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Acute HIV infec-on and Prospects for Op-mizing the Immune Response with Quan-ta-ve Modeling
Eric Rosenberg, MD Associate Professor of Medicine
MassachuseDs General Hospital
Harvard Medical School
47 year old male
Present to MGH ED with an 8 day history of : Fever to 102.5 Headache Photophobia Myalgias and arthralgias Nausea and vomi-ng
3rd visit to health care system
47 year old male
Addi-onal history: MSM
Recent unprotected sex with an HIV infected partner
PMH: prior history of syphilis
Exam: Fever
Cervical lymphadenopathy Rash (started on torso spread to limbs and scalp)
Diagnosis
Acute HIV Infec-on
Viral Infec-ons and Immunity
• Three outcomes of a viral infec-on – Death – Eradica-on – Chronic infec-on Latency Viral ac-vity
Chronic Infection: Viral Latency and Replication
Immune Response
VZV, HSV, EBV, CMV
HIV
HIV infection
J. Coffin, XI International Conf. on AIDS, Vancouver, 1996
Acute HIV Infec-on
Acute HIV Infec-on Early events and Diagnosis
CTL
The level of HIV in the blood stream following seroconversion predicts disease progression
HIV
Vira
l Loa
d
One year
Rapid Progression
Slow Progression
28, 240
59, 987
11,843
Interquartileranges
Lyles et al, 2000
Par-al Control
Why can’t the immune system more effec-vely control HIV replica-on?
Viral factors
Host immune responses
Host genetic factors
New virus assembly
Neutralizing Antibodies
B cell
• Viral debris • Rapid evolu-on and diversifica-on • Inadequate T cell “help”
Why do neutralizing an-bodies fail?
New virus assembly
2-3 Days
CTL
Solublefactors
If CTL are present, why is the immune response not more effec-ve in HIV infec-on?
An-gen Presen-ng
Cell
Class II
CD4+ Th Cell
CD4
HIV‐Specific T Helper Cells are impaired in all stages of disease
TCR
1. Ac-va-on 2. Clonal expansion
3. Cytokine secre-on
Cri-cal rela-onship between CD4 and CD8
What happens to HIV‐specific T helper cells?
Acute HIV infec-on
Acute HIV Infec-on Early events and Diagnosis
CTL
Treatment
Should individuals with Acute HIV‐1 infec-on be treated with an-retroviral therapy?
Advantages Disadvantages Preserva-on of HIV‐specific cellular immune responses
Toxici-es and unknown long‐term risks
Opportunity for structured treatment interrup-on
Short‐ and long‐term clinical benefits are not well‐defined
Lowering of HIV‐1 set point Resistance acquisi-on
Limita-on of viral evolu-on and diversity
Limita-on of future an-retroviral therapy op-ons
Decreased transmission Quality of life impact
Mi-ga-on of acute retroviral symptoms
Cost
Kassutto et al, Clinical Infectious Diseases 2006
HIV‐Specific T helper cells
Can treatment ini-ated during acute HIV infec-on preserve HIV‐specific T
helper cells?
What happens to HIV‐specific T helper cells?
Pathogenesis hypothesis: • HIV‐specific T helper cell responses are generated and subsequently lost during acute infec-on
Treatment hypothesis:
• Treatment with ARV during acute infec-on will protect these responses from being lost
Ac-va-on
&
Expansion
Impairment Infec-on CD4 cells
Class II
CD4
TCR
Ac-va-on
&
Expansion
An-retroviral therapy
CD4 cells
Class II
CD4
TCR
Characteristic Acute Early total n Median age (years)
[IQR] 35
[31,39] 37
[34,43] 102
Male gender (%) 94 94 102 HIV Risk Factor
MSM (%) 82 81 94
White race (%) 77 78 102
Mean baseline VL (copies/mL)
(range)
5.61 million
(11,000-95 million)
382,000 (2800-2.95
million) 75
Mean baseline CD4 (cells/mm3)
(range)
445 (42-1093)
567 (170-981) 100
Kassutto et al, CID 2006
control chronic acute acute LTNP 1
10
100
1000
Rx No Rx
S0mula0
on inde
x
Rosenberg et al, Science 1997
Elite controllers
Clinical Point
• Immune damage occurs in the earliest stages of acute HIV infec-on: there appears to be a “window of opportunity” to reverse this damage with treatment
• Highly drug resistant virus can be transmiDed during acute infec-on: viral genotyping is recommended if treatment is ini-ated
Treatment Interrup-on
If treatment during acute infec-on restores immune responses similar to the elite controller phenotype…
Can treatment ini-ated during acute HIV infec-on be discon-nued?
