Blocking Type I Interferon Production: A New Therapeutic Option to Reduce the HIV-1-Induced Immune Activation

Abstract

Highly active antiretroviral therapy has dramatically improved the morbidity and mortality of HIV-1-infected individuals. A total of 25 licensed drugs provide the basis for an optimized virus-suppressive treatment of nearly each subject. The promises of immune reconstitution and normal life expectancy, however, fall short for a number of patients, either through inadequate recovery of CD4+ T-cell counts or the occurrence of non-AIDS defining malignancies. In this respect, the prevalence of Epstein-Barr virus-associated Hodgkin lymphoma and human papillomavirus-related anal neoplasia is rising in aging HIV-1-infected individuals despite antiretroviral therapy. An important cause appears to be the HIV-1-induced chronic immune activation, propagated by inappropriate release of proinflammatory cytokines and type I interferons. This immune dysregulation can be reduced in vitro by inhibitors blocking the endosomal acidification. Recent data suggest that this concept is also of relevance in vivo, which opens the door for adjuvant immunomodulatory therapies in HIV-1 infection.

Modulation of Type I Interferon-Associated Viral Sensing during Acute Simian Immunodeficiency Virus Infection in African Green Monkeys

“…An earlier report by Pritschet et al found a crucial role for CD4, but not BDCA-2, in HIV endocytosis, although those confocal microscopy experiments were not quantitative (48). It is possible that BDCA-2, by binding HIV, increases the efficiency of CD4-dependent HIV endocytosis (49). Moreover, our data suggest an egress of precursor pDCs during acute SIVagm infection, similar to what has been reported for SIVmac infection (24,33).…”

Select host restriction factors are associated with HIV persistence during antiretroviral therapy

“…Curiously, these factors are not induced by interferon-α treatment in vivo , in contrast to the majority of recognized anti-HIV-1 restriction factors [28]. This regulatory feature may be pertinent to the development of interventions to attenuate HIV-associated inflammation and immune activation through the blockade of type I interferon signaling [40], as interferon-α blockade may not compromise the viral control mediated by these particular factors. The molecular biology and cellular roles of the p21 and SLFN11 factors have been extensively characterized, providing key insights into the mechanisms underlying our observations.…”

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

“…Autoimmune disorders including multiple sclerosis, rheumatic disease, asthma, and allergies are also associated with high rates of neuropsychiatric symptoms and depression (Pollak and Yirmiya, 2002). Similarly, patients with human immunodeficiency virus (HIV), which is associated with increased inflammatory cytokine production, and particularly interferon (IFN)-alpha (Ries et al, 2012), manifest neuropsychiatric complications, such as cognitive decline and psychomotor disturbance, and often depression and fatigue (Treisman et al, 1998, Wojna et al, 2006, Payne et al, 2012). These data suggest that innate immune activation during chronic medical illnesses, as characterized by elevations in inflammatory cytokines, may contribute to the high rates of depression and other neuropsychiatric (e.g.cognitive or psychomotor) symptoms observed in medically ill populations.…”