CONTENTS. NOTE TO THE READER... i LIST OF PARTICIPANTS...3

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1 CONTENTS NOTE TO THE READER i LIST OF PARTICIPANTS PREAMBLE Bac kgrou n d Objective and Scope Selection of Topics for Monographs Data for Monographs The W orking Group W orking Procedures Exposure Data Studies of Cancer in Humans... i 2 Studies of Cancer in Experimental AnimaIs Other Data Relevant to an Evaluation of Carcinogenicity and Its Mechanisms Summary of Data Reported... i 9 Evaluation References '" THE MONOGRAPHS Human immunodeficiency viruses i 1. Exposure data i i. 1 Structure, taxonomy and biology i Structure...3 i Taxonom y Phylogeny (a) Phylogenetic relationship of HIV -1 and HIV -2 to other retroviruses (b) Relationship of HIV -1 and HIV -2 isolates to one another...36 (i) Genotypes... '" (ii) Antigenic di versity Host range Cell tropism Target tissues...38 (a) L ymphoid tissue (b) Central nervous system (c) Gastrointestinal tract

2 IV IARC MONOGRAPHS VOLUME The HIV - 1 and HIV -2 genome and gene products...38 (i) Structural proteins (Gag, Pol, Env)...39 (ii) Regulatory proteins (Tat, Rev) (iii) Accessory proteins (Nef, Vif, Vpr, Vpu) Replication Methods of detection i Antibody tests (a) ELISA (b ) Western blot analysis (c) Indetermi nate HIV antibody results (d) U ndetectab1e HIV antibody (e) Diagnosis of HIV infection in infants...43 (f) Detection of antibodies in saliva Direct detection of HIV...44 (a) Viral culture (b) p24 Antigen (c) Detection of viral genomes...45 (d) HIV quantification Epidemiology of HIV infection HIV transmission (a) Sexual contact (b) B 100d contact (c) Mother-to-child transmission (d) Other modes of transmission Geographical distribution (a) Global estimates and projections...49 (b) United States and Canada...51 (c) Caribbean (d) Latin America '" (e) S ub-saharan Africa (f) Europe (g) Asia (h) Oceania (i) Middle East Clinica1 description of non-neoplastic disorders Seroconversion syndrome Immunological decline Non-AIDS-defining manifestations of HIV infection...57 (a) Classification of HIV disease (b) Non-AIDS illness (c) Time to AIDS AIDS manifestations Long-term non-progressors Human immunodeficiency virus type 2 (HIV -2)...61

3 CONTENTS v 1.5 Control and prevention...6 i 1.5. i Behavioural prevention i.5.2 Sc ree n i n g Treatment Prospects for vaccines Other approaches Studies of cancer in humans Kaposi' s sarcoma Patho10gy and c!inical disease...65 (a) C1inica1 disease in HIV -seronegative individuals...65 (b) Clinical disease in HIV-seropositive individuals i.2 Descriptive epidemiology of Kaposi's sarcoma...66 (a) Demographic variations: age and sex...66 (b) Geographical variations (c) Temporal changes Descriptive epidemiological studies...68 (a) Studies in men in relation to marital status...68 (b) Linkage studies between AIDS and cancer registries i.4 Anal ytical studies (a) Cohort studies (b) Case-contro1 studies i (c) Analytical studies of the re1ationship between degree of immunosuppression and Kaposi' s sarcoma among HIV infected persons Factors influencing the occurrence of Kaposi's sarcoma in HIV infected persons (a) Behavioura1 cofactors (i) Descripti ve studies (ii) Anal ytica1 studies (b) Infectious cofactors (i) Human herpesvirus (ii) Cytomega10virus (iii) Other infectious agents (c) Genetic susceptibi1 ity (d) Miscellaneous factors Human immunodeficiency virus type Non-Hodgkin' s lymphoma i Description of the c1inical disease and patho1ogy...88 (a) Classification of AIDS-related 1ymphomas...89 (i) Systemic non-hodgkin's lymphomas...89 (ii) Body cavity-based lymphoma...90 (iii) Primary 1ymphoma of the brain...90 (iv) Mu1ticentric Castleman' s disease (b) Phenotypic and genotypic features