Lessons from Berlin Lisziewicz et al, NEJM 340 (21), 1999
Augment HIV‐specific immunity Hypothesis
Can therapy be discon-nued?
• Will HIV‐1‐specific immune responses generated and maintained during acute infec-on be enough to control viremia?
• Can a “snap‐shot” of autologous virus further boost the immune system?
Mul-ple Treatment Interrup-ons
36
Can therapy be discon-nued?
“STI” Structured treatment interrup-on
Several paDerns have emerged – Failure – Transient control of viremia with sudden loss of containment
– Control ( durability?) • This strategy works 50% of the -me… Are we doing it correctly?
Rosenberg et al, Nature 2000 Kaufmann et al, PLoS Med 2004
Treatment Interrup-on Strategies
Terminal Treatment Discon-nua-on
39
40
Terminal Treatment Discon-nua-on
• ACTG 5187 • Four gene DNA vaccine • 20 subjects treated during acute HIV infec-on • Randomized to DNA vaccine versus placebo • Amer 4th vaccina-on (week 30), ARV was discon-nued
Rosenberg, et al: PLoSOne, 2010
1. Median viral load in placebo group (3.7 log10) 5,012 copies/ml
2. This is markedly different from expected VL based on MAC’s data (28,000 copies)
3. CD4 counts remained stable during treatment interruption
HIV RNA Terminal Treatment Interrup-on
Rosenberg, et al: PLoSOne, 2010
Future Direc-ons: Sor-ng it all out
• More ques-ons then answers… • Is treatment interrup-on a viable clinical strategy?
• Should individuals with acute infec-on be treated at all?
• Can we rely on clinical trials to sort it all out?
Future Direc-ons :Modeling Biomedical Problems
• Mul-disciplinary collabora-on is essen-al MGH‐NCSU
• Physician‐Scien-sts do not understand math! • Be prepared for skep-cism • Be the “science behind the science”
Smarter Trial Design
• In the absence of clinical data, physicians rely on “experience”, “expert opinion” and “educated guessing”
• Can sophis-cated mathema-cal and sta-s-cal models of Acute HIV infec-on more effec-vely design clinical trials?
Popula-on Based Simula-on 100 “virtual” pa-ents
Conclusions… • The early events in acute HIV infec-on may represent a unique “window of opportunity” for treatment
• It is not known whether treatment during acute infec-on is the correct thing to do
• STI may have a role in management of treated during acute infec-on but op-mal approach not known.
• Can Quan-ta-ve modeling be used to op-mize the design and conduct of clinical trials?
Acknowledgements
• The MGH Team – Marcus Alpeld – Todd Allen – Jenna Rychert – Daniel Kaufmann – Bruce Walker – Suzanne Bazner – Lindsay Jones
• The NCSU Team – H. T. Banks – Marie Davidian – Shuhua Hu
Solid Organ Transplanta-on
Solid Organ Transplanta-on • Every transplant requires a Donor and a Recipient
• Unless the donor and recipient are a perfect gene-c match, the recipient immune system will reject the transplanted organ
• Rejec-on ul-mately results in failure of the transplanted organ
• Every transplant recipient must take immunosuppressive therapy to prevent rejec-on
•
Solid Organ Transplanta-on • Every transplant recipient must take immunosuppressive therapy to prevent rejec-on
• Transplant recipients are pharmacologically immunosuppressed and therefore much more suscep-ble to serious infec-on
• A major problem in immunosuppressed pa-ents is the reac-va-on of latent viruses such as CMV, VZV, HSV and EBV
The Balance of Immunosuppression
Infec-on
Rejec-on
Latency vs re-activation: a delicate balance
Immune pressure
May result in rejection
Viral replication
Viral latency
Latency vs re-activation: a delicate balance
Immune pressure
Viral replication
Intermittent periods of viremia and control
Can modeling be used to inform and op-mize
immunosuppression strategies?
What is measurable? – Donor and Recipient tissue type/
genetics – Serologic status – Pre-transplantation immune responses – Post-transplantation immune responses – Drug-level of immunosuppression* – Levels of viremia over time – Graft function – Tissue activity (via biopsy) – Activity of other viruses