Control of HIV infection by IFN-α: implications for latency and a cure

Abstract

Viral infections, including HIV, trigger the production of type I interferons (IFNs), which in turn, activate a signalling cascade that ultimately culminates with the expression of anti-viral proteins. Mounting evidence suggests that type I IFNs, in particular IFN-α, play a pivotal role in limiting acute HIV infection. Highly active anti-retroviral treatment reduces viral load and increases life expectancy in HIV positive patients; however, it fails to fully eliminate latent HIV reservoirs. To revisit HIV as a curable disease, this article reviews a body of literature that highlights type I IFNs as mediators in the control of HIV infection, with particular focus on the anti-HIV restriction factors induced and/or activated by IFN-α. In addition, we discuss the relevance of type I IFN treatment in the context of HIV latency reversal, novel therapeutic intervention strategies and the potential for full HIV clearance.

Keywords: Anti-viral; Cure; HIV; Interferon; JAK/STAT; Latency.

Fig. 1

Innate immune detection of HIV induces anti-viral immunity via upregulation of IFN-α. HIV RNA is detected by TLR7 located in endosomes and leads to the phosphorylation and homodimerization of the transcription factor IRF7, which translocates to the nucleus and induces the expression of IFN-α. Cytosolic detection of HIV nucleic acid by the sensors IFI16 and cGAS can also lead to IFN-α induction via activation of STING and the subsequent phosphorylation and homodimerization of IRF3. IFN-α binds to its cognate receptor, which is composed of the IFNAR1 and IFNAR2 subunits, which are ubiquitously expressed on all cell types. Binding of IFN-α results in the activation of receptor-associated kinases, Tyk2 and JAK1, subsequently leading to the activation of the STAT family of transcription factors. Activated STAT1 and STAT2 bind IRF9 and form the transcription factor complex ISGF3, which can bind to the ISRE promoter element. STAT1–6 can also homo- and heterodimerise following activation with IFN-α and can bind to GAS promoter elements. Many genes activated through this response encode for proteins with potent anti-viral functions, including HIV restriction factors

Fig. 2

IFN-α-induced restriction factors block all stages of the HIV life cycle. IFN-α upregulates the expression of many proteins capable of blocking HIV replication at every stage of the viral life cycle. HIV entry into the cell is antagonised by IFITM family members. After uncoating of the viral envelope, TRIM5α inhibits HIV by directly binding to the capsid and promoting its proteasomal degradation. SAMHD1 and APOBEC3 can both block HIV at the stage of reverse transcription. SAMHD1 decreases the cellular pool of dNTPs available to the virus for cDNA synthesis, whereas APOBEC3 causes hypermutation in viral cDNA during the reverse transcription process. MX2 inhibits the nuclear import of HIV DNA and thus its integration into the host genome. SLFN11 targets tRNAs for depletion and thus inhibits translation of viral proteins. Finally, Tetherin restricts newly assembled virions from budding from infected cells. Together these restriction factors represent a powerful arsenal to block HIV infection and it is therefore not surprising that the HIV has evolved its own powerful counter mechanisms to antagonise the actions of many of these restriction factors. HIV Vpx targets SAMHD1; HIV Vif targets APOBEC3, and HIV Vpu and Nef target Tetherin