Track A Report

Guido PoliVita-Salute San Raffaele University & Scientific Institute, Milano, Italy

XVIII International AIDS Conference, Vienna, 2010

Track A - Rapporteur talk

1. HIV life cycle: road map for anti-HIV drug discovery

2. New findings in LTNP & Elite Controllers: keys for vaccine development

3. The hardest target: HIV persistence in latently infected cells and reservoirs

4. Concluding remarks

Track A - Rapporteur talk

1. HIV life cycle: road map for anti-HIV drug discovery

2. New findings in LTNP & Elite Controllers: keys for vaccine development

3. The hardest target: HIV persistence in latently infected cells and reservoirs

4. Concluding remarks

The HIV Life Cycle...

Courtesy of Anthony S. Fauci, Bethesda, USA

…Road Map for Anti-HIV Drug Discovery

Courtesy of Anthony S. Fauci, Bethesda, USA

…Road Map for Anti-HIV Drug Discovery

TBR-652(D.E. Martin)

LEDGINs(F. Christ)

Track A - Rapporteur talk

1. HIV life cycle: road map for anti-HIV drug discovery

2. New findings in LTNP & Elite Controllers: keys for vaccine development

3. The hardest target: HIV persistence in latently infected cells and reservoirs

4. Concluding remarks

Natural Control of HIV Infection

Long-Term Non Progressors (LTNP)

>7-10 years of infection No therapy No symptoms Stable CD4+ T-cell

counts > 500/mm3 1-5 % of all infected

individuals

Elite & Viremic Controllers*

plasma viremia < 50 copies/ml for >1 year

No therapy *As above, but with

viremia <2,000 copies/ml <1% of all infected

individuals

Adapted from Sara Rowland-Jones, Oxford, U.K.

Protective HLA-B Alleles Limit HIV Infection of CD4+ (central) Memory Cells

TN TCMTTM TEM

% in

fect

edC

D4

T c

ells

sub

sets

Benjamin Descours, Paris, France

CD4+ T cells from Elite Controllers Resist HIV-1 Infection by Upregulation of p21

Inhibitor of Cyclin-dependent kinases

Contributes to resistance of monocyte/macrophages and hematopoietic stem cells to HIV-1 infection

Interferes with HIV-1 both pre- and post-proviral DNA integration

Mathias Lichterfeld, Boston, USA

1 2 3 4 1 2 3 4

p21

b-actin

HIV neg progressors

5 1 2 3 4

EC

5

HIV neg EC

p=0.0079

n=5n=5

0.0

0.1

0.2

0.3

0.4

rela

tive

p2

1 p

rote

in le

vel

progressorsn=4

p=0.0159

MicroRNA Expression Pattern May Discriminate HIV Exposure from Infection

miRNAs are short RNA molecules that bind to complementary sequences in the 3' UTR of target mRNAs, usually resulting in gene silencing

The human genome may encode over 1,000 miRNAs, targeting about 60% of mammalian genes

Aberrant expression of miRNAs has been implicated in numerous diseases; miRNA-based therapies are under investigation.

MicroRNA Expression Pattern May Discriminate HIV Exposure from Infection

MEU (multiply Exposed Uninfected) show a prevalent downregulation of miRNAs

LTNP show a prevalent upregulation of miRNAs

Claudio Casoli, Milano, ItalyMEU LTNPNaïve

Track A - Rapporteur talk

1. HIV life cycle: road map for anti-HIV drug discovery

2. New findings in LTNP & Elite Controllers: keys for vaccine development

3. The hardest target: HIV persistence in latently infected cells and reservoirs

4. Concluding remarks

Potential Approaches Towards “The Cure” (i.e., HIV Eradication)

Activated CD4+ T-cell

Resting CD4+ T-cell

HAART

Sharon R. Lewin, Melbourne, Australia

Reduce CCR5

Inhibit HIV replicationshRNA (tat/rev, TAR)

Gene therapy

Deciphering the Transcriptional Complex Recruited by HIV-1 Tat…

Pol-II

Tar-RNA CTD

PS-5

NTEFs

Latent provirus / stalled LTR

Pol-II

CTD

PS-5

Transactivator

CDK9

CycT1

PS-2P-TEFb

NTEFs

Drugs:TSA, Prostratin,…

Activated provirus

Monsef Benkirane, Montpellier, France

…An Important Lead to New HIV Drug Discovery

CycT1

CDK9

Core P-TEFb

ELL AF9CDC73

PAF1

CycT1

CDK9

ENL

AFF4AFF1EAF1

Active/elongating P-TEFb

Structure of the Tat associated P-TEFb complex may provide opportunities to design inhibitory peptides or reactivate latent HIV-1 and purging the reservoirs

Activating

Latency

signals

Processive elongation

Virus Production

Monsef Benkirane, Montpellier, France)

Track A - Rapporteur talk

1. HIV life cycle: road map for anti-HIV drug discovery

2. New findings in LTNP & Elite Controllers: keys for vaccine development

3. The hardest target: HIV persistence in latently infected cells and reservoirs

4. Concluding remarks

The Track A Rapporteur’s Team!

Rienk Jeeninga(The Netherlands)

Lavina Garu(India)

Patricia Monteiro(Canada)

Takafira Mduluza(Botszwana)