infecção pelo hiv: remissão sustentada sem antirretrovirais.€¦ · g. laird et al. j clin...
TRANSCRIPT
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Infecção pelo HIV: Remissão Sustentada sem Antirretrovirais.
Ricardo Sobhie DiazProfessor Associado e Livre Docente
Chefe do Laboratório de Retrovirologia
Disciplina de Infectologia
Escola Paulista de Medicina
Universidade Federal de São Paulo
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Persistência viral
Produção de proteínas virais
Micro inflamação
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Persistência viral
Produção de proteínas virais
Micro inflamação
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Persistência viral
Produção de proteínas virais
Micro inflamação
Remissão sustentada do HIV sem
antirretrovirais
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Car
gavi
ral
Tempo
A saída da latência proporciona o retorno da viremia(jogando o dado)
TARV
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Total HIV DNA predicts time to viral rebound after Treatment interruption; The SPARTAC study
Williams et al eLife
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8
P r é T r a t a m e n t o P ó s T r a t a m e n t o
0
5 0 0
1 0 0 0
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To
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DN
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p < 0 .0 0 0 1
P ré T ra ta m e n to P ó s T ra ta m e n to
0
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To
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DN
A
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10
6 c
ell
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Painel 1: Quantificação do DNA total associado a célula nos grupos pré e pós tratamento.
DNA TOTAL ASSOCIADO A CÉLULA ENTRE
40 PACIENTES COM CV INDETECTÁVEL APÓS
4 ANOS DE TRATAMENTO
Giron, tese de doutorado, UNIFESP, orientador RSD
O reservatório viral pode decair ao longo do tempo!
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HIV Reservoir, decay?
Longitudinal measurements of the reservoir size indicate that this reservoir is extremely stable (half-life = 39-44 months in subjects who have initiated HAART during chronic infection).
Time to eliminate:105 cells: 54.8 years106 cells: 65.7 years107 cells: 76.7 years
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Qual o nosso objetivo então?
Longitudinal measurements of the reservoir size indicate that this reservoir is extremely stable (half-life = 39-44 months in subjects who have initiated HAART during chronic infection).
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Eliminação completa do HIV “competente” deixará os vírus defeituosos (defectivos)
Longitudinal measurements of the reservoir size indicate that this reservoir is extremely stable (half-life = 39-44 months in subjects who have initiated HAART during chronic infection).
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Vírus competente
Vírus defectivo
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Existe um vírus que não sai da célula com o tratamento ARV: são os vírus
defeituosos ...
... e depois de longo tempo de tratamento, o que sobra são vírus
defeituosos
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Existe um vírus que não sai da célula com o tratamento ARV: são os vírus
defeituosos ...
... e depois de longo tempo de tratamento, o que sobra são vírus
defeituosos
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Depois de longo tempo de tratamento, o que sobra são vírus
defeituosos ...
... Uma lástima que estes vírus defeituosos ainda sejam patogênicos.
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42/48 (88%) full length intact genomes
6/7 proviruses were defective with lethal mutations
Imamichi et al, Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8783-8
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Como funciona a inflamação e o tratamento?
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Ativação imune e infecção pelo HIV
Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.
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Como funciona a inflamação e o tratamento?
• O tratamento diminui a inflamação específica para o HIV (mas não normaliza)
• Este efeito é cumulativo?
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The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: a
randomised, placebo-controlled, double-blind trial.
• Randomised placebo-controlled study from adding dolutegravir
in 40 participants who had been suppressed on standard ART
for more than three years.
Rasmussen TA et al. Lancet HIV 2018
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Rasmussen TA et al. Lancet HIV 2018
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Rasmussen TA et al. Lancet HIV 2018
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Rasmussen TA et al. Lancet HIV 2018
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Como funciona a inflamação e o tratamento?
• O tratamento diminui a inflamação específica para o HIV (mas não normaliza)
• Este efeito é cumulativo? Parece que não!
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Persistência viral
Produção de proteínas virais
Micro inflamação
Medicamentos anti-inflamatórios
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We hypothesize that thalidomide, a potent anti TNF agent, would lead to a decrease in HIV related
micro-inflammation.
