Document

Report
Update on HIV Therapy
Hail M. Al-Abdely, MD
Consultant, Infectious Diseases
Clinical, Virological and Immunological Course
of HIV Infection
Symptoms
Virus in Plasma
Infection
Death
Detectable
Time 0
VIRUS IN PLASMA
Detectable
12 Years
Clinical, Virological and Immunological Course
of HIV Infection
CD4 Cell Count
Symptoms
Virus in Plasma
Infection
Time 0
Death
Detectable
VIRUS IN PLASMA
Detectable
> 500 cells
CD4 COUNTS
< 200 cells
12 Years
Clinical, Virological and Immunological Course
of HIV Infection
CD4 Cell Count
Symptoms
Virus in Plasma
Infection
Death
Detectable
VIRUS IN PLASMA
Detectable
> 500 cells
CD4 COUNTS
< 200 cells
Time 0
12 Years
Seroconversion
Asymptomatic
AIDS
Clinical, Virological and Immunological Course
of HIV Infection
1000
CD4 Cell Count
800
600
RNA in Plasma
400
Symptoms
Virus in Plasma
200
Infection0
Death
Detectable
VIRUS IN PLASMA
Detectable
> 500 cells
CD4 COUNTS
< 200 cells
Time 0
12 Years
Seroconversion
Asymptomatic
AIDS
Development of AIDS is like an
impending train wreck
Viral Load = Speed of the train
CD4 count = Distance from cliff
HIV
infection
J. Coffin, XI International Conf. on AIDS, Vancouver, 1996
Viral Dynamics of HIV-1 Infection
Latently infected
CD4 lymphocytes
Productively infected
CD4 lymphocytes
<1%
T 1/2 ~1.6d
99%
Uninfected CD4
lymphocytes
2.6 days
per
generation
T1/2 ~5.7 hrs
HIV
<1%
Uninfected activated
CD4 lymphocytes
Long-lived cell
populations
Perelson et.al. Science 271:1582 (1996)
CD4 lymphocytes
infected with
defective virus
Viral dynamics




It takes 2.6 days to produce a new
generation of viral particles
Estimated total HIV production is 10.3 x
109 virions per day
99% of the virus pool is produced by
recently infected cells
Retroviral therapy should be able to reduce
viral load within a few days
GOALS OF THERAPY
• Clinical goals: Prolongation of life and improved quality
of life
• Virologic goals: Reduction in viral load as much as
possible for as long as possible to: 1) halt disease
progression, and 2) prevent/reduce resistant variants
• Immunologic goals: Achieve immune reconstitution that
is quantitative (CD4 to normal range) and qualitative
(pathogen-specific immune response)
• Therapeutic goals: Rational sequencing of drugs in a
fashion that achieves virologic goals, but also: 1) maintains
therapeutic options; 2) is relatively free of side effects; and
3) is realistic in terms of probability of adherence
• Epidemiologic goals: Reduce HIV transmission
19
1
Antiretroviral Drugs Approved by FDA for HIV
Generic Name
Class
FDA Approval Date
Zidovudine, AZT
NRTI
March 87
Didanosine, ddI
NRTI
October 91
Zalcitabine, ddC
NRTI
June 92
Stavudine, d4T
NRTI
June 94
Lamivudine, 3TC
NRTI
November 95
Saquinavir, SQV, hgc
PI
December 95
Ritonavir, RTV
PI
March 96
Indinavir, IDV
PI
March 96
Nevirapine, NVP
NNRTI
June 96
Nelfinavir, NFV
PI
March 97
Delavirdine, DLV
NNRTI
April 97
Combivir (AZT+3TC)
NRTI
September 97
Saquinavir, SQV, sgc
PI
November 97
Efavirenz, EFV
NNRTI
September 98
Abacavir, ABC
NRTI
February 99
Amprenavir (AMP)
PI
April 99
Lopinavir (LPV)
PI
September 00
EC Didanosine(EC DDI)
NRTI
September 00
Trizivir (AZT+3TC+ABC)
NRTI
September 00
Current antiretroviral targets
Viral protease
RNA
Reverse
transcriptase
RNA
Proteins
RT
RNA
ZDV, ddI,
ddC, d4T,
3TC, ABC,
RNA
DNA
RT
DNA
DLV, NVP,
EFV
DNA
Provirus
SQV
RTV
IDV
NFV
APV
LPV
90
100
80
80
80
70
70
60
60
60
40
50
20
50
Monot herapy
Monotherapy
Monot herapy
90
Dual therapy
Monot herapy
Viral Suppression with Monotherapy
versus Multiple Drugs
Triple therapy
Deaths per 100,000 Population
Trends in Age-Adjusted* Rates of Death due to HIV Infection,
USA, 1982-1998
18
16
14
12
10
8
6
4
2
0
82
84
86
88
*Using the age distribution of the projected
year 2000 US population as the standard.
