Future directions in HIV basic science research

The hunt for a cure

Future Directions

• A new vaccine approach.• Targeting and purging the latent reservoirs.• Targeting and removing integrated virus.• Stem cell based therapies.• Targeting and controlling immune activation.

A “new” vaccine approach- Use another virus to “trick” the immune

response to SIV

• Rhesus Cytomegalovirus is a monkey herpesvirus.

• They replaced genes in Rhesus Cytomegalovirus with those of SIV.

Annual Reviews

Less restricted. Rhesus Cytomegalovirus that expresses SIV genes (strain 68-1 RhCMV) expands the CD8+ T cell response to SIV.

N Goonetilleke, and A J McMichael Science 2013;340:937-938

Published by AAAS

A new vaccine approach

• They found that vaccination with Rhesus Cytomegalovirus containing SIV allowed protection from SIV challenge in monkeys (Rhesus Macaques)

• The immune responses in these animals were not the same as the responses in animals exposed to SIV without the vaccine = better protection

Broadly Neutralizing Antibodies and Viral Inducers

• Aim: Induce the virus out of latency and kill the infected cell

Broadly Neutralizing Antibodies and Viral Inducers Decrease Rebound from HIV-1 Latent Reservoirs in Humanized Mice 

Ariel Halper-Stromberg, Ching-Lan Lu, Florian Klein, Joshua A. Horwitz, Stylianos Bournazos, Lilian Nogueira, Thomas R. Eisenreich, Cassie Liu, Anna Gazumyan, Uwe Schaefer, Rebecca C. Furze, Michael S. Seaman, Rab Prinjha, Alexander Tarakhovsky, Jeffrey V.

Ravetch, Michel C. Nussenzweig 

Cell 

DOI: 10.1016/j.cell.2014.07.043

Cell DOI: (10.1016/j.cell.2014.07.043) Copyright © 2014 Elsevier Inc. Terms and Conditions

Treating with a combination of HIV inducers of latently infected cells during ART reduced the viral reservoir.

Individuals who were treated in the chronic phase (CP) of HIV infection have greater levels ofCTL escape variants to latent virus than those in the acute phase (AP) of infection

HIV rapidly evolves around the CTL response. It will be important to enhance the CTL response to clear the virus from the body.

Targeting Integrated Virus

HIV Lifecycle

Structures of cleavage enzymes.

Schiffer J T et al. J. Virol. 2012;86:8920-8936

Targeted gene knockout by DNA-editing enzymes.

Schiffer J T et al. J. Virol. 2012;86:8920-8936

Integrated Virus Targeting

• Highly specific, efficient way of getting integrated virus out of cell.

• Problems with delivery to the cell.• Highly promising

Stem Cell Based Therapies

• Most include gene therapy to modify the hosts genetic makeup to:– Make cells that are resistant to HIV infectionAnd/or– Make cells that can target and kill HIV infected

cells.

http://www.nytimes.com/2011/11/29/health/new-hope-of-a-cure-for-hiv.html?pagewanted=all

Stem cell based Anti-HIV Gene Therapy

Kitchen SG et al. Stem cell-based anti-HIV gene therapy. Virology. 2011

Containing at least 1 anti-HIV gene

Multiple anti-HIV gene therapy approach

Selected anti-HIV genes1.Potent HIV inhibitors at early stage of viral life cycle2.Distinct anti-HIV mechanisms

Goals1.Inhibit multiple HIVs

• CCR5 tropic HIVs• CXCR4 tropic HIVs• Multi-drug resistant HIVs

2.Prevent emergence of resistant HIV mutants

CCR5-siRNAHu-TRIMcyp

C46 entry inhibitor

HIV TCR

Targeting immune responses could increase rejection of Infectious agents (chronic viruses like HIV) or tumors in certain individuals or disease states

Can this type of approach be done in humans?Can we enhance immune capabilities in humans?

Engineering ImmunityEngineering Immunity

Approaches include using stem cells or modifying peripheral (adult) cells to produce antibodies or produce T cells that target HIV infected cells, to enhance HIV immune responses.

“Engineered Immunity”

Stem cell based approachesWould allow direct genetic modification of progenitor (“baby”) cells in the bodyWould allow prolonged self-renewal of modified cells that would have long life in the bodyCells would undergo normal development and be recognized as part of the body

Virus Infected

cells

Virus Infected

cells

T cellT cell

TCR TCR

Stem cellStem cell

Viral VectorsContaining Cloned

TCRs

T cellT cell

T cellT cell

T cellT cell

T cellT cell

“Genetic Vaccination” to HIV

TCR TCR TCR TCR

TCR TCR

GMP Level Closed System Gene Transduction and Cell Processing

Isolex

Apheresis

Cytomate

Culture

Gene Transfer Product

Final Infusion Product

Isolex

Targeting Immune Activation and HIV

• HIV activates the immune response during infection

• HIV replicates in an active immune response• We can target the virus (ARV), we need to also

target the immune response to make it better able to clear HIV

• One way is to target specific molecules to lower levels of immune activation to decrease HIV levels.

HIV infection in the gut (Intestines, Colon) causes problems with the immune response

Immune activation and inflammation in HIV 1 infection: causes and consequences‐

The Journal of PathologyVolume 214, Issue 2, pages 231-241, 27 DEC 2007 DOI: 10.1002/path.2276http://onlinelibrary.wiley.com/doi/10.1002/path.2276/full#fig1

There is a lot going on in HIV infection.Like antiretroviral therapy and the HIV lifecycle, if we can target multiple events we may be able to allowthe immune response to clear HIV.