2014 “Towards an HIV Cure” Symposium, Melbourne “The Role of Therapeutic Vaccination in HIV Cure Strategies” Viral Persistence: Obstacles and Opportunities in Overcoming AIDS Virus Infection J.D. Lifson AIDS and Cancer Virus Program Leidos Biomedical Research, Inc. Frederick National Laboratory AIDS and Cancer Virus Program
2014 “To wards an HIV Cure ” Symposium, Melbourne . Viral Persistence: Obstacles and Opportunities in Overcoming AIDS Virus Infection. “The Role of Therapeutic Vaccination in HIV Cure Strategies”. J.D. Lifson AIDS and Cancer Virus Program Leidos Biomedical Research, Inc. - PowerPoint PPT Presentation
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2014 “Towards an HIV Cure” Symposium, Melbourne
“The Role of Therapeutic Vaccination in HIV Cure Strategies”
Viral Persistence: Obstacles and Opportunities in Overcoming AIDS Virus Infection
J.D. LifsonAIDS and Cancer Virus ProgramLeidos Biomedical Research, Inc.
Reservoir: Virus that persists despite apparently effective suppressive cART, and is capable of giving rise to recrudescent infection if/when cART is stopped
Cure (definitive treatment beyond lifetime cART):
Eradication: Elimination through treatment of all virus capable of giving rise to recrudescent infection if/when cART is stopped
Functional Cure (sustained off treatment remission): Not complete elimination of reservoir, but reduction of reservoir to levels sufficiently low, with sufficient host control, to limit/abrogate pathogenesis and minimize/eliminate risk of transmission
Challenges for HIV Cure
• Residual virus replication (“active reservoir”)• Long lived/self renewing infected cells• Latent reservoirs–Epigenetic and transcriptional mechanisms of
latency –Anatomic and cell lineage compartments
• Pharmacological or immunological sanctuary sites• Must eliminate or control “last virus” capable of
initiating recrudescence
Approaches to HIV Cure: Mechanism Based and Empirical
• cART regimen: Compliance, flexibility for initiation, interruption
• Flexibility for experimental interventions: Preliminary proof of concept, risk/benefit
• Monkeys are not people, HIV is not SIV/SHIV
cART in NHP• Drug Considerations• Activity/potency vs. SIV• Drug delivery: Dosage, Route (“compliance”)• Bioavailability, PK (plasma and tissue levels!)• Toxicity• Sustainability over experimental duration• Drug availability/cost• 2012-14: Regimens able to achieve and sustain
suppression of SIVmac239 to < 30 RNA copies/mL
Evaluation of Pharmacologic Interventions (HDACi/SAHA) in cART Suppressed NHP (Merck)
• Test SAHA, establish NHP model• cART regimens• In vitro/Ex vivo validation–SIV vs. HIV, macaque cells vs. human cells
• Safety• In vivo activity
SIVmac239
cART Necropsy
4 wk
26-2
8 wk
3 wk
3 wk
3 wk
6-7 w
k
3 wk
3 wk
5-6 w
k
SAHA 45mg/kg/day
SAHA 57 mg/kg/day
Ex Vivo SAHA Treatment Increases Histone Acetylation and Induces SIV Expression from CD4+ T Cells From SIV-Infected
Macaques on Suppressive cART
cART + SAHA in NHP
• cART treatment for > 1 yr
• SAHA safe; cumulative 84 doses
• Treatment effects; histone acetylation, SIV transcriptional ratio (vRNA:vDNA)
• Results complex; PK/PD; decr. response with repeat dosing
• Despite activity, extensive dosing, no viral clearance
• HDACi may have role, but alone unlikely to meaningfully impact reservoirs without other interventions
• Romidepsin also studied (Gilead); histone acetylation, incr PVL, but not viral clearance
• Similarities to emerging clinical data support utility/relevance of NHP models
• Activity (potency, specificity)• PK/PD• Fractional hit rate per dose/cycle• Interpretation/significance of readouts • Fate of “induced” cells• Toxicity/off target effects• Must eliminate/control “last virus”; potential role for
immune surveillance, immune clearance• Role for therapeutic vaccination? Cellular vs. Ab
HIV Cure: Limitations of “Pharmacological Only” Approaches
HIV Cure: Therapeutic Vaccination (TVX)
Limitations of conventional TVX:• Kinetics: –Transient vaccine Ag–Later responses depend on Ag from infection;
responses chase the virus• Specificity: –Limited breadth vs. sequence diversity, viral plasticity–MHC allele dependence–Potential boosting of responses to already escaped
• Extremely high frequency of CD4+ and CD8+ T cell responses• Effector memory biased• Indefinitely persistent• Widely distributed, incl mucosal effector sites, viral portals of entry• Capable of locally containing, aborting infection?• Clearly different from other approaches; even if it doesn’t protect, likely to learn something!
Exploiting the Evolutionarily Acquired Immune Wisdom of CMV: Predicted Properties of T Cell Responses to
CMV-Vectored Vaccines
Kinetic Mismatch Barrier for AIDS Vaccines:“Too Little, Too Late”
Picker, LJ, Hansen, SG, and Lifson, JD, Ann Rev Med, 2011
Rh-rCMV
“Prophylactic” Rh-CMV/SIV Vaccination: Properties and Mucosal Challenge Cumulative Results
• No superinfection block• Uniquely broad CD4 + (TNF+, IFN-g+, IL-2+, MIP-1b+ ) and
CD8+ (TNF+, IFN-g+, MIP-1b+, CD107+) TEM responses• Maintained indefinitely • Widely distributed, incl mucosal effector sites• No NAb responses• Post-acquisition control of infection
Implications of Apparent Viral Clearance for Therapeutic Vaccination
• Can TVX with RhCMV/SIV clear infection in SIVmac239 infected macaques on cART?• Indefinitely persistent immune surveillance, broad, atypical T cell responses• Considerations for evaluation of therapeutic vaccination• Effective, sustainable cART in NHP• Timing of cART initiation• Duration of cART• Vaccine immunogenicity in infected NHP on cART• Virological readouts (Bx vs. Nx)
• Extremely broad epitope coverage; epitopes not recognized in natural infection, including promiscuous supertopes; advantages for both prophylactic and therapeutic vaccination