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“ Towards an HIV Cure ” Pre -Conference Symposium 20 & 21 July 2012. SIVagm infection of rhesus macaques: a model of functional cure with persistent reservoirs of replication-competent virus. Cristian Apetrei Center for Vaccine Research , University of Pittsburgh , Pittsburgh PA, USA.

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slide1

“Towards an HIV Cure”

Pre-Conference Symposium

20 & 21 July 2012

SIVagm infection of rhesus macaques: a model of functional cure with persistent reservoirs of replication-competent virus

Cristian Apetrei

Center for Vaccine Research,

University of Pittsburgh,

Pittsburgh PA, USA

slide2

Background-Definitions (1)

  • HIV Eradication/Cure: complete eradication of HIV and infected cells from the body
  • Functional HIV cure: control of HIV infection without complete HIV eradication
  • undetectable viremia without ART
  • no disease progression
  • no CD4 T cell loss
  • lack of HIV transmission
slide3

Background (2)

  • Obstacles for an HIV cure include:
  • Rapid establishment of latently infected cells
  • Residual viral replication (hamper a proper characterization of the virus from the reservoirs)
  • Existence of anatomic reservoirs (privileged sites of latency insufficiently penetrated by drugs)
  • Obstacles for cure research:
  • Ethical (cannot stop therapy-knowing the risks of emergence of drug-resistant strains)
  • Technical: no marker for latently infected cells
  • Lack of an animal model (SIVmac/RM is difficult to control with ARVs, infection with molecular clones does not permit tracking the virus etc)

An animal model for HIV cure/functional

cure is badly needed

slide4

Background-Definitions (3)

An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process. The animal chosen will usually meet a determined taxonomic equivalency to humans, so as to react to disease or its treatment in a way that resembles human physiology as needed.

(Wikipedia)

slide5

SIVagm infection of RMs

Model of functionally-cured SIV infection

Plasma Viral Loads

Mucosal CD4+ T cells

High levels of viral replication during acute infection, followed by complete control during the chronic stage (6 years p.i.)

Massive mucosal CD4+ T cell depletion during acute infection, followed by COMPLETE mucosal CD4+ T cell restoration

slide6

Control of SIVagm in RMs is a functional cure and not an elite control

Seroreversion of anti-SIVagm binding and neutralizing antibodies.

To date, the only other case of seroreversionwas recorded in the Berlin patient

slide7

Functional cure of SIVagm infection in RMs

  • Control of SIVagm replication
  • Complete restoration of CD4+ T cells, including at mucosal sites (demonstrating that if virus replication is completely controlled, restoration is possible)
  • Control of apoptosis at mucosal sites resulting in
  • Control of microbial translocation resulting in
  • Normalization of immune activation
  • Seroreversion
  • Normalization of innate immune effectors (mDCs, pDCs, Macrophages, NKs)
  • Normal ratio of Treg/Th17
slide9

Controlof SIVagm infection does not apper to be exclusively due to intrinsic immunity to the virus

In vitro replication of SIVagm and SIVmac on AGM and RM PBMCs

slide10

Significant purifying selection is observed in SIVagm-infected RMs by deep sequencing

slide11

SIVagm infection of RMs

Single copy VL quantification of SIVagm demonstrate the complete control of viral replication in this in vivo

model of viral latency

D250 pi

D1440 pi

Animal VL (copies/ml)

RM1 19

RM2 <0.5

RM3 181

RM4 10

RM5 30

Animal VL (copies/ml)

BA38 <0.8

V492 <1

P373 <1

slide12

Is SIVagm infection cured or functionally cured?

In vivo depletion of CD8+ cells

(with the human-mouse cM-T807

monoclonal antibody)

slide13

SIVagm rebounded during CD8+ cell depletion in RMs and was controlled with the CD8+ cell restoration

slide14

Is the rebounding virus replication competent or just a reactivated virus from the reservoirs unable to complete full cycles of replication?

slide15

Caveats

  • Virus levels are very low in controllers (less than 1 in 106 CD4+ T cells may contain virus) and the volume of serial samples collected from SIVagm-infected RMs is relatively small-virus isolation from the reservoirs may prove difficult
  • SIV is very difficult to isolate from plasma, especially from chronically-infected animals - rebounding virus isolation from plasma will likely fail
  • Reservoir activation protocols involve SIV passage on human T cell lines, which may alter the phenotype of the virus through truncations in the transmembrane envelope glycoprotein (gp41) or nonsense mutations in accessory genes
slide16

Rebounding virus after CD8+ cell depletion is replication competent

Pooled plasmas at the peak of rebound and inoculated RMs

slide17

Rebounding virus after CD8+ cell depletion is replication competent

RMs infected with the original SIVagmSab stock

RMs infected with the pooled rebounding virus

slide18

Rebounding virus after CD8+ cell depletion is clonal

A limited number of viral variants were

reactivated following CD8+ cell depletion

These variants were close to the original

Viral stock, suggesting that the reservoirs

Were seeded very early upon infection

Diversity of the

original

SIVagmSab

stock used

in RMs

Pooled plasmas at the peak of rebound and inoculated RMs

slide19

Conclusions

  • Our results further validate SIVagm-infected RMs as a model of functional cure of replication-competent retrovirus infection
  • Deciphering the mechanisms of control may identify new strategies to achieve functional cure of HIV
  • This model is well suited to assess new therapeutic strategies to deplete viral reservoirs without the complexity of multidrug antiretroviral therapy
slide20

Acknowledgements

  • Apetrei lab TNPRC

ThaidraGaufin

Rajeev Gautam

Daniel Mandell

  • Pandrea lab TNPRC

Jeanne Macfarland

Melissa Pattison

  • Apetrei/Pandrea lab CVR PITT

Jan Kristoff

Fang Jeri Zhong

Cui Ling Xu

Dongzhu Ma

ViskamVijewardana

George S. Haret-Richter

Kevin Raehtz

    • TNPRC Vet Med

Jason Dufour

Marion Ratterree

Rudolf Bohm

  • Univ. of Pittsburgh Vet Services

Anita Trichel

  • TNPRC
  • Ronald Veazey
  • Preston Marx
  • Andrew Lackner
  • Univ. of Wisconsin

David O’Connor

Shelby O’Connor

  • NIH
  • Vanessa Hirsch
  • Brandon Keele
  • Univ. of Pittsburgh
  • John Mellors

Funded by

NIH R01 RR025781 (IP, CA); RO1 AI065325 (CA) RO1 AI064066 (IP); AMFAR (CA)