graft-versus-host responses, nk cells and hiv persistenceregist2.virology-education.com › 2016 ›...
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Graft-Versus-Host Responses, NK Cells and HIV Persistence
Louise Hogan, PhDUniversity of California San Francisco
Division of Experimental Medicine
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• Very few strategies have led to substantial decreases in the size of the latent HIV-1 reservoir
• Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is one of the few approaches that can lead to sustained, significant reduction in blood and tissue HIV-1 in patients with established viral reservoirs
Allogeneic HSCT and HIV-1 Persistence
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• Rapid recovery of NK cells after HSCT
• CD8 T cells and B cells take longer
• NK-cells important in the beneficial graft-versus-host-responses following allogeneic HSCT
• NK-cell infusion induces no GVHD while maintaining GVL effects
NK Cells Recover More Rapidly Following HSCT
Modlrem et al. Nat Med 2005
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• NK cells from Post-Treatment Controllers have high capacity to control autologous CD4+ T cell HIV infection in vitro (Scott-Algara et al. CROI 2016)
• NK cells may also play an important role in HIV reduction following HSCT or in other therapeutic settings
NK Cells Important in Immune Control of HIV
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Graft-Versus-HIV-1 Reservoir (GVHR)
Latently infectedcellART ART
Donor NK Cell Ljunggren & Malmberg 2007
• HLA-B is downregulated by HIV-1 nef (Blais et al. 2011)
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• Does reactivation of HIV-1 provide an opportunity for NK or other immune cells to selectively target infected cells?
HIV-1 Reactivation Following HSCT and GVH
GVHD
Pt C Pt D
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Ex Vivo GVHR AssayEx Vivo Determination of Graft-Versus-Residual HIV-1 Reservoir Effects
8 – 12 Months
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Ex Vivo GVHR Assay
(Allo) (Auto)
Ex Vivo Determination of Graft-Versus-Residual HIV-1 Reservoir Effects
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HIV-Reactivation Ex Vivo
Increasing frequency of less mature, less exhausted CD16low NK cells
HIV-1 Reactivation After 6 Days of Ex Vivo Culture
(Post-Transplantation)
(Pre-Transplantation)
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% e
GFP
+ Pr
olife
ratin
g CD
4+T-
Cells
(H
IV R
eact
ivat
ion)
Allogeneic(Pre-HSCT RecipientCD4+ T-Cells)
Autologous Control(Post-HSCT DonorCD4+ T-Cells)
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Increased CD4+ T cell death in allogeneic versus autologous experiments
Perc
ent D
ead
Reci
pien
t CD4
+ Ce
lls
Day 1 Day 3 Day 7
Allogeneic AutologousControl
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P = 0.014 P = 0.20
P = 0.672 P = 0.011
Allogeneic HLA-Matched(Pre-transplantation)
Autologous(Post-transplantation)
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Allogeneic HLA-Matched(Pre-transplantation)
Autologous(Post-transplantation)
P = 0.102 P = 0.638
P = 0.61P = 0.003
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% e
GFP
+ Pr
olife
ratin
g CD
4+T-
Cells
(H
IV R
eact
ivat
ion)
Allogeneic(Pre-HSCT RecipientCD4+ T-Cells)
Autologous Control(Post-HSCT DonorCD4+ T-Cells)
KIR-HLA interactions may play an important role in strength of allogeneic effect or HIV-specific immune targeting
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NK Cell Phenotype/Function Before and After HSCT↑ NK Cell Frequency ↓ Maturity and Exhaustion ↓ Inhibitory KIR Expression
↑ Cytotoxic Degranulation and INF-γ Production
Pre-HSCTPost-HSCT
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Conclusions
• Allogeneic HSCT provides important and unique insights into HIV-specific immune responses
• GVH responses may have preferential activity against HIV-1 reactivated cells
• NK and NKT cells may play an important role in targeting residual HIV reservoirs following reactivation or leading to immune control off ART
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AcknowledgementsHenrich Lab(UCSF/Harvard):Emily HanhauserKristen HobbsRobert Yucha
BWH/HarvardZixin HuYvonne RoblesJonathan LiAndrea HeiseyAthe TsibrisHadi ShaiffeeDaniel Kuritzkes
Ragon Institute:Marcus AltfeldMichael SirignanoChristian KornerStephanie JostChristine Palmer
DFCI-BWH/Harvard:Francisco MartyRobert SoifferPhilippe ArmandJerome RitzAnn LaCasce
HSPS:Ed Goldberg
BSRI/UCSF:Michael BuschSheila KeatingTzong-Hae LeeMila LebadevaSteve Deeeks
BIDMC/Harvard:Kathryn StephensonDan BarouchAyad HamdanDmitri Tzanakis
Harvard University:Alison HillHelen Bae
Funding / Support:amfAR (Foundation for AIDS Research ARCHE)
NIH/NIAIDTo TJH:grants 1K23AI098480-01A1; 1 R21AI11027701A1; 1R21AI11027701A1
P30 AI060354 [to the Harvard CFAR Program in Therapeutics], U19 AI096109 [to the DARE Collaboratory]