Single-cell multi-omics understanding of HIV-induced immune dysfunction
Despite effective antiretroviral therapy, HIV persists as an integrated provirus. These HIV-infected cells are resistant to immune clearance and antiretroviral therapy. Upon treatment interruptions, viral rebound will resume. Therefore, all HIV-infected individuals need to take life-long antiretroviral therapy. Given the adverse effects, drug resistance and economical burden of lifelong antiretroviral therapy, a cure is needed to control the global HIV endemic.
The mission of the Ho lab is to understand HIV persistence and find a cure for HIV infections. The scientific goal is to understand how HIV persists in cells, particularly CD4 T lymphocytes, and whether epigenetic silencing can permanently and irreversibly silence HIV expression. We use a molecular virology approach to examine mechanisms of HIV persistence using blood samples from HIV-infected individuals.
We are currently recruiting postdocs working on a combination of HIV-induced immune dysfunction, single-cell genomics, and bioinformatics.
Despite effective antiretroviral therapy (ART), HIV persists in the latent reservoir as the major barrier to cure. Although ART effectively suppresses plasma viral load to clinically undetectable levels, once ART is interrupted, high levels of viremia will inevitably occur. Therefore, all 37 million people living with HIV need to take lifelong ART. This is because HIV hides in the memory CD4+ T cells and evades immune clearance. First, HIV stably integrates into chromosomes of infected cells. ART cannot remove these integrated proviruses. Second, HIV infects the long-lived memory CD4+ T cells and persists for decades. Third, HIV enters latency and becomes transcriptionally silent when memory CD4+ T cells return to a quiescent state. Latently infected cells do not express viral antigens and cannot be recognized and cleared by the immune system. Fourth, HIV-infected cells undergo clonal expansion through antigen stimulation, homeostatic cytokine-mediated proliferation, and integration-site driven proliferation. This means that HIV-infected cells not only survive but also increase over time. Finally, despite ART, millions of HIV-infected cells already established the latent reservoir within 3 days of infection. Since ART does not inhibit HIV LTR promoter activity, these infected cells express viral antigens through stochastic activation and continue to induce immune activation and immune exhaustion. The exhausted and dysfunctional immune effector cells cannot effectively eliminate HIV-infected cells. A cure is desperately needed. However, many questions remain unsolved: how does virally suppressed HIV infection induce chronic immune exhaustion? How do HIV-infected cells survive, proliferate, and persist over time? How can we specifically target HIV-infected CD4+ T cells without harming uninfected cells?
Our goal is to understand how HIV induces immune dysfunction over different stages of HIV infection over time, both at the systemic level characterizing all CD4+ T cells and the single-cell level in HIV-infected cells. We will focus on CD4+ T cells, the central orchestrator of adaptive immunity and the major target of HIV infection. We hypothesize that despite the heterogeneity of HIV-infected cells, HIV drives a distinct cellular program that promotes persistence. We propose that identifying and targeting HIV-driven immune dysregulation leads to cure. The challenge to answering this question is the heterogeneity, rarity, and lack of marker of HIV-infected cells. Our approach is to develop cutting-edge single-cell methods, to apply these methods to challenging clinical samples, and to validate with CRISPR-mediated up- and down-regulation of candidate cellular pathways.