Interferon-α Subtypes As an Adjunct Therapeutic Approach for Human Immunodeficiency Virus Functional Cure

Abstract

Human immunodeficiency virus (HIV) establishes life-long latency in infected individuals. Although highly active antiretroviral therapy (HAART) has had a significant impact on the course of HIV infection leading to a better long-term outcome, the pool of latent reservoir remains substantial even under HAART. Numerous approaches have been under development with the goal of eradicating the latent HIV reservoir though with limited success. Approaches that combine immune-mediated control of HIV to activate both the innate and the adaptive immune system under suppressive therapy along with “shock and kill” drugs may lead to a better control of the reactivated virus. Interferon-α (IFN-α) is an innate cytokine that has been shown to activate intracellular defenses capable of restricting and controlling HIV. IFN-α, however, harbors numerous functional subtypes that have been reported to display different binding affinities and potency. Recent studies have suggested that certain subtypes such as IFN-α8 and IFN-α14 have potent anti-HIV activity with little or no immune activation, whereas other subtypes such as IFN-α4, IFN-α5, and IFN-α14 activate NK cells. Could these subtypes be used in combination with other strategies to reduce the latent viral reservoir? Here, we review the role of IFN-α subtypes in HIV infection and discuss the possibility that certain subtypes could be potential adjuncts to a “shock and kill” or therapeutic vaccination strategy leading to better control of the latent reservoir and subsequent functional cure.

Chronic simian immunodeficiency virus infection is associated with contrasting phenotypes of dysfunctional Bcl6+ germinal center B cells or Bcl6−Bcl2+ non‐germinal center B cells

“…There were no correlation between plasma viral loads and either Tfh cells or Bcl6 expression on B cells suggesting that the changes we observed may be likely related to the local LN microenvironment. It is possible that Type I IFN may play a role as some studies have suggested and elevated levels of IFNα have been reported in the LN during SIV and HIV infections . Additional studies are needed to delineate these changes in detail and to determine the consequences they have for immune responses.…”

“…22 We observed similar contrasting phenotypes in chronically infected rhesus macaques with significantly higher frequencies of Bcl6 + IgG + 26,27 and elevated levels of IFNα have been reported in the LN during SIV and HIV infections. 28,29 Additional studies are needed to delineate these changes in detail and to determine the consequences they have for immune responses. Early treatment with reverse transcriptase inhibitors significantly suppresses peak plasma IFNalpha in vivo during acute simian immunodeficiency virus infection.…”

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

“…Recent studies highlighted IFNα as a potential adjunct to an HIV-1 curative strategy [6][7][8][9][10]. However, almost all HIV-1 clinical trials with IFNα were performed with only one subtype, IFNα2, with mixed results (reviewed in [2,3]).…”

Dose-Dependent Differences in HIV Inhibition by Different Interferon Alpha Subtypes While Having Overall Similar Biologic Effects

“…The prevailing ambiguity regarding the IFN-α subtypes’ functional role (reviewed in reference 28) spurred us to reexamine whether these 12 highly similar cytokines, which all trigger the same JAK/STAT signaling pathway, can genuinely induce differential activities or whether our understanding of the IFN-α subtypes’ intrinsic properties has been masked by dose-related effects. To this end, we investigated the antiviral properties of IFN-α subtypes in ex vivo HIV-infected primary cells with a focus on assessing the dose-dependent effects of a selected set of IFN-α subtypes.…”