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Molecular analysis of resistance to interferon in patients with laryngeal papillomatosis
R Garciá-Millián1, A Santos, S E Perea
1Department of Cellular Biology, Center for Biological Research, Havana, Cuba. farma3@cigb.edu.cu
Abstract:
Although interferon (IFN)-alpha has been used successfully as an adjuvant therapy in laryngeal papillomatosis, some patients are resistant to this treatment. In order to know which patients will benefit from the therapy, we have tried to find a relationship between the IFN response and the viral and host parameters in the lesion. Detection of viral type and copy numbers by polymerase chain reaction (PCR) showed that all patients infected with human papillomavirus (HPV)-11 were sensitive to the treatment, in contrast to those infected with HPV-6. These differences could be explained in part by the inability of HPV-11 E7 to inhibit the induction of an IFN-responsive element, whereas HPV-6 E7 almost completely inhibited the activity of this promoter in transient transfection experiments. Local immune status in the lesion showed that all HPV-11-infected patients had detectable levels of interleukin (IL)-15 and IFN-gamma mRNA, in contrast to HPV-6-infected patients, in whom mRNA for these cytokines was almost absent. Viral copy numbers and levels of IL-4 mRNA could not be correlated with IFN response. Only one patient resistant to recombinant IFN-alpha2b and negative for HPV DNA presented high titers of neutralizing anti-IFN-alpha2b antibodies. This patient became sensitive when natural IFN-alpha was administered. These results suggest that response to IFN may be a complex phenomenon resulting from the interaction between viral and host elements.
Insights
Human papillomavirus (HPV) type influences interferon (IFN) therapy response in laryngeal papillomatosis. HPV-11 infections are sensitive, while HPV-6 infections show resistance, linked to viral and host immune factors.
Area of Science:
- Virology
- Immunology
- Oncology
Background:
- Interferon (IFN)-alpha is an adjuvant therapy for laryngeal papillomatosis.
- Some patients exhibit resistance to IFN-alpha treatment, necessitating predictive markers.
Purpose of the Study:
- To identify viral and host factors predicting IFN-alpha response in laryngeal papillomatosis.
- To elucidate the mechanisms behind differential treatment sensitivity.
Main Methods:
- Polymerase chain reaction (PCR) for human papillomavirus (HPV) typing and viral load.
- Transient transfection assays to assess viral E7 protein function.
- Detection of cytokine mRNA (IL-15, IFN-gamma, IL-4) in lesions.
- Analysis of anti-IFN-alpha antibodies.
Main Results:
- All HPV-11 infected patients responded to IFN-alpha, unlike HPV-6 infected patients.
- HPV-6 E7 protein significantly inhibited IFN-responsive element activity, while HPV-11 E7 did not.
- HPV-11 infections correlated with detectable IL-15 and IFN-gamma mRNA; HPV-6 infections showed minimal levels.
- Viral copy number and IL-4 mRNA levels did not correlate with IFN response.
- One patient resistant to recombinant IFN-alpha2b responded to natural IFN-alpha after antibody neutralization.
Conclusions:
- HPV type is a critical determinant of IFN-alpha therapy response in laryngeal papillomatosis.
- Differential inhibition of IFN-responsive elements by HPV-6 and HPV-11 E7 proteins contributes to treatment resistance.
- Host immune status, particularly IL-15 and IFN-gamma expression, is associated with IFN sensitivity.
- The complex interplay between viral and host factors dictates the efficacy of IFN-alpha therapy.
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