46,66
Need for updated recommendations for the laboratory diagnosis of HIV-1 and HIV-2 infection
The previous algorithm, consisting of a repeatedly reactive immunoassay for HIV antibodies and
positive HIV-1 Western blot or HIV-1 IFA, has been the gold standard for laboratory diagnosis
of HIV-1 infection in the United States since 1989. False-positive results from this combination
are rare.67
HIV-2 infection remains uncommon in the United States, and no definitive criteria
have been recommended for HIV-2 diagnosis.27
Developments and observations in five areas led
CDC to update recommendations for the laboratory diagnosis of HIV-1 and HIV-2 infections:
1. The previous testing algorithm for HIV-1 fails to identify acute HIV-1 infections
Since 1999, blood screening centers in the United States have used pooled HIV-1 NAT to
identify acute HIV infection in donors who had nonreactive 3rd generation immunoassay
results.68
(To reduce costs, multiple specimens are pooled for screening with a single NAT;
specimens from reactive pools undergo individual NAT to identify the specimen with HIV-1
RNA.) Among persons seeking HIV testing, programs that used pooled NAT after a nonreactive
Días
HIV LIFE CYCLE AND ART
VIRAL LOAD FOLLOWING TREATMENT INTERRUPTION
Ananworanich J. CROI 2017, Seattle, WA. #124.
Median time to viral rebound: 26 days (range 13-48)
Highest VL at rebound (median): 5169 (2005 – 13462)
• N=8
• ART started at Fiebig I (HIV RNA+,
p24 Ag-, Ab-) for ≥ 96 w.
• VL <50 c/mL ≥48 w & CD4 >400 cells.
• Resume ART if two VL >1000 c/ml or
two CD4 <350 cells.
• TI for 24 w. VL every 3-7 days.
Hypothesis.
• At least 30% of individuals will have
delayed time to VL rebound (VL<50 at
24 w).
• Proceed to stage 2 if ≥ 1 person has
VL <50 c/ml at week 12.
HIV is the greatest escapist
NK
B
CD8
CD4 Adaptive immunity
Innate immunity
HIV-1 Strategies to counteract host immunity
TRIM
TETHERIN
Intrinsic immunity
CypA
Vif
Vpx
Population level Individual level
HUGE GENETIC DIVERSITY
Sanger sequencing
Deep
sequencing
1. High replication rate: 109-12 new virions/day
2. Error-prone polymerase:
- 1 mutation / 10,000 bp
- 3-8 recombination events / mutation event
3. Cellular mechanisms: MDR1 gene codes for P-glycoprotein
4. Role of RNAseH
5. Selective pressure of Abs & CTLs against HIV epitopes
6. Viral pool size and availability of target cells
• Balance between mutation rate, drift and selection
QUASISPECIES
“A population of viruses that share a
common origin but which have distinct
genomic sequences as a result from
mutation, drift and the impact of
selection”
In ARV-naïve subjects chronically infected with a “wild-type” HIV-1
• All non-deletereous single mutants likely preexist
• Few double mutants preexist
• Almost no triple mutants are expected
Pressure 1
Pressure 2
Pressure 1
Stop pressure
Pressure 2
Pressure 1
Stop pressure
Mutation rate
Drift Selection
DIVERSITY
Drift
Pereyra et al, Science 2010
Kiepiela et al, Nature 2004
HLA-I molecules are a major driving force of HIV-1 evolution
K
A
F S
P E
V I
P
HLA-I
P2 P9
N
K P
E V I
P G
S F
CD8+ T-cell responses and HIV-1 escape
HLA class I alleles are also highly diverse
Host HLA genetics and HIV diversity: frequent transmission of
escaped epitopes and epitope loss over time
GP160 FROM THE OUTSIDE
RESTRICTION FACTORS Typesof Host RestrictionFactors
MX2
TRIM5
CD8 C
op
ies
Vir
al R
NA
/ml
CD
4+ T cells/m
l
HOST RACE HIV EVOLUTION
WT
R2
E1
R3
E2
R4
E3 E4
R1
Metzner K, Paredes R, CHAIN Training slides
QUASISPECIES AS A SURVIVAL STRATEGY
Brenchley J M et al. J Exp Med 2004;200:749-759
HIV INFECTION DAMAGES THE GALT
% CD4+ T-cells
MICROBIAL TRANSLOCATION IN HIV
Nature Reviews | Microbiology
Enterocytea
b
Commensalbacterium
Secretory IgA
Secretory IgA
HEV
NeutrophilCD4+ T cell
CD8+ T cell
B cell
Macrophage Defensin
BacteriumInfected CD4+ T cell
Dendritic cell
HEV
Increased TNF production
Loss of tightjunctions
Decreased IgAproduction
Increased TNFand IFNg production;failed ionic balance HIV infection
Villus
CD8+ T cell in ltration
Crypt
Decreased ratio ofvillus height to crypt depth
Abnormal enterocytedi erentiation
CD4+ T cell loss;preferential TH17 cell lossEnterocyte
apoptosis
Coeliac disease
A chronic inflammatory
condition of the upper small
intestine in humans that is
caused by immunological
hypersensitivity to gliadin, a
component of wheat gluten. It
often occurs in infants during
the introduction to solid foods.
