Quiescent memory CD4 T cells harboring integrated, actively repressed HIV proviruses currently form a formidable barrier to viral eradication. This latent reservoir could be attacked by activating proviral gene expression thereby sensitizing the virus to antiretroviral therapy . For success, this strategy must both prevent viral spread and result in the death of all latently infected cells without producing a toxic state of generalized cellular activation. Currently, no effective therapies for HIV latency exist. We hypothesize that a more complete understanding ofthe molecular underpinnings of HIV latency?notably, the full range of the host's regulatory factors that promote and antagonize latency?will facilitate the development of effective therapies.
In Aim 1, we will examine five novel candidate HIV repressors identified by genome wide siRNA screening of HIV-infected HeLa cells. These candidates have biological properties consistent with a role in latency and are expressed in lymphoid tissues. Expression of these candidate genes will be analyzed in biologically relevant cells and their function assessed by lentiviral shRNA knockdown.
In Aim 2, we will screen a CD4 T-cell model of HIV latency for microRNAs (miRs) that promote viral latency by impairing the expression of cellular activators. We will validate mlR action using antagomirs in latently infected primary CD4 T-cells.
In Aim 3, we will use bioinformatics and transcriptional profiling approaches to identify the host gene products that are suppressed by these miRs. Using this dual experimental approach, we will identify cellular factors that naturally promote and antagonize HIV latency. Where appropriate, mechanism-of-action studies will be performed. Identified targets will be prioritized, based on the robustness of their activity and overall """"""""drugability,"""""""" for entry into small-molecule high-throughput screening assays and primary and secondary screening assays will be developed. These proposed studies could identify small molecules that either inhibit the most interesfing cellular repressors or activate the most compelling mlRNAregulated HIV activators. These studies fully support the goal of the Collaboratoryto identify combinafions of nontoxic small molecules that can eradicate the virus or produce a funcfional cure (drug-free remission).
These studies promise to deepen our understanding ofthe cellular factors that both promote and antagonize HIV latency and ultimately to provide new approaches for purging HIV from the latent reservoir. Ultimately, we seek to translate these basic insights into HIV latency into combinations of small molecule inducers that effectively purge the latent reservoir. Success in these studies could radically change the landscape of clinical care for HIV-infected patients throughout the world.
|White, Cory H; Beliakova-Bethell, Nadejda; Lada, Steven M et al. (2018) Transcriptional Modulation of Human Endogenous Retroviruses in Primary CD4+ T Cells Following Vorinostat Treatment. Front Immunol 9:603|
|Chaillon, Antoine; Gianella, Sara; Lada, Steven M et al. (2018) Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc. J Virol 92:|
|Jiang, Guochun; Nguyen, Don; Archin, Nancie M et al. (2018) HIV latency is reversed by ACSS2-driven histone crotonylation. J Clin Invest 128:1190-1198|
|Dubé, Karine; Dee, Lynda; Evans, David et al. (2018) Perceptions of Equipoise, Risk-Benefit Ratios, and ""Otherwise Healthy Volunteers"" in the Context of Early-Phase HIV Cure Research in the United States: A Qualitative Inquiry. J Empir Res Hum Res Ethics 13:3-17|
|Prakash, Katya; Gianella, Sara; Dubé, Karine et al. (2018) Willingness to participate in HIV research at the end of life (EOL). PLoS One 13:e0199670|
|Papasavvas, Emmanouil; Lada, Steven M; Joseph, Jocelin et al. (2018) Analytical ART interruption does not irreversibly change pre-interruption levels of cellular HIV. AIDS :|
|Honeycutt, Jenna B; Liao, Baolin; Nixon, Christopher C et al. (2018) T cells establish and maintain CNS viral infection in HIV-infected humanized mice. J Clin Invest 128:2862-2876|
|Power, Jennifer; Westle, Andrew; Dowsett, Gary W et al. (2018) Perceptions of HIV cure research among people living with HIV in Australia. PLoS One 13:e0202647|
|Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93|
|Beliakova-Bethell, Nadejda; Hezareh, Marjan; Wong, Joseph K et al. (2017) Relative efficacy of T cell stimuli as inducers of productive HIV-1 replication in latently infected CD4 lymphocytes from patients on suppressive cART. Virology 508:127-133|
Showing the most recent 10 out of 221 publications