HIV-1 and interferons: who's interfering with whom?

Abstract

The ability of interferons (IFNs) to inhibit HIV-1 replication in cell culture models has long been recognized, and the therapeutic administration of IFNα to HIV-1-infected patients who are not receiving antiretroviral therapy produces a clear but transient decrease in plasma viral load. Conversely, studies of chronic HIV-1 infection in humans and SIV-infected animal models of AIDS show positive correlations between elevated plasma levels of IFNs, increased expression of IFN-stimulated genes (ISGs), biomarkers of inflammation and disease progression. In this Review, we discuss the evidence that IFNs can control HIV-1 replication in vivo and debate the controversial role of IFNs in promoting the pathological sequelae of chronic HIV-1 infection.

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…Innate immune responses, in particular type 1 IFNs, represent a potent first-line defense against many pathogens, including primate lentiviruses (29)(30)(31)(32)(33). Consistent with these data, treatment of rhesus macaques with pegylated IFNα2 increased the number of intrarectal challenges required to achieve systemic simian immunodeficiency virus (SIV) infection and decreased the number of transmitted founder viruses (34).…”

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

“…One hesitation in using IFN-␣ as a therapeutic is that plasma IFN-␣ levels in HIV-1 patients have been shown to correlate with pathogenic immune activation (20) and possibly induction of apoptosis in CD4 ϩ T cells (21). However, whether all IFN-␣ subtypes are associated with this chronic activation has not been delineated, and while studies suggest that there is dysregulation of the IFN-␣ response in pathogenic HIV/simian immunodeficiency virus (SIV) infections, a direct role for IFN-␣ in mediating chronic activation and disease progression has yet to be definitively proven (reviewed in reference 22).…”

Understanding Interferon Subtype Therapy for Viral Infections: Harnessing the Power of the Innate Immune System.

“…Protection with IFN-α1 correlated with an expansion of virus-specific CD8+ T cells and NK cells in the spleen, whereas IFN-α4 and IFN-α9 treatment exclusively correlated with NK cell activation, demonstrating distinct biological effects of the subtypes. However, chronic HIV-1 infection stimulates prolonged IFN expression with more subtypes being produced leading to detrimental ISG sets with an associated longer duration, which does not return to baseline levels [53].…”

“…Although IFNs antagonise viral gene expression, aiming to ultimately protect the host and are seen as key in controlling viral-mediated morbidity and mortality, they may in part be responsible for co-morbidities seen with some chronic virus infections. Chronic HIV-1 infection is positively correlated with elevated plasma IFN levels and sustained expression of ISGs, that can be utilised as biomarkers of inflammation and disease progression to AIDS [53]. Paradoxically, therapeutic IFN-α administration significantly reduces plasma HIV-1 viral loads in infected patients [53].…”

“…Chronic HIV-1 infection is positively correlated with elevated plasma IFN levels and sustained expression of ISGs, that can be utilised as biomarkers of inflammation and disease progression to AIDS [53]. Paradoxically, therapeutic IFN-α administration significantly reduces plasma HIV-1 viral loads in infected patients [53].…”