There has been a lot of optimism about potentially eradicating HIV-1 using strategies such as reactivation of latently infected cells by small molecules. A recent study has suggested that this approach may in fact be possible;a single dose of the molecule vorinostat was shown to induce HIV expression in CD4+ T cells in vivo. While this strategy may end up being effective, it may be very challenging to reactivate every last latently infected CD4+ T cell. A complementary strategy may be to physically eliminate latently infected cells using antibodies conjugated to toxins. This may be analogous to surgically "debulking" a tumor prior to initiating chemotherapy. However, targeting latently infected CD4+ T cells has been a challenging task because the phenotype of these cells remains largely unknown. In this new proposal, we plan to use antibodies to more than 200 different T cell markers in order to determine the phenotype of latently infected CD4+ T cells. Such an approach has been successfully used to determine the phenotype of activated T cells in a recent study. This will be analogous to screening for small molecules that activate latently infected CD4+ T cells, but in this case, a library of monoclonal antibodies (Mabs) rather than compounds will be used and the readout will be binding of Mabs to infected resting CD4+ T cells or recently reactivated latently infected CD4+ T cells rather than reactivation itself. We plan to validate our results by sorting resting CD4+ T cells from HIV-1 infected patients on suppressive HAART regimens. We specifically will sort for markers that are identified in our screen to determine whether there is an overrepresentation of HIV-1 DNA and latent replication-competent virus in these cells. This work will have major implications for strategies for HIV-1 eradication since it will potentially lead to the clearance of latently infectd cells.

Public Health Relevance

Latently infected CD4+ T cells represent a major barrier to the eradication of HIV infection with HAART. This project plans to determine whether certain surface markers are frequently found on latently infected CD4+ T cells;the results may be have implications for the eradication of HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI106491-01A1
Application #
8610757
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Stansell, Elizabeth H
Project Start
2013-08-05
Project End
2015-07-31
Budget Start
2013-08-05
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$228,420
Indirect Cost
$87,420
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218