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Talidomida
• Study design: Open label controlled randomized pilot proof of concept clinical trial.
• Methods:
– 30 HIV+ ART naïve male adults with TCD4 ≥ 350 cell/mm³
– 100 mg of thalidomide BID for 3 weeks (Group-1, 16 patients) or not (Group-2, 14 patients) - 48 week.
– viral loads, CD4+CD8+ T-cell counts, ultra-sensitivity C-reactive protein (US-CRP), CD38 and/or HLADR on CD4+ and CD8+ T-cells LPS.
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Vergara et al, Ebiomedicine, 2017
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Vergara et al,
Ebiomedicine, 2017
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Vergara et al,
Ebiomedicine, 2017
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Vergara et al, Ebiomedicine, 2017
Vis 0 Vis 1 Vis 2 Vis 3 Vis 7 Vis 11 Vis 15 Vis 23
CD4_CD38_HLADR 0,67 1,01 0,71 1,17 0 0,35 0,14 0,56
CD8_CD38_HLADR 3,29 5,22 6,43 11,32 2,25 2,39 1,83 7,13
0
2
4
6
8
10
12Ativação paciente controlador de elite
Talidomida
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Talidomida transitoriamente diminuiu o CD4 e aumentou a inflamação
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Persistência viral
Produção de proteínas virais
Micro inflamação
Remissão sustentada do HIV sem antirretrovirais
Por que isto seria possível?
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Cura da infecção pelo HIV é tecnicamente possível, posto que o HIV não infecta células permanentes do hospedeiro.
• Linfócito T CD4+ de memória
• Linfócito T CD4+ naïve
• Macrófagos, monócitos, astrócitos e microglia.*
• Não infecta células permanentes (ex SNC, não infecta neurônios ou oligodendrócitos*).
*Hsiao-Nan et al,.1999, Brain Research, 823, 1-2, 27:24-32
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Persistência viral
Produção de proteínas virais
Micro inflamação
Remissão sustentada do HIV sem antirretrovirais
É então possível?
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CLARO!É “SÓ” FAZER UM TRANSPLANTE DE MEDULA...
(PACIENTE DE BERLIM, PACIENTE DE LONDRES E TALVEZ UM TERCEIRO)
É então possível a cura da infecção pelo HIV?
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O Paciente de Londres (2ª cura por TMO)
• 2003: HIV diagnosticado
• 2013: Linfoma de Hodgkin Ivb
• 2013: Atripla -> TDF/FTC + RAL -> ABV
• Falha a múltiplas QTs
• 2016: Transplante com Doador homozigoto CCR5 delta-32
• Lomustine, Ciclofosfamida, Citarabina, Ectoposídio
• Colite -> biopsia com GVHD
• Reativação de EBV e CMV -> Ganciclovir + rituximab
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Timeline of Allo-HSCT and Viral Load Measures
▪ Patient has experienced 18-mos HIV “remission” without ART following allo-HSCT
‒ Adaptive immune responses declining or absent after transplant
Slide credit: clinicaloptions.com
TDF +FTC +RAL10,000
1000
100
10VL
(co
pie
s/m
L p
lasm
a)
< 1.3
-215 -141 -27 +290
+77 +150 +424 +510
Time Post HSCT (Days)+1028
CD
4+ C
ou
nt (ce
lls/mm
3)0
200
400
600RPV + 3TC + DTG
< 0.9 < 0.8 < 0.8
Ultrasensitive VL, value shows copies/mL
Allo-HSCT May 2016
Stop ART Sep
2017
PET CT: HL remission Dec 2017
18 mos off ART
Feb 2019
Gupta. Nature. 2019;[Epub]. Gupta. CROI 2019. Abstr 29LB.
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Compação entre os 2 casos de cura (2106 e 2019)
“Paciente de Londres”
▪ Homozigoto WT CCR5
▪ HIV R5
▪ Linfoma de Hodgkin
▪ Sem irradiação corporal
▪ Depleção de céls. T com aCD52
▪ GVHD leve
▪ 100% quimerismo
“Paciente de Berlin”
▪ Heterozigoto CCR5Δ32
▪ HIV R5 com 2.9% X4
▪ Leucemia Mieloide aguda
▪ irradiação corporal total
▪ Depleção de céls. T com ATG
▪ GVHD leve
▪ 100% quimerismo
Gupta. Nature. 2019;[Epub]. Gupta. CROI 2019. Abstr 29LB.
