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 tha 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 stimulatin, thereby preventing efficient induced HIV-1 reactivation (3). 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 will 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 (i) act to control HIV transcription and (ii) and suppress T cell responsiveness. In addition to our ongoing systems analysis-based 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 directly probed. These molecular studies will be combined with the findings of Aim 1 to expand our knowledge of HIV latency control in different T cell populations. We will further address roadblock #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 predit 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.
In Aim 3, we will finally use the insights gained from our studis in Aim 1 and Aim 2, and will 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.
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 here propose to combine the use of new biomarkers that could demarcate latently HIV-1 infected reservoir T cell populations with high-throughput kinomic profiling, to reveal the complex interactions of cellular factor that control latent HIV-1 infectio in order to identify such novel drug targets.
| Robinson, Tanya O; Zhang, Mingce; Ochsenbauer, Christina et al. (2017) CD4 regulatory T cells augment HIV-1 expression of polarized M1 and M2 monocyte derived macrophages. Virology 504:79-87 |
| Schaaf, Kaitlyn; Smith, Samuel R; Duverger, Alexandra et al. (2017) Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis. Sci Rep 7:42101 |
| Seu, Lillian; Tidwell, Christopher; Timares, Laura et al. (2017) CD151 Expression Is Associated with a Hyperproliferative T Cell Phenotype. J Immunol 199:3336-3347 |
