Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2-Dependent Mechanism

Abstract

In this study, we report that gamma interferon (IFN-␥) treatment, but not IFN-␣, -␤, or -treatment, dramatically decreased infection of human papillomavirus 16 (HPV16) pseudovirus (PsV). In a survey of 20 additional HPV and animal papillomavirus types, we found that many, but not all, PsV types were also inhibited by IFN-␥. Microscopic and biochemical analyses of HPV16 PsV determined that the antiviral effect was exerted at the level of endosomal processing of the incoming capsid and depended on the JAK2/STAT1 pathway. In contrast to infection in the absence of IFN-␥, where L1 proteolytic products are produced during endosomal capsid processing and L2/DNA complexes segregate from L1 in the late endosome and travel to the nucleus, IFN-␥ treatment led to decreased L1 proteolysis and retention of L2 and the viral genome in the late endosome/lysosome. PsV sensitivity or resistance to IFN-␥ treatment was mapped to the L2 protein, as determined with infectious hybrid PsV, in which the L1 protein was derived from an IFN-␥-sensitive HPV type and the L2 protein from an IFN-␥-insensitive type or vice versa.IMPORTANCE A subset of HPV are the causative agents of many human cancers, most notably cervical cancer. This work describes the inhibition of infection of multiple HPV types, including oncogenic types, by treatment with IFN-␥, an antiviral cytokine that is released from stimulated immune cells. Exposure of cells to IFN-␥ has been shown to trigger the expression of proteins with broad antiviral effector functions, most of which act to prevent viral transcription or translation. Interestingly, in this study, we show that infection is blocked at the early step of virus entry into the host cell by retention of the minor capsid protein, L2, and the viral genome instead of trafficking into the nucleus. Thus, a novel antiviral mechanism for IFN-␥ has been revealed. KEYWORDS HPV, papillomavirus, interferon, IFN-␥, L2P apillomaviruses (PV) are members of a large group of nonenveloped DNA tumor viruses that infect epithelial tissues of a wide range of vertebrate species. A subset of oncogenic mucosal human PV (HPV) types are the causal agents of cervical cancer. These high-risk types, especially HPV16, are also linked to vulvar, vaginal, anal, and oropharyngeal cancers (1). The cascade of viral protein expression is integrally tied to epithelial differentiation, with virion production only occurring in the terminally differentiated upper layers (2). These features combine to allow circumvention of host innate and adaptive immune responses, as few proinflammatory signals are elicited during these early stages (3). However, most PV infections that induce overt hyperproliferation are eventually cleared with the apparent involvement of lymphocytic infiltrates (reviewed in reference 4). Also, HPV infections are often superimposed on colonization with other microbial agents, e.g., in the female reproductive tract (reviewed in reference 5). It is, therefore, of interest to determine if antiviral molecules that are known compon...

Human Papillomavirus 16 Capsids Mediate Nuclear Entry during Infection

“…Although it appears that PV types across genera utilize similar intracellular pathways (26,27), different host proteins may be involved in this trafficking (28). We chose to examine PsV from two other oncogenic types for mitotic chromosome association.…”

Suppression of Stromal Interferon Signaling by Human Papillomavirus 16

“…Thus, the raft culture system reflects an important aspect of constitutive innate immune activity of the epithelia in vivo. It is likely that the constitutive activation of IFNs in epithelial keratinocytes represents a barrier for the establishment and maintenance of HPV infections (21,91). Importantly, both of these markers of chronic IFN signaling were reduced by HPV16 in our experiments.…”

Development of HPV16,18,31,45 E5 and E7 peptides-based vaccines predicted by immunoinformatics tools

“…In addition, the E5 peptide construct had 2 positive charge residues and the E7 peptide construct consisted of 2 positive and 11 negative charge residues. On the other hand, IFN-c has a key role in intracellular immunity against HPV infection (Day et al 2017). Our data showed that SPATAFTVYVFCFLLA (E5-type 18) and TLQEIVLHLEPQNELDPVDLL (E7-type 45) had the highest scores for stimulation of IFN-gamma against HPVs.…”