Persistent viral infection places a significant burden on global heath. Pathogens such as human immunodeficiency virus (HIV), and hepatitis B and C are able to replicate at high levels within their host, outpacing the immune response and ultimately leading to its attenuation. This attenuation is largely the result of host-derived suppressive factors produced in response to the chronic inflammation and immune-mediated damage to critical lymphoid organs accrued throughout the course of the immune response itself. The landscape of the persistently infected immune environment is thus profoundly altered from its naïve state, raising the possibility that new CD4 and CD8 T cell responses that develop and differentiate in the midst of persistent infection could function differently than T cell responses in a healthy environment.

Using lymphocytic choriomeningitis virus (LCMV) as a model system of persistent infection, we determined that de novo virus-specific T cell responses primed in the midst of persistent infection are impaired. Virus-specific CD8 T cells primed in the midst of persistent infection assume a terminally differentiated phenotype and form defective peripheral effector memory, while virus-specific CD4 T cell responses fail to generate Th1 immunity, instead becoming almost exclusively T follicular helper cells (Tfh). This alteration in the T cell differentiation pattern was mediated by chronic type I interferon (IFN-I) signaling, and blockade of IFN-I signaling restored normal differentiation. Moreover, we observed that IFN-I signaling in the context of persistent LCMV infection led to profound thymic atrophy and disrupted the development of T cell precursors. Together, our data demonstrate several novel mechanisms by which IFN-I acts to modulate the immune response during persistent viral infection. Moreover, the data suggest that modulation of the IFN-I signaling pathway or its downstream targets could lead to treatments to purge persistent viral infection.

Understanding how viruses subvert host immunity and persist is essential for developing strategies to eliminate infection. T cell exhaustion during chronic viral infection is well described, but effects on antibody-mediated effector activity are unclear. Herein, we show that increased amounts of immune complexes generated in mice persistently infected with lymphocytic choriomeningitis virus (LCMV) suppressed multiple Fcγ-Receptor (FcγR) functions. The high amounts of immune complexes suppressed antibody-mediated cell depletion, therapeutic antibody-killing of LCMV infected cells and human CD20-expressing tumors, as well as reduced immune complex-mediated cross-presentation to T cells. Suppression of FcγR activity was not due to inhibitory FcγRs or high concentrations of free antibody, and proper FcγR functions were restored when persistently infected mice specifically lacked immune complexes. Thus, we identify a mechanism of immunosuppression during viral persistence with implications for understanding effective antibody activity aimed at pathogen control.

The determinants of CD8(+) cytotoxic T-lymphocyte (CTL) antiviral activity against human immunodeficiency virus type 1 (HIV-1) remain poorly defined. Although recent technological advances have markedly enhanced the ability to detect HIV-1-specific T cells, commonly used assays do not reveal their direct interaction with virus. We investigated two determinants of CTL antiviral efficiency by manipulating HIV-1 and measuring the effects on CTL suppression of viral replication in acutely infected cells. Translocation of a Gag epitope into the early protein Nef markedly increased the activity of CTL recognizing that epitope, in comparison to HIV-1 expressing the epitope normally in the late protein Gag. Because this epitope translocation resulted not only in earlier expression but also in loss of major histocompatibility complex class I downregulation by Nef, the activities of CTL against a panel of viral constructs differing in kinetics of epitope expression and class I downmodulation were compared. The results indicated that both the timing of epitope expression and the reduction of class I have profound effects on the ability of CTL to suppress HIV-1 replication in acutely infected cells. The epitope targeting of CTL and viral control of class I therefore likely play important roles in the ability of CTL to exert pressure on HIV-1.