Papillomaviruses replicate in stratified epithelia of skin and mucosa. Infection with certain human papillomavirus (HPV) types is the main cause of anogenital neoplasia, in particular cervical cancer. Early events of papillomavirus infectivity are poorly understood. While heparan sulfate proteoglycans (HSPGs) mediate initial binding to the cell surface, the class of proteins carrying heparan sulfates has not been defined. Here we examined two processes of papillomavirus infection, attachment of virus-like particles (VLP) to cells and infection with authentic HPV type 11 (HPV11) virions. Of the HSPGs, syndecan-1 is the major epithelial form and is strongly upregulated in wound edge keratinocytes. We employed K562 cells, which lack HSPGs except minor amounts of endogenous betaglycan, and stable clones that express cDNAs of syndecan-1, syndecan-4, or glypican-1. Binding of VLP correlated with levels of heparan sulfate on the cell surface. Parental K562 bound HPV16 VLP weakly, whereas all three K562 transfectants demonstrated enhanced binding, with the highest binding capacity observed for syndecan-1-transfected cells, which also expressed the most HSPG. For HPV11 infectivity assays, a high virion inoculum was required to infect K562 cells, whereas ectopic expression of syndecan-1 increased permissiveness eightfold and expression of syndecan-4 or glypican-1 fourfold. Infection of keratinocytes was eliminated by treatment with heparitinase, but not phospholipase C, further implicating the syndecan family of integral membrane proteins as receptor proteins. Human keratinocytes with a homozygous deletion of ␣6 integrin are permissive for HPV11 infection. These results indicate that several HSPGs can serve as HPV receptors and support a putative role for syndecan-1, rather than ␣6 integrin, as a primary receptor protein in natural HPV infection of keratinocytes.Papillomaviruses comprise a large group of species-and tissue-specific DNA tumor viruses found in higher vertebrates from chaffinches to humans and include more than 90 known human papillomavirus (HPV) genotypes. Papillomaviruses cause mainly benign epithelial papillomas or warts on skin and mucosa (condylomata acuminata). Several high-risk HPV types, most often HPV type 16 (HPV16), are the primary etiologic agents for anogenital malignancy, in particular cervical cancer, which is the second most common cause of cancerrelated deaths in women worldwide (41, 57). The papillomavirus virion consists of a nonenveloped capsid comprised of the L1 major and L2 minor structural proteins surrounding a minichromosome of ϳ8 kb of double-stranded closed circular and histone-associated DNA. Even in the absence of other viral proteins, the L1 protein self-assembles into empty capsids or virus-like particles (VLP) (24). Subunit vaccines based on VLP have been developed, and prophylactic immunizations have demonstrated safety and efficacy in preventing papillomavirus infection and associated neoplasia (18,23,25,28,44).Papillomaviruses do not complete their life cycle leading to pr...

Chronic inflammation may induce an increased growth pattern of fibromuscular tissue in BPH similar to that of wound healing.

SUMMARY:The aim of the study is to characterize the type of immune response in benign prostatic hyperplasia (BPH) tissue.BPH tissue-derived T cells (n ϭ 10) were isolated, activated (PMA ϩ ionomycin), and analyzed for intracellular reactivity with anti-IFN-␥ and IL-2, -4, -5, -6, -10, and -13, as well as TNF-␣ and -␤ by four-color flow cytometry. Lymphokine release was tested using Th1/Th2 cytokine bead arrays. The amount of IFN-␥ and IL-2, -4, -13, and TGF-␤ mRNA expressed in normal prostate (n ϭ 5) was compared with that in BPH tissue separated into segments with normal histology (n ϭ 5), BPH histology with (n ϭ 10) and without (n ϭ 10) lymphocytic infiltration, and BPH nodules (n ϭ 10). Expression of lymphokine receptors was analyzed by immunohistology, flow cytometry, and RT-PCR. We found that 28 Ϯ 18% of BPH T helper cells were IFN-␥ ϩ /IL-4 Ϫ Th1 cells, 10 Ϯ 2% were IFN-␥ Ϫ /IL-4 ϩ Th2, and 12 Ϯ 6% were IFN-␥ ϩ /IL-4 ϩ Th0 cells. In relation, cytotoxic and double-negative BPH T lymphocytes showed a slight decrease in Th1 and Th0 in favor of Th2. In double-positive BPH T lymphocytes, the trend toward Th2 (35 Ϯ 15%) was significant (Th1: 12 Ϯ 7%; Th0: 5 Ϯ 4%). Lymphokine release upon stimulation was found in the case of IL-2, IL-5, IFN-␥, and TNF-␣ Ͼ 4 g; of IL-4 Ͼ 2 g; and of IL-10 Ͼ 1 g/ml. Expression of lymphokine mRNA in tissue was increased (2-to 10-fold) in infiltrated BPH specimens with and without BPH histology. The infiltrated BPH specimens with normal histology differed from those with BPH histology, most evident by the significant decrease in IFN-␥ and the increase in TGF-␤ mRNA expression. Infiltrated BPH specimens with BPH histology expressed significantly more IFN-␥ (5-fold), IL-2 (10-fold), and IL-13 (2.8-fold) when compared with noninfiltrated BPH specimens. BPH nodules, however, showed the highest level of expression of IL-4 and IL-13, with only intermediate levels of IFN-␥ and very low levels of IL-2 mRNA. Immune response in histologically less transformed BPH specimens is primarily of type 1, whereas in chronically infiltrated nodular BPH and especially within BPH nodules, it is predominantly of type 0 or type 2. (Lab Invest 2003, 83:1131-1146.

The immunocytes that regulate papillomavirus infection and lesion development in humans and animals remain largely undefined. We found that immunocompetent mice with varying H-2 haplotypes displayed asymptomatic skin infection that produced L1 when challenged with 6×1010 MusPV1 virions, the recently identified domestic mouse papillomavirus (also designated “MmuPV1”), but were uniformly resistant to MusPV1-induced papillomatosis. Broad immunosuppression with cyclosporin A resulted in variable induction of papillomas after experimental infection with a similar dose, from robust in Cr:ORL SENCAR to none in C57BL/6 mice, with lesional outgrowth correlating with early viral gene expression and partly with reported strain-specific susceptibility to chemical carcinogens, but not with H-2 haplotype. Challenge with 1×1012 virions in the absence of immunosuppression induced small transient papillomas in Cr:ORL SENCAR but not in C57BL/6 mice. Antibody-induced depletion of CD3+ T cells permitted efficient virus replication and papilloma formation in both strains, providing experimental proof for the crucial role of T cells in controlling papillomavirus infection and associated disease. In Cr:ORL SENCAR mice, immunodepletion of either CD4+ or CD8+ T cells was sufficient for efficient infection and papillomatosis, although deletion of one subset did not inhibit the recruitment of the other subset to the infected epithelium. Thus, the functional cooperation of CD4+ and CD8+ T cells is required to protect this strain. In contrast, C57BL/6 mice required depletion of both CD4+ and CD8+ T cells for infection and papillomatosis, and separate CD4 knock-out and CD8 knock-out C57BL/6 were also resistant. Thus, in C57BL/6 mice, either CD4+ or CD8+ T cell-independent mechanisms exist that can protect this particular strain from MusPV1-associated disease. These findings may help to explain the diversity of pathological outcomes in immunocompetent humans after infection with a specific human papillomavirus genotype.