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CLARO!É “SÓ” FAZER UM TRANSPLANTE DE MEDULA...
(MAS E OS PACIENTES DA HOLANDA?)
É possível a cura da infecção pelo HIV?
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Os pacientes da Holanda
• Oito pacientes HIV+ com transplante de medula por neoplasias hematológicas
• Sete à óbito antes da avaliação sobre cura.
• Um avaliado plenamente, mas foi à óbito após a avaliação (Paciente de Essen)
IAC, Holanda 2018
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• Essen patient: diagnosed with anaplastic large-cell lymphoma and transplanted with
CCR5Δ32 donor cells3
• 27 year old HIV-1 infected patient transplanted in 2012• Successful engraftment• Treatment interruption 7 days before transplantation
Background:
Nijhuis M et al, IAC 2018
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Case description: Essen patient
Kordelas, NEJM, 2014
• ART was stopped 7 days before SCT and resumed 3 weeks after SCT• Patient died a year later due to relapse of the T cell lymphoma (ART stopped)• Longitudinal deep sequence analyses of viral envelope to get insight the viral rebound
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-287d/RNA/V03-103d/DNA/V02
-103d/DNA/V11-103d/RNA/V03-103d/RNA/V04-103d/RNA/V01-103d/RNA/V05-103d/RNA/V02
-18d/DNA/V05-103d/DNA/V04
-103d/DNA/V10-287d/RNA/V01-103d/DNA/V01
-103d/DNA/V08-18d/DNA/V06
-18d/DNA/V04-18d/DNA/V02
-18d/DNA/V03-287d/RNA/V02-18d/DNA/V01
-103d/DNA/V03-103d/DNA/V09
-18d/DNA/V07-103d/DNA/V07
-103d/DNA/V06-287d/RNA/V04
+373d/RNA/V06+20d/RNA/V01+373d/RNA/V02-103d/DNA/V05+373d/DNA/V01
+373d/RNA/V03+373d/RNA/V08+20d/RNA/V02+373d/RNA/V01+373d/RNA/V05+373d/DNA/V02+373d/DNA/V03+373d/RNA/V04+373d/RNA/V07
0.01
Verheyen et al. , CID, 2018
Case description: Essen patient
• clearly two distinct viral populations
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-287d/RNA/V03-103d/DNA/V02
-103d/DNA/V11-103d/RNA/V03-103d/RNA/V04-103d/RNA/V01-103d/RNA/V05-103d/RNA/V02
-18d/DNA/V05-103d/DNA/V04
-103d/DNA/V10-287d/RNA/V01-103d/DNA/V01
-103d/DNA/V08-18d/DNA/V06
-18d/DNA/V04-18d/DNA/V02
-18d/DNA/V03-287d/RNA/V02-18d/DNA/V01
-103d/DNA/V03-103d/DNA/V09
-18d/DNA/V07-103d/DNA/V07
-103d/DNA/V06-287d/RNA/V04
+373d/RNA/V06+20d/RNA/V01+373d/RNA/V02-103d/DNA/V05+373d/DNA/V01
+373d/RNA/V03+373d/RNA/V08+20d/RNA/V02+373d/RNA/V01+373d/RNA/V05+373d/DNA/V02+373d/DNA/V03+373d/RNA/V04+373d/RNA/V07
0.01
Verheyen et al. , CID, 2018
Case description: Essen patient
• clearly two distinct viral populations• 100% of the viral sequences detected after SCT were predicted to be X4-tropic
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-287d/RNA/V03-103d/DNA/V02
-103d/DNA/V11-103d/RNA/V03-103d/RNA/V04-103d/RNA/V01-103d/RNA/V05-103d/RNA/V02
-18d/DNA/V05-103d/DNA/V04
-103d/DNA/V10-287d/RNA/V01-103d/DNA/V01
-103d/DNA/V08-18d/DNA/V06
-18d/DNA/V04-18d/DNA/V02
-18d/DNA/V03-287d/RNA/V02-18d/DNA/V01
-103d/DNA/V03-103d/DNA/V09
-18d/DNA/V07-103d/DNA/V07
-103d/DNA/V06-287d/RNA/V04
+373d/RNA/V06+20d/RNA/V01+373d/RNA/V02-103d/DNA/V05+373d/DNA/V01
+373d/RNA/V03+373d/RNA/V08+20d/RNA/V02+373d/RNA/V01+373d/RNA/V05+373d/DNA/V02+373d/DNA/V03+373d/RNA/V04+373d/RNA/V07
0.01
Verheyen et al. , CID, 2018
Case description: Essen patient
• clearly two distinct viral populations• 100% of the viral sequences detected after SCT were predicted to be X4-tropic• dominant X4-tropic viral sequence observed after SCT
-present prior to SCT-present prior to treatment interuption
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Como eliminar os vírus competentes + os vírus defeituosos?