90
Year
92
94
96
**Preliminary 1998 data
98**
Good News
Highly active antiretroviral therapy has
Changed our view toward HIV from
inevitably fatal to a manageable disease
over several decades
Bad News
1.
2.
3.
4.
5.
Incomplete response
Complexity of treatment
Short and long term side effects
Resistance
Drug-drug interactions
Bad News
1. Incomplete response
•
•
2.
3.
4.
5.
Complete RNA suppression and sustained CD4
increase happens only in 60-80%.
Effectiveness is even lower in patients with high
replication rates and extensive antiretroviral
experience.
Complexity of treatment
Short and long term side effects
Resistance
Drug-drug interactions
Viral Suppression with Monotherapy
versus Multiple Drugs
90
90
80
80
70
70
60
60
Monot herapy
Monotherapy
50
Monot herapy
50
Dual therapy
Monot herapy
Triple therapy
Virologic nadir predicts duration of response
Bad News
1. Incomplete response
2. Complexity of treatment
•
•
•
Too many tablets.
Difficult schedule.
Food factor
3. Short and long term side effects
4. Resistance
5. Drug-drug interactions
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Drug-drug interactions
5. Resistance
Side Effects of NRTIs
Drug
Common Side effects
Zidovudine
(azt, zdv)
Initial nausea, headache, fatigue, anemia, neutropenia,
neuropathy, myopathy.
Lamivudine
(3TC)
GI side effects.
Didanosine (ddl)
GI side effects. Peripheral neuropathy in 15%, pancreatitis.
Zalcitabine
(ddC)
Peripheral neuropathy in 17-31% of trial participants; oral
ulcers.
Stavudine (d4T)
Peripheral neuropathy (1-4% in early studies; 24% in
expanded access patients with CD4+ counts < 50)
Abacavir (ABC)
About 3%-5% hypersensitivity reaction: malaise, fever,
possible rash, GI. Resolves within 2 days after
discontinuation.
Side Effects of NNRTIs
Drug
Common Side effects
Delavirdine
Transient rash. P450 3A4 inhibitor
Nevirapine
Transient rash, hepatitis. P450 3A4 inducer.
Efavirenz
Initial dizziness, insomnia, transient rash,
P450 3A4 inducer.
Side Effects of PIs
Drug
Common Side effects
Amprenavir
Rash (20%), diarrhea, nausea
Indinavir
Kidney stones in 6 to 8%: good hydration essential.
Occasional nausea and GI upset.
Nelfinavir
Diarrhea common; occasional nausea
Ritonavir
Nausea, diarrhea, numb lips for up to 5 weeks; occasional
hepatitis.
Saquinavir
Nausea, diarrhea.
Metabolic Complications of PIs
• Hyperbilirubinemia
• Hyperlipidemia
– Coronary artery disease
• Insulin resistance
• Abnormal fat distribution.
