Overcoming HIV-1 transcriptional latency in unresponsive CD4 T cells

University Of Alabama At Birmingham, Birmingham AL

Investigators

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Abstract

? DESCRIPTION (provided by applicant): 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.