This week in the Journal of Clinical Investigation, two independent studies describe results obtained by blocking type 1 interferon signaling pathways in humanized mouse models of chronic HIV infection. The papers are both open access (see Anjie Zhen et al and Liang Cheng et al). Type 1 interferons are cytokines that interact with specific receptors on cells in order to modulate activity of interferon-stimulated genes (ISGs), and these interactions are known to play important roles in antiviral immunity (e.g. alpha interferon is an approved treatment for hepatitis C). But the effects of type 1 interferons are complex, and can also involve potentially harmful exacerbation of immune activation and inflammation. In these new studies, the researchers used antibodies to block interferon receptors in humanized mice with chronic HIV infection, and converged on congruent findings: HIV viral loads and virus reservoirs were diminished, as were markers of immune activation and exhaustion.
In the work of Anjie Zhen et al, type 1 interferon receptor blockade was studied both with and without antiretroviral therapy (ART). Blockade alone reduced HIV viral loads and markers of immune activation and exhaustion, as well as enhancing the functionality of HIV-specific CD8 T cell responses. The combination with ART displayed similar effects and reduced the size of the persistent HIV reservoir. Liang Cheng et al evaluated type 1 interferon receptor blockade in combination with ART, producing comparable results.
An accompanying commentary notes that the results contrast with those obtained in acute SIV infection, where blocking IFN receptors had mostly negative effects, increasing the SIV reservoir and promoting faster CD4 T cell loss and progression to AIDS, despite reducing markers of immune activation. The commentary authors point out that these differing findings have a clear parallel in murine LCMV infection, where blockade of type 1 interferon inhibits virus clearance during acute infection but enhances long-term control of viremia in chronic infection.
Because antibodies blocking type 1 interferon activity are already being tested in human trials for other diseases (such as lupus), it may eventually be possible to test whether the promising results obtained in the humanized mouse model can be translated to humans. As Liang Cheng et al state in the discussion section of their paper, an important first step will be testing the approach in macaques with chronic SIV infection.