Abstract
T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT) against human papillomavirus 16 (HPV16) E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN) and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2) by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women.
Highlights
Human papillomaviruses 16 (HPV16) is involved in more than 50% of uterine cervical cancers and is the second cause of mortality by cancer in women worldwide, with an incidence of 500 000 cases and 230 000 deaths annually [1,2]
Previous experiments done with HPV16 E6 and E7 in vulvar intraepithelial neoplasia (VIN) indicated that the blood-T cell responses against these proteins are very low [12,13,14,15] and we predicted that the response toward an earlier more abundant viral protein would be higher
The aim of the present study was to longitudinally follow, over an 18 months period, anti-E2 blood T cell responses in 8 women presenting with usual HPV16related VIN in order to search for a relationship between blood anti-E2 T-cell responses and healing
Summary
Human papillomaviruses 16 (HPV16) is involved in more than 50% of uterine cervical cancers and is the second cause of mortality by cancer in women worldwide, with an incidence of 500 000 cases and 230 000 deaths annually [1,2]. E2 protein is a marker of viral infection specific of the early stages of viral gene expression in infected cells This has formally been demonstrated in a recent work that showed a strong staining of the E2 protein in the intermediate differentiated layers of HPV16-infected tissues and low grade CIN of the cervix [8]. The immune response specific of the two oncogenic viral proteins E6 and E7 has already been analyzed in studies aiming at understanding the local immune microenvironment in VIN as well as in cervical cancer and their precursor stages [9,10,11] These viral proteins, probably expressed from the early stages of replicative cycle, may be expressed at levels too low to be useful markers for HPV infection. We hypothesized that male partners exposed to replicative HPV16 could develop immunologic responses against the early E2 viral protein allowing control of infection
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