COINFECTION OF MACAQUES WITH STLV-1 AND SIV

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Because of reports of apparently more rapid progression to AIDS in co- infected individuals, there is concern about the increasing number of people being exposed to and becoming infected with the pathogenic human retroviruses, HIV (human immunodeficiency virus) types and 1 and 2, and HTLV (human T-cell leukemia/lymphoma virus) types I and II. Furthermore, the incidence of cancers, particularly B-cell lymphomas, appears to be increasing among HIV-infected persons whose lives have been extended due to therapeutic interventions, but whose immune systems are still compromised. Although HTLV-associated proliferative disease generally develops over more than 20 years in a small percentage of infected persons, it is possible that co-infection with HIV could not only shorten the latent period but also enhance the likelihood of developing proliferative or neurologic diseases caused by HTLV. Thus, an animal model is needed to define in vivo interactions between members of these two retrovirus families and to assess the possible consequences of dual infection on immunodeficiency and neoplastic diseases. The development of such a model is the long-term goal of this proposed research, which will be achieved through a combination of in vivo and in vitro studies. Pig- tailed macaques (Macaca nemestrina) will be singly infected or co-infected with SIVsmm and STLV-I(sm), which were isolated from a naturally infected sooty mangabey and are simian counterparts of the human viruses. During long-term follow-up of the animals, various virologic (such as virus burden), immunologic, and clinical parameters will be compared. Viruses recovered from infected animals will be characterized for genomic mutations and for changes in biologic properties, including formation of pseudotypes. STLV-I(sm) has been fully sequenced, which will facilitate molecular analyses an infectious molecular clone and partial clones will be generated to aid in the evaluation of biologic properties and interactions with SIVsmm. To understand possible in vivo interactions between these two viruses, replication kinetics, cytopathicity, and formation of pseudotypes during co-infection of primary lymphocytes will also be evaluated in vitro. Finally, C.B-17 SCID mice will be reconstituted with PBMC from macaques infected with STLV-I(sm) that have evidence of preleukemic cells or leukemia/lymphoma to evaluate tumorigenesis. The proposed research will provide model systems (i) to evaluate, at cellular and organismal levels, the potential interactions and impact on disease on these two retrovirus families; (ii) to define factors important in development of hematologic neoplasms; and (iii) to explore therapeutic intervention strategies in co-infected persons.