1. Eliminando as células infectadas
1. Quimioterápicos – luz da oncologia e reumatologia.
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Disrupting latency in vitro
G. Laird et al. J Clin Invest 2015; S. Reuse et al. Plos One 2009
Combinations of anti-latency drugs induce robust levels of HIV production in latently infected cells
Single “latency reversing agent”
N. Chomont, IAS 2015
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Repensando mecanismos: talidomida transitoriamente diminuiu o CD4 e
aumentou a inflamação
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Vergara et al,
Ebiomedicine, 2017
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Mecanismo da Latência
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HDAC classification
• Class I, which includes HDAC1, -2, -3 and -8
• Class II, which includes HDAC4, -5, -6, -7, -9 and -10
• Class III, also known as the sirtuins and include SIRT1-7 -> inhibited by Nicotinamide (B3)
• Class IV, which contains only HDAC11 has features of both Class I & II.
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Purging HIV-1 from Latent Reservoirs
Nicotinamide(1 better than 2!?)
Samer et al, tese de doutorado, orientador RSD
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When 1 is better than 2
Samer et al, tese de doutorado, orientador RSD
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Samer et al, tese de doutorado, orientador RSD
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Samer et al, tese de doutorado, orientador RSD
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Como eliminar os vírus competentes + os vírus defeituosos?
1. Eliminando as células infectadas 1. Quimioterápicos – luz da oncologia e reumatologia.
2. Imunoterapia
![Page 57: Infecção pelo HIV: Remissão Sustentada sem Antirretrovirais.€¦ · G. Laird et al. J Clin Invest 2015; S. Reuse et al. Plos One 2009 Combinations of anti-latency drugs induce](https://reader036.vdocuments.mx/reader036/viewer/2022070807/5f059e347e708231d413dae2/html5/thumbnails/57.jpg)
Como eliminar os vírus competentes + os vírus defeituosos?
1. Imunoterapia
1. Vacina com DNA viral
CD4 CD8 CD4/HIV
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Sneller et al. Sci Transl Med. 2017 Dec 6;9(419).
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A importância do grupo controle
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Sneller et al. Sci Transl Med. 2017 Dec 6;9(419).
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Sneller et al. Sci Transl Med. 2017 Dec 6;9(419).
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Intervenções únicas não funcionaram (e provavelmente nunca irão).
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Como eliminar os vírus competentes + os vírus defeituosos?
1. Imunoterapia
1. Vacina com DNA viral
2. Vacina com proteínas virais
CD4 CD8 CD4/HIV
CD4 CD8 CD4/HIV
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A two-arm (proof of concept) randomised phase II trial Vorinostat plus a prime boost Vaccine
A-899-0059-12977
Presented by Professor Sarah Fidler
on behalf of the RIVER study team and investigators
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RIVER: ART ± (Vorinostat + Prime/Boost Vaccine) in Primary HIV Infection
Persons with primary HIV infection treated
with immediate triple-drug ART with INSTI until undetectable HIV-1 RNA
(N = 60)
ART + Vorinostat 400 mg PO q72h x 10 + Vaccine*(n = 30)
ART Alone(n = 30)
Wk 18
*Prime: ChAdV63.HIVconsv at randomization, boost: MVA.HIVconsv at Wk 8.
