The objective of this proposal is to develop an effective method for providing a 'functional cure' for HIV-infected individuals. The approach is based on the observation that subjects lacking CCR5 expression can behighly resistant to HIV infection. Our hypothesis is that hematopoietic CD34+ stem and progenitor cells(HSPC) can be made resistant to HIV infection via mutation or deletion in the CCR5 gene. These cellstransplanted back to autologous donors will prevent HIV replication and effect a 'cure.' First, purified humanCD34+ stem cells or peripheral blood mononuclear cells from uninfected individuals will be converted intoinduced pluripotent stem (iPS) cells by a variety of strategies with emphasis given to non-integrating vectors.These iPS cells will then be genetically modified to either lack the CCR5 gene or have the natural mutation ofCCR5. Cells naturally lacking CCR5 expression were given to the 'Berlin patient' who has no evidence of HIVinfection after several years.The iPS-derived CCR5-mutated cells will be differentiated into CD34+ cells (i.e. iPS-derived HSPC) and thendifferentiated into hematopoietic progeny cells. These cells will be evaluated for normal cell function andresistance to HIV infection in cell culture and after transplantation into humanized mice. The same procedureswill be undertaken with CD34+ cells from HIV-infected individuals.These studies are directed at optimizing our approaches for providing iPS-HSPC to HIV-infected individuals toprevent HIV disease progression and potentially establish a 'functional cure.'

Public Health Relevance

The proposed studies are directed at developing approaches for a functional cure for HIV- infected individuals using genetically modified autologous stem cells/progenitor cells lacking CCR5 expression. We will take CD34+ cells from HIV-infected individuals, convert them into iPS cells using non-viral integrated vectors, mutate the CCR 5 gene and subsequently direct the differentiation of these cells into HIV-resistant hematopoietic cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI102825-01
Application #
8470397
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Bridges, Sandra H
Project Start
2012-06-07
Project End
2013-08-31
Budget Start
2012-06-07
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$518,244
Indirect Cost
$182,811
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143