New concepts in HIV: HIV immunopathogenesis, treatment and vaccine strategies - report back

from pre-conference

Nicolas Chomont

VGTI-Florida

Christine Katlama: The HAART reality

HAART is not perfect!• Long term Toxicity• CD4/VL monitoring• Resistance• Cost

New objectives for HIV therapy• Increased survival, stop progression, stop transmission• Decrease drug burden (number of ARV) to decrease

toxicity and cost• Stop HAART (at least transitorily)• Functional cure / Eradication

How can we measure the efficacy of interventions aimed at reducing the viral reservoirs?

Doug Richman: Measuring HIV persistence

Sensitivity and precision of current assays?

S. Lewin and C. Rouzioux, AIDS 2011

Optimal suppression of viral replication

Mechanisms of HIV persistence

Residual viremia in treated subjects:- Ongoing viral replication?- Viral production by long lived cells?

Viral replication

Viral productionHAART

Viral production: Identifying the source

Large variety of candidates:

- CD4 T cells- Macrophages (Mario Stevenson)- Hematopoietic stem cells (C. Carter and K. Collins)- CNS- Others

• We need to explore tissues (cell sorting and RNA/DNA quantification)

• Can we match the sequence of the virus in plasma with the sequence in other compartments?

• Intensification with drugs that penetrate tissues?

Doug Richman: Mechanisms of HIV persistence

Evidences for the absence of ongoing viral replication• Little or no impact of treatment intensification• No evolution (resistance to ARV)

BUT

• Buzon et al (Nat Med 2010) observed increased levels of 2-LTR circles upon Raltegravir intensification and reduced levels of activation

• Yukl et al (AIDS 2010) observed an impact of HAART intensification in the ileum (unspliced HIV RNA)

C. Katlama: Optimal suppression of viral replication

• Nevirapine is associated with a higher rate of VL<1 copy/mL when compared with EFV or LPV (Bonora, J Med Virol 2009)

• 40 virally suppressed patients with VL<1 copy/mL

Some of them still show high levels of immune activation (n=17) which are associated with:

• A low Nadir CD4• A low CD4/CD8 ratio (ongoing replication somewhere, bacterial

translocation?)

Is residual viremia a good marker to monitor HIV persistence?

Acute Chronic LTNP controllers Visconti

HIV DNA in PBMCs

S. Lewin and C. Rouzioux, AIDS 2011

The VISCONTI patients

Five out of 32 patients who received very early and prolonged antiretroviral therapy showed sustained immunovirological control for more than 6 years of treatment discontinuation.

2 conditions:• Treat early (median 2.3 weeks)• Treat for long (median 5 years)

Circ

ulat

ing

viru

s

HAART

Circ

ulat

ing

viru

s

Time

HAART

T cell survival

Proliferation

Viral replication

Rafick Sekaly: Mechanisms of HIV persistence

CD4 TCM cell survival

Suberoylanilide hydroxamic acid

Histone deacetylase inhibitors

SAHA

Targeting the latent reservoir

D. Margolis, D. Hazuda, C. VanLint, A. Savarino

PD-1 expression correlates with the reservoir size

0 10 20 301

10

100

1000

10000

% PD-1+ T cells

Inte

gra

ted

HIV

DN

A c

op

ies

per

106

CD

4+ T

cel

ls

p=0,01

Targeting the cells: A role for PD-1 in HIV latency

CD3/CD28 + IgG2CD3/CD28 + PD-L1

NS

0 3 6 91

10

100

1000

10000

100000

1000000

p2

4 (

pg

/ml)

Time (d)

The negative signal conferred by the PD-1/PD-L1 interaction inhibits viral production in primary CD4+T cells from viremic donors

CD4 T cell homeostaticproliferation

IL-15

IL-7

IL-7: Necessary for homeostatic renewal

IL-15: Prompts cell maturation and viral replication

Targeting the proliferative reservoir

Correlates of control

• T cells predict control (but not protection, Gary Nabel)

• The magnitude and function of CD8 T cells are associated with control of the viral reservoir (Brigitte Autran).

• NK cells (and their KIR receptors) are associated with viral control (Marcus Altfeld)

Boosting immune responses: Vaccines

Interventions for HIV Cure

Reduce residual replication/production: Optimize HAART (J. Martinez Picado, Stefano Vella)• Intensification• Drug penetrationReduce immune activation (Steve Deeks)• Anti-inflammatory drugs• Reduce gut damage and /or microbial translocation• Anti CMV drugsTarget latent reservoirs• IL-7 (Eramune) or anti IL-7• HDAC• Anti PD-1• Gene Therapy (Jan Van Lunzen)Immune control of reservoirs (Brigitte Autran)• IL-7• HIV-specific IgG2 are associated with control in LTNP• NK cells

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