4 Vi IARC MONOGRAPHS VOLUME Descriptive epidemio10gy of non-hodgkin's 1ymphoma...91 (a) Cancer registry data (b) Cohort data Ro1e of immunosuppression Co- factors (a) Demographic (b) Geographic (c) Behavioural (d) 1 n fecti ons (i) Epstein-Barr virus (ii) HHV (iii) HHV (e) Zidovudine and other therapy HIV -2 and non-hodgkin 's Iymphoma Cervical, anal and other cancers Cervical intraepithelia1 neoplasia and invasive cancer (a) Precancerous lesions (i) Association with HIV (ii) Association with HIV and HPV (iii) HIV, HPV and CD4+ T-cell counts (iv) Progression of disease and treatment of CIN 1esions (b) Invasive cervical cancer (i) Case series (ii) Prognosis (iii) Descriptive epidemiology (i v) Case-control studies Anorecta1 intraepithelia1 neoplasia and invasive cancer (a) Precancerous 1esions (i) Association with HIV (ii) Association with HIV and HPV (iii) HIV, HPV and CD4+ T-cell count (iv) Progression of disease...1 i 9 (b) Invasive anal cancer (i) Case reports and series (ii) Prognosis (iii) Descriptive epidemio10gy Hodgkin' s disease (a) Distribution of histo1ogical types (i) Hodgkin's disease in HIV-uninfected persons (ii) Hodgkin's disease in HIV-infected persons (i i i) Prognosis (b) Descriptive epidemiology (c) Cohort studies (d) Cofactors

5 CO NTENTS VII Testicular cancer (a) Case reports and series (b) Descriptive and cohort studies Non-melanoma cancers of the skin (a) Case reports and series (b) Descriptive and cohort studies Conjuncti val tumours (a) Case reports (b) Descriptive study (c) Case-control studies Leiomyosarcoma (a) Case reports and series (b) Descriptive studies (c) Cofactors Other cancers Studies of cancer in animais HlV -1 and HlV Lymphomas in non-human primates Occurrence of lymphomas in nonhuman primates infected with simian immunodeficiency virus Pathological and molecular features of Iymphoma Other neoplastic conditions Cofactors in SLV oncogenesis Feline immunodeficiency virus infection in cats Occurrence of Iymphosarcomas in FIV infection Pathological and molecular features of lymphosarcoma Other data relevant to an evaluation of carcinogenesis and its mechanisms lmmunity and cancer Types of cancer seen in non-hiv -associated human immunodeficiency Time of onset of cancers in non-hiv -associated immunodeficiency Similarities and differences between AIDS and transplantationassociated tumours (a) ln immunity (b) ln cancer types (c) ln onset Occurrence of other viruses in malignancies associated with non-hiv immunosuppression Mechanisms by which immune dysfunction may contribute to the genesis of cancer (a) Activation of oncogenic viruses with immunosuppression (b) Stimulation and hyperreactivity of remaining cells in immunosuppressed persons...150

6 VIII IARC MONOGRAPHS VOLUME Kaposîs sarcomas Cell biology of Kaposîs sarcoma les ions (a) Origins of Kaposi's sarcoma spindle cells...15 i (b) Vascular lesions induced by Kaposîs sarcoma cell cultures i n n ude in i ce (c) Growth factors involved in the proliferation of spindle cells..153 (i) Fibroblast growth factors (i i) Platelet -de ri ved growth factor (d) Clonality of Kaposîs sarcoma and chromosomal abnorma1 Ities The mie of HlV -1 Tat in the development of Kaposi' s sarcoma 1esions An infectious agent as a cause of Kaposi's sarcoma The role of human herpesvirus (a) Genomic organization and relationship to other primate herpesviruses (b) ln-vivo tropism and association with Kaposi's sarcoma Non-Hodgkiils Iymphomas and other lymphopro1iferative disorders Pathologica1 models of lymphomagenesis (a) HIV infection of Iymphoid tissues and po1yc1ona1 B-cell hyperp1asia (i) Patho10gical changes in HIV -infected Iymphoid follicles (ii) Destruction of follicu1ar centres and B-cell hyperp1asia (iii) Chronic antigen stimulation (iv) Presence of HIV in tumour cells (b) Oligoc1onal B-cell proliferation (i) Immu nosuppression (i I) Cytokines (c) Genetic abnormalities ( i ) c - mye (i i) BCL (I i i) ras (i v) p (v) 6q De1etions (vi) Chromosome 1 q abnormalities Lymphotropic viruses (a) EB V (b) HHV (c) HHV Concl usion Cofactors in anal and cervical carcinomas and other cancers...174

7 CONTENTS lx The role of HPV in the molecular pathogenesis of anogenital cancers in immunocompetent patients (a) Status and level of HPV DNA in the natura1 history of i n fec t ion (b) Expression of HPV proteins in the natural history of i n fec t ion (c) Molecular mechanisiis of transforming activity of HPV (i) Intrinsic properties of high-risk HPV E6 and E (ii) Regulation of E6 and E7 expression Interactions between HIV and HPV (a) Effects of HIV -related immunosuppression on HPV rep1ication and HPV -associated anogenita1 lesions (b) HIV Tat stimulation of cytokines and their role in genital les ions (c) Possible effect of HIV - i Tat on HPV E6/E7 expression Summary of data reported and evaluation Exposure data Human carcinogenicity data Animal carcinogenicity data Othcr relevant data and mechanistic considerations on HIV - 1 -associated neoplasiiis Evaluation References Human T -ceillymphotropic viruses Ex posure data Structure, taxonomy and biology Structure Taxonomy and phylogeny Host range Relatcd non-human primate viruses Target tissuc (iii l'ilm and itl i'ii'o) Genomic structure and properties of gene products Othcr genes cncoded hy the open reading frames L Il and III in the HTI"V -1 px region Met h od s 0 f de t cet i 0 Il Serological detection of specifie antibodics Detection and characterization of viral nuc1eic acids Isolation of HTL V -1 and HTL V -II Sero-indeterminate HTL V -1 western blots Seronegative HTL V -I-infected individua1s Epidemio10gy of HTL V infection HTL V -1 transmission (a) Mother -to-chi Id transmission

