Latent HIV-1 infection has been recognized as a major obstacle to the development of a curative HIV-1 therapy, but host cell-virus interactions that control latent infection are still ill defined. Key to this application is the realization that the host cells of latent HIV-1 infection events are actually phenotypically altered in a manner that (i) forces the virus into a latent state and that (ii) renders the host cells unresponsive to stimulation, thereby preventing efficient therapeutic induction of HIV-1 reactivation. These changes go beyond a simple quiescent state that is characteristic for functional memory T cells. This proposal will extend on these findings and seek to address three major roadblocks in the field of HIV latency research. Roadblock #1 (Aim 1) concerns our inability to identify biomarkers that specifically define T cell sub-populations in which latently infected T cells are highly enriched. Such biomarkers would allow us to detail the molecular biology of the host cell state that enables and maintains latent HIV-1 infection. Leading to this application, we found that the intracellular changes allowing latent HIV-1 infected to persist are associated with a unique CD4+CD28? CD9+CD151+ phenotype, a T cell phenotype that also demarcates a small CD4 T cell sub-population that is increased in HIV patients on ART. We already demonstrate that CD151 expression by itself is associated with reservoir capacity. We will now detail the viral reservoir capacity of T cell sub-populations described by CD28, CD151 and CD9 expression. Roadblock #2 (Aim 2) addressed in this application is the question how the intracellular changes observed in host cells of latent HIV infection events act (i) to control HIV transcription and and (ii) to suppress T cell responsiveness. In addition to the proposed research on host-cell factors/networks controlling latent HIV infection, we already have identified several targets/interaction networks that control latent infection and that will be immediately probed. We will further address roadblock #3 (Aim 3), the question why stimulation of ex vivo T cell material from HIV patients seems to only trigger HIV-1 reactivation in a small fraction of the latently HIV-infected cells. Based on our results, we predict that T cell subpopulations described by differential CD28, CD9 and CD151 expression patterns, will exhibit varying levels of unresponsiveness to stimulation, allowing latent HIV infection to persist with different efficacies. Based on the results we have obtained leading to this application and the additional results we will generate, we will immediately begin to rationally design compound-based intervention strategies that would (i) first reconstitute T cell responsiveness in reservoir populations and then (ii) trigger efficient HIV reactivation, a prerequisite for any HIV-1 eradication strategy and the ultimate goal of this application.

Public Health Relevance

Latent HIV-1 infection represents the principal obstacle to a curative AIDS therapy. Previous attempts to therapeutically eradicate these latent HIV-1 reservoirs have failed, creating a need to identify novel HIV-1 reactivating therapeutic strategies to eliminate this reservoir. We propose to combine the use of new biomarkers that could define latently HIV-1 infected reservoir T cell populations with an integrative systems biology approach that generates data describing the complex interactions of cellular factors that control latent HIV-1 infection with the goal to identify novel HIV-1 reactivating drug targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI122842-03
Application #
9737796
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcdonald, David Joseph
Project Start
2017-08-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Seu, Lillian; Tidwell, Christopher; Timares, Laura et al. (2017) CD151 Expression Is Associated with a Hyperproliferative T Cell Phenotype. J Immunol 199:3336-3347