It causes severe villus atrophy,
which can lead to malabsorption
and malnutrition if gluten-
containing foods are not
removed from the diet.
C-reactive protein
(CRP). An acute-phase reactant
protein produced in the liver.
The concentration of CRP in
plasma increases during
inflammation.
can bind, at sites with epithelial barrier disruption may
facilitate this microbial translocation79.
Loss of TH17 cells. Depletion of CD4+ T cells is greater in
the gastrointestinal tract than in blood or lymph nodes
during HIV infection80–84. C-C chemokine receptor type
5 (CCR5)+ CD4+ T cells are depleted probably because
they become directly infected by the virus78,85,86, as CCR5
acts as a receptor for HIV virions87. On the basis of stud-
ies on rhesus macaques, depletion of CD4+ T cells from
the gastrointestinal tract occurs primarily during acute
infection88,89. Of these T cells, TH17 cells, which express
both CCR5 and the gut homing marker CCR6, are pref-
erentially depleted21,84,90,91, probably because they are
more susceptible to HIV infection than CCR5+CCR6−
cells, although the exact mechanism underlying this
REVIEWS
658 | SEPTEM BER 2012 | VOLUM E 10 www.nature.com/reviews/micro
© 2012 Macmillan Publishers Limited. All rights reserved
MICROBIAL TRANSLOCATION IN HIV PATHOGENESIS
Marchetti et al. Clin Microbiol Rev. 2013
Bacterial translocation and clinical progression
Marchetti G, et al. AIDS 2011;25(11):1385-94.
ICONA Cohort
- Documented last HIV-negative test and
first HIV-positive
- Plasma sample stored while ART-naive
N=379.
Circulating LPS in the first year of infection is a good predictor of progression
INFLAMMAEGING
Immune senescence Inflammageing
CV disease
Metabolic disorders
Osteoporosis
Chronic kidney disease Liver disease (NASH)
Cognitive problems
HIV persistence
GALT + GI wall
damage
Bacterial translocation
HIV Disbyosis?
GUT BLOOD
Inflammation
Residual HIV
replication Other
diseases, Tx Other viral
infections
B-Debate 2015: The Human Microbiome, Present Status & Future Prospects
IS THERE AN HIV-SPECIFIC DYSBIOSIS?
MICROBIOME IN HIV
0e+00
1e−06
2e−06
250000 500000 750000
0.00000
0.00025
0.00050
0.00075
0.00100
3500 4000 4500 5000 5500
0
25
50
75
100
late
pre
sent
er
disc
ordan
t
conc
orda
nt
early
-trea
ted
ART n
aive
virem
ic co
ntro
ller
elite
con
trolle
r
HIV
-1 n
egat
ive
Fre
qu
ency
(%
)
0e+00
1e−06
2e−06
3e−06
250000 500000 750000
Gene richness, all subjects
HIV-1
negative
HIV-1
positive
0e+00
1e−06
2e−06
3e−06
4e−06
Gene richness, MSM
400000 800000600000
2
9
3
15
11
42
5
8
7
8
6
5
3
5
16
11
a b
c d
e
De
ns i
tyD
ensi ty
LGC HGC
HIV-1
positive
HIV-1
negative
Gene counts (10 M) KEGG counts (10 M)
Gene counts (10 M) Gene counts (10 M)
2p-value = 0.001
2p-value = 0.009
2p-value = 0.055
Gene richness KEGG richness
Gene richness by HIV-1 phenotype
HGC
LGC
f Gene richness by nadir CD4+ T-cell counts
< 100
100
- 200
200
- 500
> 500
0
25
50
75
100
18
1
18
4
34
16
21
15
11
16
2p-value = 0.002
HIV
-1 n
egat
ive
CD4+ T cells / mm3
Guillén et al. Mucosal Immunology 2018
DYSBIOSIS BY GENE RICHNESS
