Role of retroviral restriction factors in the interferon-α–mediated suppression of HIV-1 in vivo

Abstract

The antiviral potency of the cytokine IFN-α has been long appreciated but remains poorly understood. A number of studies have suggested that induction of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) and bone marrow stromal cell antigen 2 (BST-2/tetherin/CD317) retroviral restriction factors underlies the IFN-α-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-α treatment, retroviral restriction factors, and HIV-1 in vivo. APOBEC3G, APOBEC3F, and BST-2 expression levels were measured in HIV/hepatitis C virus (HCV)-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated IFN-α/ribavirin (IFN-α/riba) combination therapy. IFN-α/riba therapy decreased HIV-1 viral load by −0.921 (±0.858) log 10 copies/mL in HIV/ HCV-coinfected patients. APOBEC3G/3F and BST-2 mRNA expression was significantly elevated during IFN-α/riba treatment in patientderived CD4+ T cells (P < 0.04 and P < 0.008, paired Wilcoxon), and extent of BST-2 induction was correlated with reduction in HIV-1 viral load during treatment (P < 0.05, Pearson's r). APOBEC3 induction during treatment was correlated with degree of viral hypermutation (P < 0.03, Spearman's ρ), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-α/riba treatment was suggestive of increased BST-2-mediated selection pressure. These data suggest that host restriction factors play a critical role in the antiretroviral capacity of IFN-α in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals.

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

“…Also upregulated by IFN-␣14 was tetherin, which inhibits the release of virions from infected cell membranes and is antagonized by HIV-1 Vpu (62). The extent of tetherin induction has been shown to correlate with reduced viral loads in HCV/HIV-1-coinfected patients treated with ribavirin and IFN-␣2 (16). In addition to its direct antiviral effects, tetherin has also been associated with improved antiretroviral NK cell responses (63,64).…”

“…IFN-␣ is rapidly induced and secreted by cells to limit virus replication through numerous and varied mechanisms, including the induction of intrinsic restriction factors (15)(16)(17)(18) and the activation of innate and adaptive immune responders. In vitro studies with pDCs, which are the primary producers of IFN-␣, indicated that the predominant IFN-␣ subtypes produced by pDCs in response to HIV-1 (IFN-␣1, -2, and -5) have only weak anti-HIV-1 activities (14).…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…During acute infection, pDCs may be a critical antiviral agent. IFN-a has long been known to block HIV-1 replication in vitro and in vivo [74][75][76][77]. Several studies performed during the past few years have identified a number of IFN-stimulated cellular factors (e.g.…”

“…Several studies performed during the past few years have identified a number of IFN-stimulated cellular factors (e.g. MX2, BST-2/tetherin, TRIM5a, APOBEC3G and SAMHD1) that can restrict retroviral replication [74,[78][79][80][81]. During acute infection, transmitted founder viruses (HIV strains that succeed in establishing a persistent infection [82]) are more resistant to IFN-I than chronic-phase HIV strains [83,84].…”

“…Treatment with IFN-a has been shown to transiently decrease viral loads during chronic infection [74,213], and IFN-a monotherapy was recently shown to allow control of viraemia and reduction of viral reservoirs after antiretroviral treatment interruption in 48% of individuals who received IFNa for several weeks in addition to their HIV-suppressive cART regimens [214]. The mechanisms underlying this effect are still unclear, but as discussed above, IFNa treatment may enhance the immune response in treated individuals and also upregulate HIV restriction factors, thereby rendering target cells less susceptible to HIV infection.…”