Fidler S, et al. AIDS 2018. Abstract TUAA0202LB.
Vaccination:Prime ChAdV63.HIVconsv at randomisationBoost MVA.HIVconsvweek 8 post-randomisation
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67
Total HIV DNA over time for all participants
3.84 3.14 3.03 3.06 3.04 3.04 log10, mean
Individual results plus median (for both arms combined)
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68
Total HIV DNA over time, by arm
ART only ART +V+V
Primary endpoint: Difference (ART+V+V minus ART only) in mean log10 HIV DNA copies/million CD4+T cells averaged across PR weeks 16 and 18: 0.04 (95% CI: -0.03 to 0.11); p=0.26
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69
ART only ART +V+V
p = 0.402
Viral outgrowth assay: a measure of replication competence Professor Andrew Lever (Cambridge)
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• The interventions used in this trial did no harm
• No significant difference in measures of HIV DNA at weeks 16 & 18 post randomisation between arms.
• Outstanding commitment from participants
• No loss to follow-up
• 97% adherence to intervention.
• Vorinostat significantly increased histone deacetylation.
• ART + V + V significantly stimulated HIV-specific CD4 and CD8 T-cell responses compared with controls.
• Study highlights importance of a control arm. The result is definitive, but disappointing
Summary of findings
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Nosso estudo: 100% nosso.
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Decreasing HIV-1 replication
Treatment intensification
Eliminating latency
Stimulating HIV replication using HDAC inhibitor (purging)
Targeting reservoirs in sanctuaries
Turning long-lived central memory (TCM) into transitional memory (TTM) CD4+ T-cells
Maraviroc and/or Dolutegravir
Nicotinamide Gold Salt auranofin
Dendritic cell vaccine
Multi interventional study exploring HIV-1 residual replication: a step towards HIV-1 eradication and sterilizing cure (Diaz PI)
Novo! 1a vez que intensificação é feita com 2 ARVs
Novo! 1a vez que vacina de células dendríticas é usada com (e não ao invés de) ARV. Metodologia única e patente sendo preparada
Novo! 1a vez quenicotinamida é usada com HDACi
Novo! 1a vez queauranofina é usada emhumanas em estudo de cura do HIV
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Decreasing HIV-1 replication
Treatment intensification
Eliminating latency
Stimulating HIV replication using HDAC inhibitor (purging)
Targeting reservoirs in sanctuaries
Turning long-lived central memory (TCM) into transitional memory (TTM) CD4+ T-cells
Maraviroc and/or Dolutegravir
Nicotinamide Gold Salt auranofin
Dendritic cell vaccine
Multi interventional study exploring HIV-1 residual replication: a step towards HIV-1 eradication and sterilizing cure (Diaz PI)
Novo! 1a vez que intensificação é feita com 2 ARVs
Novo! 1a vez que vacina de células dendríticas é usada com (e não ao invés de) ARV. Metodologia única e patente sendo preparada
Novo! 1a vez quenicotinamida é usada com HDACi
Novo! 1a vez queauranofina é usada emhumanas em estudo de cura do HIV
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Persistência viral
Produção de proteínas virais
Micro inflamação
Levar as células infectadas à morte e
extinção
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Auranofin and nicotinamide (NA) decrease viral DNA in intensified ART-treated individuals
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P26 P29
0
50
100
150
200
Overall impact of the treatment on Group 6:P = 0.0425 (Two-way ANOVA)
Study subject
HIV
DN
A c
op
ies/1
0^
6 c
ells
Control
Treated
* One of the duplicates
was undetectable
*
PBMC
RB
PBMC
RB
95% detection limit
*
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Ativação imune e infecção pelo HIV
Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.
Efeito não cumulativo
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Mean % of CD4+ T cells CD38+, and CD8+ T cells and CD38+ among individuals of Group 6
Diaz RS, Shytaj IL, Giron LB, Obermaier B, della Libera EJ, Galinskas J, Dias D, Hunter J, Janini M, Gosuen G, Abrão Ferreira P, Sucupira MC, Maricato J, Fackler O, Lusic M, Savarino A. Potential impact of the antirheumatic agent auranofin on the HIV reservoir in individuals under intensified antiretroviral therapy: results from a randomized clinical trial. Int J AntimicrobAgents, 2019 in press
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Como eliminar os vírus competentes + os vírus defeituosos?
