Deeks: Experimental medicine trial to assess the impact of interferon-alpha inhibition on immune function and viral persistence in HIV disease
Although combination antiretroviral therapy (ART) can maintain inde nite control of HIV replication, it is not curative. As a consequence, HIV-infected individuals have to remain on complex regimens for decades, which is often challenging given their toxicities and costs. There is intense interest in developing therapeutic inter- ventions that result in sustained remission of the disease in the absence of therapy (a “cure”).
During long-term ART, HIV resides within circulating memory CD4+ T cells and perhaps discrete CD4+ T and myeloid cell subpopulations in various tissues, particularly lymphoid tissues (including spleen, gut and secondary lymph nodes) and the CNS. Based on observations made in “elite” controllers and other experi- mental models, controlling this persistent reservoir in the absence of antiretroviral therapy will likey require sustained and effective T cell immunity. Chronic type I IFN signaling contributes to T cell dysfunction and persistence of chronic virus infections (e.g., LCMV) in animal models. Chronic type I IFN signaling has been observed in antiretroviral-treated HIV infection, and associated with a number of persistent immunologic defects that might plausibly contribute to HIV persistence, including persistent T cell activation, altered T cell homeostasis and blunted HIV-speci c T cell responses.
In order to de ne if chronic type I IFN signaling during treated HIV disease contributes to during effective ART, we will perform a pathogenesis-oriented proof-of-concept (POC) clinical trial of a clinically available inhibitor of type I IFN administered for 16 weeks to HIV-infected adults on potent ART. Several such inhibitors are in clinical development; recent data from study of systemic lupus erythematosus (SLE) indicates that even when administered with other immunosuppressive drugs, type I IFN inhibitors are well-tolerated, safe and effective in reducing disease burden (through at least one year of exposure). We anticipate that the data obtained from these experiments will lead to a mechanistic de nition of the role of type I IFNs in the context of treated HIV disease and may lead to the development of an effective therapeutic intervention to promote immune recovery and cure of HIV infection. The human clinical studies will utilize inhibitors of the type I IFN pathway that are currently in clinical development by MedImmune; in addition, a sub-project to this grant will be examining the IFNα blockage in SIV infected nonhuman primates, utilizing an alternative inhibitor from Argos Therapeutics that will be administered while the animals are under ART.
The work is a collaborative effort led by Steven G. Deeks, MD (University of California, San Francisco), with clinical enrollments at UCSF and Monash Universities. The award was made in December, 2014, with an initial agreement length of 4 years.
1. To determine the safety and tolerability of mAb-mediated blockade of type I IFN activity in antiretroviral-treated adults.
2. To determine if inhibition of chronic type I IFN signaling during ART improves HIV-speci c CD8+ T cell responses
3. To determine if inhibition of chronic type I IFN signaling during ART reduces CD4+ and CD8+ T cell activation
1. To determine if inhibition of chronic type I IFN signaling during ART reduces expression of ISGs
2. To determine if inhibition of chronic type I IFN signaling during ART reduces innate immune activation
3. To determine if inhibition of chronic type I IFN signaling during ART reduces frequency CD4+ T cells with inducible HIV
4. To determine if inhibition of chronic type I IFN signaling during ART reduces plasma HIV RNA levels
5. To determine if inhibition of chronic type I IFN signaling during ART reduces prolongs the time to virologic rebound during a treatment interruption