• Lipodystrophy
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Drug-drug interactions
5. Resistance
Drugs That Should Not Be Used With Antiretrovirals
Drug Category
Indinavir
Ritonavir*
Saquinavir
Nelfinavir
Amprenavir
Nevirapine
Delavirdine
Efavirenz
Ca++ channel
blocker
(none)
bepridil
(none)
(none)
bepridil
(none)
(none)
(none)
Cardiac
(none)
amioderone
flecainide
propafenone
quinidine
(none)
(none)
(none)
(none)
(none)
(none)
Lipid Lowering
Agents
simvastatin
lovastatin
simvastatin
lovastatin
simvastatin
lovastatin
simvastatin
lovastatin
simvastatin
lovastatin
(none)
simvastatin
lovastatin
(none)
AntiMycobacterial
rifampin
none
rifampin
rifabutin
rifampin
rifampin
(none)
rifampin
rifabutin
(none)
Antihistamine
astemizole
terfenadine
astemizole
terfenadine
astemizole
terfenadine
astemizole
terfenadine
astemizole
terfenadine
(none)
astemizole
terfenadine
astemizole
terfenadine
cisapride
cisapride
cisapride
cisapride
cisapride
(none)
cisapride
H-2 blockers
Proton pump
inhibitors
cisapride
Neuroleptic
(none)
clozapine
pimozide
(none)
(none)
(none)
(none)
(none)
(none)
Psychotropic
midazolam
triazolam
midazolam
triazolam
midazolam
triazolam
midazolam
triazolam
midazolam
triazolam
(none)
midazolam
triazolam
midazolam
triazolam
Gastrointestinal
Drugs
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Drug-drug interactions
5. Resistance
Resistance
Genotypic Mutations Associated With Resistance to NRTI & NNRTIs
Agent
ZDV
41
67
69*
3TC
69*
ddI
65
ddC
65
d4T
70
Resistance mutations
151
69
50
ABC
151
184
69*
74
151
184
69*
74
151
184
69*
65
210
75
69*
74
Agent
151
115
215
219
333
333
178
151
184
Resistance mutations
DLV
103
EFV
100
103
NV
100
103
181
108
106
108
179
236
181
188
190
181
188
190
225
Resistance
Genotypic Mutations Associated With Resistance to PIs
Agent
APV
10
IDV
10
NFV
10
RTV
10
20
SQV
10
20
LPV
10
20
24
32
30
32
24
30
32
33
36
Resistance mutations
46 47 48 50 54
63
71
36
46
48
63
71
36
46
48
36
46
36
46
46
54
48
47
50
82
84
82
84
71
82
84
82
84
90
82
84
90
54
63
71
54
63
71
73
73
84
90
88
90
Overcoming Drug Resistance
Increase
exposure
to drug
RESISTANCE
Change to a
drug to which
virus shows
greater
susceptibility
Drug
Overcoming Drug Resistance
Change to a drug to which virus shows
greater susceptibility
Guided by Genotypic resistance testing
Switching within a drug class
Example - Switching within PI class of drugs:
• Primary mutation associated with reduced
susceptibility to nelfinavir is D30N
• Timely switching of patients on a failing NFV regimen
harboring D30N has resulted in good clinical response
• New PI regimen has increased susceptibility due to
non-cross resistance to D30N
Switching to a different drug class
• Often switching within a drug class not
effective due to class cross-resistance
– NRTI: Q151M, 69 insertion (other multiple MU)
– NNRTI: K103N (others)
– PI: G48V + V82A (other multiple primary)
• Switching to new class of drugs not
previously used most effective
Percentage of patients with plasma HIV-RNA
below 200 copies/ml in the VIRADAPT study
%
<200 copies/ml
Randomized Study
35
30
25
Control
Genotypic
20
15
10
5
0
0
3
6
9
Months
(Adapted from Clevenbergh et al. Antiviral Therapy 2000; 5:65–70)
12
Percentage of patients with plasma HIV-RNA
below 200 copies/ml in the VIRADAPT study
%
<200 copies/ml
Open Study
Randomized Study
35
30
25
Control
Genotypic
20
15
10
5
0
0
3
6
9
Months
(Adapted from Clevenbergh et al. Antiviral Therapy 2000; 5:65–70)
12
Overcoming Drug Resistance
Increase
exposure
to drug
RESISTANCE
Change to a
drug to which
virus shows
greater
susceptibility
Drug
Saquinavir boosted by ritonavir
SQV conc
(ng/mL)
9000
8000
7000
Fortovase 1600 mg + ritonavir 100 mg qd
6000
5000
4000
Fortovase
1200 mg tid
3000
2000
1000
0
0
5
10
15
20
25
Time (hours)
Kilby et al. Antimicrob Agents Chemother Vol 44 2000