1. Imunoterapia
1. Vacina com DNA viral
2. Vacina com proteínas virais
3. Vacina de células dendríticas
CD4 CD8 CD4/HIV
CD4 CD8 CD4/HIV
CD4 CD8 CD4/HIV
![Page 80: Infecção pelo HIV: Remissão Sustentada sem Antirretrovirais.€¦ · G. Laird et al. J Clin Invest 2015; S. Reuse et al. Plos One 2009 Combinations of anti-latency drugs induce](https://reader036.vdocuments.mx/reader036/viewer/2022070807/5f059e347e708231d413dae2/html5/thumbnails/80.jpg)
Figure 11, Panel A Figure 11, Panel B
Figure 11, Panel C Figure 11, Panel D
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(A viremia típica na interrupção do tratamento: modelo da Interrupção analítica dos ARV no
paciente de Boston)
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Patient (2.6 years post-HSCT)
Sample Input Assay Result / Detection Limit
PBMC DNA 50 x 106 cells qPCR for
LTR/gag
Not Detected
< 0.04 copies/106 cells
Peripheral
CD4+ T Cells
150 x 106 cells Co-culture Not Detected
< 0.01 IU/106 cells
Rectal Biopsies DNA from
1.3 x 106 cells
qPCR for
LTR/gag
Not Detected
< 2 copies/106 cells
≥3.5 – 4 log10 reduction of PBMC DNA after alloHSCT
PBMC DNA CD4+ T Cell Count
Henrich et al 7th IAS Conference, Kuala Lumpur 2013
DRK/3.14.14/NIAID
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ATI
DRK/3.14.14/NIAID
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ATI
DRK/3.14.14/NIAID
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CSF VL 269 copies/ml
ATI
HIV-1 DNA Copies/106
PBMC1100 318
DRK/3.14.14/NIAID
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ATI no SPARC7
Grupo Descrição ATI Carga viral
1 controle 3 semanas 145.057
5 Intensificação e vacina de DC 3 semanas e 5 semanas
1.390
5 Intensificação e vacina de DC 3 semanas e 5 semanas
2.068
5 Intensificação e vacina de DC 3 semanas e 5 semanas
2.924
5 Intensificação e vacina de DC 3 semanas 288
6 Intensificação, HDACi, auranofin e vacina de DC
3 semanas e 5 semanas
100
6 Intensificação, HDACi, auranofin e vacina de DC
3 semanas e 5 semanas
<40
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Dinâmica da CV após Interrupção analítica dos ARV
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• Lab Retrovirologia,
EPM/UNIFESP
– Leila B Giron
– James Hunter
– Juliana Galinskas
– Danilo Dias
– Sadia Samer
– M Shoaib Arif Maria
– Dalila Suterio
– Nicoly Cruz
– Juliana Maricato
– M Cecilia Sucupira
– Luiz Mario Janini
– Marcella Vassão
– Michele Camargo
• Lab Imunologia Disc Infect,
EPM/UNIFESP
– Reinaldo Salomão
– Milena K C Brunialti
• CCDI/EPM-UNIFESP
– Paulo R Abrão Ferreira
– Gisele Gosuen
– Simone Tenore
– Enf. Marli F OliveiraCampos
• Laboratório LIM 56, FMED – USP– Alberto S Duarte
– Telma Youshiro
– Laís Teodoro
• Gastroenterologia, EPM/UNIFESP
– Ermelindo Dela Libera
• Dep Microbiologia, Imunoloiga,
Parasitologia, EPM/UNIFESP
– Luis Travassos
• Dep De Farmacologia, EPM/UNIFESP
– Maria Juliano
• Imunologia, FMED, USP
– Edécio Cunha Neto
• Italian Institute of Health, Rome, Italy.
– Andrea Savarino
– Luca Shytaj
Participantes do SPARC 07.