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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;340:937938 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 Treating with a combination of HIV inducers of latently infected cells during ART reduced the viral reservoir. Cell DOI: (10.1016/j.cell.2014.07.043) Copyright © 2014 Elsevier Inc. Terms and Conditions Individuals who were treated in the chronic phase (CP) of HIV infection have greater levels of CTL 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 infection And/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 Containing at least 1 anti-HIV gene Kitchen SG et al. Stem cell-based anti-HIV gene therapy. Virology. 2011 Multiple anti-HIV gene therapy approach Selected anti-HIV genes 1. Potent HIV inhibitors at early stage of viral life cycle 2. Distinct anti-HIV mechanisms Goals 1. Inhibit multiple HIVs • CCR5 tropic HIVs • CXCR4 tropic HIVs • Multi-drug resistant HIVs 2. Prevent emergence of resistant HIV mutants CCR5-siRNA Hu-TRIMcyp C46 entry inhibitor HIV TCR Engineering Immunity 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? 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 approaches Would allow direct genetic modification of progenitor (“baby”) cells in the body Would allow prolonged self-renewal of modified cells that would have long life in the body Cells would undergo normal development and be recognized as part of the body “Genetic Vaccination” to HIV Stem cell TCR TCR TCR TCR TCR TCR TCR TCR Viral Vectors Containing Cloned TCRs T cell T cell Virus Infected cells T cell T cell T cell GMP Level Closed System Gene Transduction and Cell Processing Apheresis Final Infusion Product Cytomate Gene Transfer Product Isolex Isolex Culture 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 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 allow the immune response to clear HIV. The Journal of Pathology Volume 214, Issue 2, pages 231-241, 27 DEC 2007 DOI: 10.1002/path.2276 http://onlinelibrary.wiley.com/doi/10.1002/path.2276/full#fig1
