The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis

Abstract

The productive human papillomavirus (HPV) life cycle is tightly linked to the differentiation and cycling of keratinocytes. Deregulation of these processes and stimulation of cell proliferation by the action of viral oncoproteins and host cell factors underlies HPV-mediated carcinogenesis. Severe HPV infections characterize the wart, hypogammaglobulinemia, infection, and myelokathexis (WHIM) immunodeficiency syndrome, which is caused by gain-of-function mutations in the CXCR4 receptor for the CXCL12 chemokine, one of which is CXCR41013. We investigated whether CXCR41013 interferes in the HPV18 life cycle in epithelial organotypic cultures. Expression of CXCR41013 promoted stabilization of HPV oncoproteins, thus disturbing cell cycle progression and proliferation at the expense of the ordered expression of the viral genes required for virus production. Conversely, blocking CXCR41013 function restored virus production and limited HPV-induced carcinogenesis. Thus, CXCR4 and its potential activation by genetic alterations in the course of the carcinogenic process can be considered as an important host factor for HPV carcinogenesis.

HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions

“…Although background staining was higher than we would have liked using this antibody, the conclusion was supported by digital scanning across the length of the raft tissue (S7C Fig). In contrast to the situation in undifferentiated monolayer cells however, the detectable E2 protein seen in the differentiated raft cultures was predominantly nuclear in our hands, although previous studies have reported both nuclear and cytoplasmic E2 protein using this antibody [63]. In an attempt to substantiate these observations, we next went on to examine E2 by western blotting (S7D, S7E and S7F Fig), using the microdissection approach used previously to assess L1 accumulation.…”

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

“…Importantly, HPV-mediated keratinocyte transformation required HPV oncogene E6- and E7-enabled signaling through the CXCL12-CXCR4 WHIM axis. Conversely, a recent study indicated that CXCR4 WHIM promotes stabilization of E6 and E7 in differentiated keratinocytes [52]. While CXCR4 itself did not promote keratinocyte proliferation, HPV-infected keratinocytes expressing CXCR4 WHIM receptors demonstrated increased proliferation compared to infected cells with wild type CXCR4.…”

WHIM syndrome: Immunopathogenesis, treatment and cure strategies

“…Since WHIM patients respond less robustly to vaccination than normal individuals (see below), whether or not HPV vaccination will offer similarly effective protection to genital types is not currently known but the favorable risk‐benefit profile strongly favors vaccination of WHIM patients of both sexes prior to likely exposure. Previous in vitro experimental data have implicated expression of the mutant WHIM CXCR4 receptor on keratinocytes as a factor in wart development and possible progression to malignancy . While this may play a role, several lines of evidence point to the primary defect in WHIM patients being a lack of immune response to the virus: (a) anecdotal evidence suggests that some lesions can regress after immune stimulatory therapies, (b) a patient who spontaneously lost her WHIM allele in the myeloid compartment cleared her lesions, and (c) lesions can regress after patients are treated with anti‐CXCR4 drugs .…”