Increase - above efficacy, below toxicity
Drug conc
(ng/mL)
9000
8000
7000
6000
5000
4000
3000
2000
Drug A
1000
Drug A level required to overcome WT virus
0
0
5
10
Time (hours)
15
20
25
Increase - above efficacy, below toxicity
Drug conc
(ng/mL)
9000
8000
7000
Boosted Drug A
6000
5000
Drug A level required to overcome “resistant” virus
4000
3000
2000
Drug A
1000
Drug A level required to overcome WT virus
0
0
5
10
Time (hours)
15
20
25
Increase - above efficacy, below toxicity
Drug conc
(ng/mL)
Drug A Toxicity threshold
9000
8000
7000
Boosted Drug A
6000
5000
Drug A level required to overcome “resistant” virus
4000
3000
2000
Drug A
1000
Drug A level required to overcome WT virus
0
0
5
10
Time (hours)
15
20
25
The benefits of therapeutic drug
monitoring
HIV RNA*
0.05
-0.15
Control sub-optimal
concentration
-0.35
-0.55
-0.75
-0.95
-1.15
-1.35
-1.55
0
* viral load from baseline,
log10 copies/ml
3
6
Months
(Adapted
from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75–
76)
The benefits of therapeutic drug
monitoring
HIV RNA*
0.05
-0.15
Control sub-optimal
concentration
-0.35
-0.55
Genotypic sub-optimal
concentration
-0.75
-0.95
-1.15
-1.35
-1.55
0
* viral load from baseline,
log10 copies/ml
3
6
Months
(Adapted from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75–
76)
The benefits of therapeutic drug
monitoring
HIV RNA*
0.05
-0.15
Control sub-optimal
concentration
-0.35
-0.55
Genotypic sub-optimal
concentration
-0.75
Control optimal
concentration
-0.95
-1.15
-1.35
-1.55
0
* viral load from baseline,
log10 copies/ml
3
6
Months
(Adapted
from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75–
76)
The benefits of therapeutic drug
monitoring
HIV RNA*
0.05
-0.15
Control sub-optimal
concentration
-0.35
-0.55
Genotypic sub-optimal
concentration
-0.75
Control optimal
concentration
-0.95
-1.15
-1.35
Genotypic optimal
concentration
-1.55
0
* viral load from baseline,
log10 copies/ml
3
6
Months
(Adapted
from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75–
76)
Indications for the Initiation of Antiretroviral
Therapy in the Chronically HIV-Infected Patient
Clinical Category
CD4+ T-Cell Count
and HIV RNA
Recommendation
Symptomatic (AIDS, thrush,
unexplained fever)
Any value
Treat
Asymptomatic
CD4+ T Cells < 350
cells/mm3
or
HIV RNA > 10,000
(bDNA)
or > 20,000 (RT-PCR)
copies/mL
Treatment should be offered. Strength of
recommendation is based on prognosis for
disease-free survival and willingness of the
patient to accept therapy.
Asymptomatic
CD4+ T Cells > 350
cells/mm3
and
HIV RNA < 10,000
(bDNA)
or < 20,000 (RT-PCR)
copies/mL
Many experts would delay therapy and observe;
however, some experts would treat.
Recommended Antiretroviral Agents for
Treatment of Established HIV Infection
Column A
Column B
Efavirenz
Indinavir
Nelfinavir
Ritonavir + Saquinavir (SGC or HGC*)
Stavudine + Lamivudine
Stavudine + Didanosine
Zidovudine + Lamivudine
Zidovudine + Didanosine
Recommended as an alternative
Abacavir
Amprenavir
Delavirdine
Nelfinavir + Saquinavir-SGC
Nevirapine
Ritonavir
Saquinavir-SGC
Didanosine + Lamivudine
Zidovudine + Zalcitabine
No recommendation; insufficient
data
Hydroxyurea in combination with other antiretroviral drugs
Ritonavir + Indinavir
Ritonavir + Nelfinavir
Strongly recommended
Not recommended; should not be
offered
(All monotherapies, whether from column A or B§)
Saquinavir-HGC
Stavudine + Zidovudine
Zalcitabine + Lamivudine
Zalcitabine + Stavudine
Zalcitabine + Didanosine
New agents in the pipeline
New agents should:
1.
2.
3.
4.
Exhibit high potency.
Adequate drug levels.
Activity against resistant isolates.
Penetration into all cellular and bodily compartments
(eg, central nervous system, genital tract).
5. Favorable drug interaction profile.
6. Minimal side effects.
7. Convenient to take, with no food restrictions and
minimal dosing requirements; preferably once daily.