Guillén et al. Mucosal Immunology 2018
LOW MICROBIAL GENE RICHNESS LINKED TO NADIR CD4
Guillén et al. Mucosal Immunology 2018
MICROBIOME IN HIV
Guillén et al. Mucosal Immunology 2018
MICROBIOME IN HIV
Guillén et al. Mucosal Immunology 2018
VAGINAL DYSBIOSIS RECOGNIZABLE AS COMMUNITY-TYPES
CAPRISA-004
CAPRISA-004
TDF DEPLETED BY GARDENERELLA BUT NOT LACTOBACILLUS
TDF METABOLISED TO ADENINE
MULTIPLE BV BACTERIA (BUT NOT L ACTOBACILLUS) CAN METABOLIZE TENOFOVIR
Maier Nature 2018
EXTENSIVE IMPACT OF NON -ANTIBIOTIC DRUGS ON HUMAN GUT BACTERIA
MICROBIOME IN CANCER
Gopalakrishnan et al, Cancer Cell 2018
X4 (SI) R5 (NSI)
CXCR4 CCR5 CD4
T-cell lines Primary lymphocytes Monocyte/macrophages
CD4 Naïve CD4 memory
Dual tropic
TROPISM PREDICTION
Koot M, et al: Prognostic Value of HIV-1 Syncytium-Inducing Phenotype for Rate of CD4+ Cell Depletion and Progression to AIDS. Annals Int Med 1993
TROPISM
RATE OF PROGRESSION TO CD4+<350, INITIATION OF ART OR DEATH
Goetz. JAIDS 2009
TIME OF X4 VIRUS EMERGENCE IN RELATION TO CD4 INFLECTION POINT
Shepherd. MACS cohort, JID 2008
TROPISM & CD4 LOSS BEFORE ART
Waters CID 2008
TROPISM & CD4 GAIN AFTER ART
Waters CID 2008
WHY DO WE NEED TO CURE HIV?
Life expectancy remains reduced on cART
Ongoing morbidity on cART
Prevent HIV transmission
Substantial stigma and discrimination
Lifelong cART:
adherence toxicity long term-cost
J.Martinez-Picado
Lohse, Ann Int Med 2007; Hogg. Lancet 2008; Deeks & Phillips, BMJ 2009; May, BMJ 2011
Estimated 2015 AIDS investment for
universal prevention, treatment, care and
support
22 billion USD
BARRIERS TO CURE HIV INFECTION
J.Martinez-Picado
Where is the virus and how is it maintained in the
face of suppressive therapy?
Residual
replication
Latent
infection
inflammation
immune activation
HIV CURE: 2-MODELS
J.Martinez-Picado
J.Martinez-Picado
STRATEGIES TO CURE HIV
Treatment
optimization
& intensification
(eliminate
all replication)
Reversal of
HIV latency
(increase viral
production)
Immune-based
therapies
(reverse pro-latency signaling)
Therapeutic
vaccination
(to enhance host-
control)
Gene
therapy
CONCLUSIONS
• HIV is the great scapist
–Diversity
• HIV
• HLA
– Integrated DNA
–Env glycosylation
–GALT damage
– Inflammaging
FLSida: Isabel Bravo, Pep Coll, Carla Estany, Cristina HerreroBCN Checkpoint: Jorge SazIrsiCaixa: Bea Mothe, Jorge Carrillo, Christian Brander, Julià Blanco,
Bonaventura ClotetVall d’Hebron: Manel Crespo, Jordi Navarro, Ariadna Torrela
UVIC-UCC: Malu Calle
This study is supported by the University and Resear ch Secretary - Department of Economy and Knowledge of the Government of Catalonia and the European Social Fund (Ref. 2015 FI_B 00184) and the Fondo de Investigaciones Sanitarias (PI13/02514) & Fondos FEDER & the RED de SIDA RD16/0025/0041
Marc Noguera
Yolanda Guillén
Cristina Rodríguez
Chiara Mancuso
Muntsa Rocafort
Maria Casadellà Mariona
Parera
Javier Rivera
Gràcies!
Thanks for the slides to : Christian Brander
Javier Martínez Picado
Miguel Ángel Martínez
Júlia Garcia-Prado
Ester Ballana
Josep Maria Llibre