Abstract
The biomolecular mechanisms controlling latent HIV-1 infection, despite their importance for the development of a cure for HIV-1 infection, are only partially understood. For example, ex vivo studies have recently shown that T cell activation only triggered HIV-1 reactivation in a fraction of the latently infected CD4+ T cell reservoir, but the molecular biology of this phenomenon is unclear. We demonstrate that HIV-1 infection of primary T cells and T cell lines indeed generates a substantial amount of T cell receptor (TCR)/CD3 activation-inert latently infected T cells. RNA-level analysis identified extensive transcriptomic differences between uninfected, TCR/CD3 activation-responsive and -inert T cells, but did not reveal a gene expression signature that could functionally explain TCR/CD3 signaling inertness. Network analysis suggested a largely stochastic nature of these gene expression changes (transcriptomic noise), raising the possibility that widespread gene dysregulation could provide a reactivation threshold by impairing overall signal transduction efficacy. Indeed, compounds that are known to induce genetic noise, such as HDAC inhibitors impeded the ability of TCR/CD3 activation to trigger HIV-1 reactivation. Unlike for transcriptomic data, pathway enrichment analysis based on phospho-proteomic data directly identified an altered TCR signaling motif. Network analysis of this data set identified drug targets that would promote TCR/CD3-mediated HIV-1 reactivation in the fraction of otherwise TCR/CD3-reactivation inert latently HIV-1 infected T cells, regardless of whether the latency models were based on T cell lines or primary T cells. The data emphasize that latent HIV-1 infection is largely the result of extensive, stable biomolecular changes to the signaling network of the host T cells harboring latent HIV-1 infection events. In extension, the data imply that therapeutic restoration of host cell responsiveness prior to the use of any activating stimulus will likely have to be an element of future HIV-1 cure therapies.
Highlights
Antiretroviral therapy (ART) efficiently suppresses HIV-1 replication below detection levels of diagnostic assays, but ART does not eliminate latent viral reservoirs, enabling HIV-1 to persist for the lifetime of a patient and rebound whenever ART is interrupted [1]
A curative therapy for HIV-1 infection will at least require the eradication of a small pool of CD4+ helper T cells in which the virus can persist in an inactive, latent state, even after years of successful antiretroviral therapy
We demonstrate that a large part of latent HIV-1 infection events reside in T cells that have been rendered activation inert
Summary
Antiretroviral therapy (ART) efficiently suppresses HIV-1 replication below detection levels of diagnostic assays, but ART does not eliminate latent viral reservoirs, enabling HIV-1 to persist for the lifetime of a patient and rebound whenever ART is interrupted [1]. The most comprehensive evidence for viral persistence has been presented for latent HIV-1 infection events residing in long-lived, resting CD4 memory T cells [2,3,4] This would explain the stability of the latent HIV-1 reservoir, as T cell memory can persist for the life-time of an individual. The absence of a measurable reservoir decay despite the expected continuous encounter of cognate-antigen and subsequent T cell activation could be explained by the idea that memory T cells hosting latent HIV-1 infection events have been altered to exhibit an activation-inert phenotype. An activation-inert host cell phenotype would explain findings that a significant part of Extensive molecular changes render latently HIV-1 infected T cells resistant to TCR activation the latent HIV-1 reservoir is resistant to ex vivo T cell activation, mostly based on impaired host cell signaling pathways, without any requirement for a repressive chromatin environment at the viral LTR, which is often not present, as latent HIV-1 is usually integrated into actively expressed genes [15]
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