Potential new targets
Binding, fusion
and entry
Viral zinc-finger
nucleocapsid
proteins
Viral protease
RNA
RNA
Proteins
Reverse
transcriptase
RT
RNA
RNA
DNA
RT
Viral regulatory
proteins
DNA
DNA
Viral integrase
Provirus
HIV viral membrane fusion
Stein et al. (1987) Cell 49: 664
HIV interaction with CD4 cell
CXCR4
CCR5
CD4
Cell
HIV interaction with CD4 cell
gp41
gp120
CD4
Attachment
CXCR4
CCR5
CD4
Cell
HIV interaction with CD4 cell
Co-receptor
Interaction
gp41
gp120
CD4
Attachment
CXCR4
CCR5
CD4
Cell
HIV
HIV interaction with CD4 cell
Co-receptor
Interaction
HIV
gp41
Anchorage
gp120
HIV
CD4
Attachment
CXCR4
CCR5
CD4
gp41
Cell
HIV interaction with CD4 cell
Co-receptor
Interaction
HIV
gp41
Anchorage
gp120
HIV
CD4
Attachment
CXCR4
CCR5
CD4
gp41
Cell
HIV
HR1-HR2
Interaction
HIV interaction with CD4 cell
Co-receptor
Interaction
HIV
gp41
Anchorage
gp120
HIV
CD4
Attachment
CXCR4
CCR5
CD4
gp41
Cell
Fusion
Complete
HIV
HR1-HR2
Interaction
Entry inhibitors under development
Class
Attachment
Inhibitors
Co-receptor
Inhibitors
Fusion
Inhibitors
Target
gp120, CD4
CXCR-4
Example Compounds
specific Mab,
soluble CD4 and CD4-Ig
AMD-3100
CCR-5
SCH-C, specific Mab,
gp41
T-20, T-1249, D-peptides
HIV attachment inhibitors
PRO 542 - Novel protein
– Human IgG-2 Fv replaced with HIV binding
domains of CD4 molecule
– Neutralized broad range of HIV variants in vitro
– Active in SCID-Hu model with primary isolates
– Phase II clinical testing
HIV attachment inhibitors
• PRO 542 (rCD4-IgG2)
– Single injection dose-ranging trial
~ 4 doses, 3-6 subject/dose, HIV RNA > 3,000
CD4 > 50
~ Well tolerated, single dose non-immunogenic, linear
pharmacokinetics
~ 6/6 high dose subjects had decrease in HIV RNA,
infectious titers of virus declined
Chemokine receptor inhibitors
• CCR-5 Inhibitors
– SCH-C (Schering-Plough)
– PRO 140 (anti-CCR-5 monoclonal antibody)
• CXCR-4 Inhibitors
– AMD-3100
CCR-5 inhibitors: SCH-C
• Small molecule antagonist of CCR-5
• PK profile in animals supports oral
administration
• Active in SCID-hu Thy/Liv model against
primary HIV
• Risk of switch to SI (CXCR-4) virus?
CXCR-4 inhibitors: AMD 3100
• Targets CXCR-4 and dual tropic virus
• Resistance develops in vitro
• Active SCID-hu mouse (CXCR-4, dual tropic
HIV)
• IV and SC administration well tolerated
• CXCR-4: importance in embryogenesis and
immune function?
T-20 (Fusion inhibitor)
41 patients, monitored for 48 weeks
after adding T-20 to failing therapy,
and a mean HIV RNA decline of -1.4
log10 copies/mL has been reported
New agents - NRTI
New agents:
1. Emtricitabine (FTC, Coviracil)
2. DAPD/DXG
3. Emivirine (MKC-442, Coactinon).
New formulations:
1. Enteric-coated didanosine (Videx EC). 400 mg once
daily.
2. Extended-release formulation of stavudine.
3. Zidovudine +lamivudine + abacavir single tablet
(Trizivir)
New agents - NRTI
Emtricitabine:
•
•
•
Fluorinated cytosine analogue with a similar
resistance profile to lamivudine, but 4- to 10-fold
more active in vitro.
Administered once daily.
Phase II study: given with didanosine and efavirenz
once daily
•
•
93% of patients had HIV RNA below 50 copies/mL at week
24, and 48-week
lone virologic failure in this study had rebounded from
below 50 copies/mL to below 400 copies/mL.