8 x IARC MONOGRAPHS VOLUME 67 (b) Sexual transmission (c) Transmission by blood Animal models of HTL V -1 transmission Geographical distribution of HTL V HTL V -1 prevalence and demographic features of HTL V-I i n fec t ion " Epidemiology of tropical spastic paraparesis/htl V -I-associated 1l1yelopathy '" Natural history of HTL V -1 primary infection Molecular epideiniology of HTL V HTL V-II epidemio1ogy Clinical description of non-neoplastic disorders HTL V -1 infection (a) Tropical spastic paraparesis/htl V - 1 associated myelopathy (b) U vei tis (c) Other i ntlammatory diseases... '" '" (i) Infecti ve dermatitis (ii) P()lymyositis (i i i) Alveol itis '".284 (i v) Arthritis (HTL V -I-associated arthropathy) (v) Thyroiditis '" (vi) SjÖgren' s syndrome '" 285 (ci) Immune suppression HTL V-II infection HTL V /HIV co-infection Control and prevention Studies of cancer in humans T -cell mal ignancies HTL V -1 infection ancl adult T-cellleukaemia/lymphoma (a) Ci inical description '" (i) Distribution by subtype (i i) Laboratory findings (i i i) Histological characteristics (i v) Genetic studies (v) Prognosis (vi) Prevention of A TLL (b) Epidemiology '" (i) Geographica1 distribution (ii) Age- and sex-distribution of A TLL (i ii) Cohort studies (iv) Case-control studies on co-factors HTL V -1 infection and cutaneous T-cell lymphomas HTL V-II infection

9 CONTENTS Xl 2.2 Other mal ignancies HTL V (a) Case reports and case series (b) Cohort studies (c) Case-control studies HTL V-II Studies of cancer in animais HTL V - 1 in animal mode1s Non-human primates Other models STL V - 1 in non-human primates STL V - I-associated lymphomas Pathologica1 and molecu1ar aspects Bovine leukaemia virus in sheep and cattle Disorders induced by BL V (a) Catt1e (b) Sheep Pathological and molecular aspects...~ (a) Cattle , (b) S h ee p (c) Mechanistic studies...3 i Vaccination trials Other data relevant to an eva1uation of carcinogenesis and its mechanisms General observations on retrovira1 oncogenesis Host factors The role of the HLA system in HTL V -1 infection Immune surveillance and escape (a) Anti bodies (b) T -cells Host genetic factors required during the transition to A TLL Viral factors '" Provira1 load and clonai integration of HTL V - 1 infection The role of Tax in cellular transformation/immortalization (a) Transforming/immortalizing properties of HTL V -1 Tax i n vif ro (i) Immortalizing effects on T-cells in vifro (ii) Transforming effect of Tax on fibroblasts cultures i 11 vif ro (b) Tumorigenic properties of fax in transgenic mice Pathways of Tax-mediated transactivation of cellular genes Differences between HTL V -I-transformed T -cells and A TLL cells The ro1e of other viral and host cell proteins in lymphocyte stimulation and leukaemogenesis

10 XII IARC MONOGRAPHS VOLUME Differences between HTL V -1 and HTL V Summary of data reported and evaluation...; Exposure data Human carcinogenicity data Animal carcinogenicity data Mo1ecular mechanisms of leukaemogenesis Evaluation References AB BRE VIA TIONS SUPPLEMENT ARY CORRIGENDA TO VOLUMES CUMULATIVE INDEX TO THE MONOGRAPHS SERIES...397

11 NOTE TO THE REA DER The term 'carcinogenic risk' in the IARC Moiiographs series is taken to mean the probability that exposure to an agent will 1ead to cancer in humans. Inclusion of an agent in the MOl1ographs does not imp1y that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a monograph does not mean that it is not carcinogenic. The eva1uations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. No recommendation is given for regulation or 1egislation. Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk of an agent to humans is encouraged to make this information avai1ab1e to the Unit of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon Cedex 08, France, in order that the agent may be considered for re-evaluation by a future Working Group. Although every effort is made to prepare the monographs as accurately as possible, mistakes may occur. Readers are requested to communicate any errors to the Unit of Carcinogen Identification and Evaluation, so that corrections can be reported in future volumes. -1-