Diverse effects of interferon alpha on the establishment and reversal of HIV latency.

Author summary Antiretroviral therapy (ART) cannot cure HIV or eliminate infection from long-lived and proliferating latently infected CD4(+) T cells. Plasmacytoid dendritic cells (pDC) are major producers of interferons (IFNs), which have multiple effects on viral replication and immunity including suppression of viral expression that could favor HIV latency. Van Der Sluis et al. show that type I IFNs inhibit the establishment of HIV latency, however, once established, latency can be reversed by IFN alpha but not by other type I or type III IFNs. These observations demonstrate that pDC through type I IFNs are important in HIV latency and can potentially be manipulated to eliminate latent infection. HIV latency is the major barrier to a cure for people living with HIV (PLWH) on antiretroviral therapy (ART) because the virus persists in long-lived non-proliferating and proliferating latently infected CD4(+) T cells. Latently infected CD4(+) T cells do not express viral proteins and are therefore not visible to immune mediated clearance. Therefore, identifying interventions that can reverse latency and also enhance immune mediated clearance is of high interest. Interferons (IFNs) have multiple immune enhancing effects and can inhibit HIV replication in activated CD4(+) T cells. However, the effects of IFNs on the establishment and reversal of HIV latency is not understood. Using an in vitro model of latency, we demonstrated that plasmacytoid dendritic cells (pDC) inhibit the establishment of HIV latency through secretion of type I IFN alpha, IFN beta and IFN omega but not IFN epsilon or type III IFN lambda 1 and IFN lambda 3. However, once latency was established, IFN alpha but no other IFNs were able to efficiently reverse latency in both an in vitro model of latency and CD4(+) T cells collected from PLWH on suppressive ART. Binding of IFN alpha to its receptor expressed on primary CD4(+) T cells did not induce activation of the canonical or non-canonical NF kappa B pathway but did induce phosphorylation of STAT1, 3 and 5 proteins. STAT5 has been previously demonstrated to bind to the HIV long terminal repeat and activate HIV transcription. We demonstrate diverse effects of interferons on HIV latency with type I IFN alpha; inhibiting the establishment of latency but also reversing HIV latency once latency is established.