The main objective in human immunodeficiency virus (HIV) therapy is the identification, targeting and elimination of viral reservoirs. While significant progress has been made in the field, the low levels of viral RNA detected in patients under antiretroviral therapy as well as the rebound of viral replication after cessation of such therapy suggest that there are additional HIV reservoirs present. Recent studies have suggested that hematopoietic stem/progenitor cells (HSPC) in the bone marrow can be infected by HIV and harbor latent virus. The goal of the proposed studies is to fully characterize HIV infection in the bone marrow in vivo and to assess the ways to target HIV infected progenitors. As stem cell based gene therapy is considered a potentially new avenue to eradicate HIV, it is essential to fully understand how this new reservoir impacts engraftment of and reconstitution by new stem cells. To address this question we aim to (i) fully characterize HIV infection in HSPC using both humanized mice and human tissues (fetal liver, cord blood) ex vivo, (ii) examine the effect HIV infection has on the bone marrow microenvironment and its ability to support proper lineage development in vivo, and (iii) evaluate gene therapy approaches to impact the viral reservoir, including the development of ways to protect genetically modified antiviral effector cells.

Public Health Relevance

Hematopoietic progenitor stem cells (HSPC) have been shown to be susceptible to HIV infection and become latently infected. HSPC give rise to multiple hematopoietic lineages and are a potential candidate for gene therapy protocols against HIV. In this proposal, the goals are to characterize the HIV infection in HSPC, assess the impact of infection on immune reconstitution and evaluate aproaches to impact this reservoir.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI103385-02
Application #
8514512
Study Section
Special Emphasis Panel (ZAI1-RB-A (J1))
Program Officer
Bridges, Sandra H
Project Start
2012-07-23
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$434,280
Indirect Cost
$152,280
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zhen, Anjie; Krutzik, Stephan R; Levin, Bernard R et al. (2014) CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection. J Virol 88:9934-46
Nixon, Christopher C; Vatakis, Dimitrios N; Reichelderfer, Scott N et al. (2013) HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice. Blood 122:2195-204