New agents - NRTI
DAPD:
•
•
•
•
Guanosine analogue, which is metabolized to the
active form, DXG.
A 15-day monotherapy dose-ranging study in
antiretroviral-naive patients demonstrated HIV RNA
declines of 0.5-1.6 log10 copies/mL, and 0.5-1.1 log10
copies/mL in antiretroviral-experienced patients.
No adverse events were reported during these studies.
DAPD is likely to be active against HIV carrying the
Q151M mutation, which confers cross-class
resistance.
New agents– Protease Inhibitors
1.
2.
3.
4.
5.
Lopinavir/ritonavir (ABT-378/r, Kaletra) – approved by
FDA.
BMS-232632.
Tipranavir.
DMP-450.
PD 178390
New agents– Protease Inhibitors
Lopinavir/ritonavir (ABT-378/r, Kaletra):
• uses a low dose of ritonavir to achieve very high
plasma levels of lopinavir, enabling it to retain
activity against virus with low-to-moderate levels of
resistance to PIs (including to lopinavir itself).
• 96% of patients with 0 to 5 PI mutations achieved
HIV RNA less than 400 copies/mL at week 24
compared with 76% of those with 6 or 7 mutations
and 33% of those with 8 to 10 mutations.
New agents– Protease Inhibitors
BMS-232632:
• Active against 89% of virus isolates resistant to fewer
than 4 PIs in vitro.
• Loss of sensitivity is correlated with high-level
resistance to at least 4 PIs.
• High incidence of unconjugated hyperbilirubinemia
Tipranavir
• Active against multi-PI resistant isolates.
• 87% of isolates > 10-fold resistance to 4 PIs remained
completely susceptible to tipranavir in vitro
New agents– NNRTI
1.
2.
3.
4.
Capravirine.
Emivirine
DMP-961
DMP-083
All show activity against viruses with 1 or more of
the common NNRTI mutations.
Barriers to the Development of an
Effective AIDS Vaccine
• Sequence variation
• Protective immunity in natural infection not clearly
established
• Lack of adequate animal model to study vaccine protection
with HIV
• Latency and integration of HIV into host genome
• Transmission by cell-associated virus
• Limited knowledge about mucosal transmission and
immune responses
• Financial disincentives
• Ethical issues
Conclusion
• Better understanding of the HIV has allowed better
treatment modalities.
• Cure is beyond reach at this stage, but patients can
survive years to decades longer.
• More drugs and drug problems are on the horizon.
• Control of HIV replication by the host immune
system may be the best outlook for future research.
• Intense vaccine research is ongoing and ultimately
will be the major preventive measure against HIV
infection
Immunotherapy
Immunotherapy
• Directions
– Augmentation of specific immune response to
control viral replication.
– Preventive Vaccines.
Clues to immune control of HIV?
Subject JP:
Sx:
Dx:
F/U:
Subject 161J:
Fever, Rash, Headache Sx:
HIV ELISA Neg.
Dx:
HIV RNA >700,000
Extensive Rx
F/U:
AIDS at 11 mo.
Rapid CD4 cell decline
Viral Load >750,000
Fever, Rash, Headache
HIV ELISA Neg.
HIV ELISA Pos.
No Rx
Well at 19 yrs.
CD4 1000
Viral Load < 500
Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4 cells
(Helper cells)
Generation of
HIV-1-specific killer cells
(CTL)
Loss of CTL function
due to inadequate HIV-1-specific
helper cells
Infection of
activated helper cells
Loss of HIV-1-specific helper
cells
Progression
T helper cells are the central
orchestrator of the immune system
CTL
Function
T helper cell
B Cell
Function
Antibody Production
NK Cell
Function
APC
Function
Cytokine production
Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4 cells
(Helper cells)
Antiviral
Rx
Generation of
HIV-1-specific killer cells
(CTL)
Maintenance of CTL function
due to adequate HIV-1-specific
helper cells
Nonprogression
Protection of activated
helper cells
Maintenance of HIV-1specific helper cells
HIV-1-specific T helper cells in individuals
treated during acute infection (n=7)
100
0 Months
2 Months
10
1
MB
JC
KM
ND
SJ
DK
KS

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