Malaria is a growing public health problem. The transmission of malaria parasites by vector species of Anopheles mosquitoes is difficult to interrupt. The site-specific transmission potential of each vector species is governed by the immediate environment, vector behavior, and innate vector competence. The complex relationships which affect malaria parasite transmission by Anopheles vectors are poorly understood and this presents a major obstacle for effective malaria control. This proposal seeks to investigate how species of Anopheles mosquitoes differ in their ability to support the sporogonic development of Plasmodium parasites. New approaches for examining innate vector competence and Plasmodium development will provide insights into how basic mosquito-parasite interactions affect patterns of transmission in nature. Species of Anopheles mosquitoes from three major geographic areas of malaria endemicity will be infected with in vitro cultured gametocytes of P. falciparun, the most pathogenic human malaria. Parameters of parasite development for each anopheline species, determined by quantifying each major sporogenic stage over 20 d, will be related to infections in a reference species included in each experiment. Profiles of blood-feeding behavior and digestive physiology will be developed for each anopheline species. These studies will define Anopheles species differences in susceptibility and parasite development. Further comparative studies on anopheline vector competence will focus on environmental determinants of Plasmodium development, sporozoite invasion and survival in the salivary glands, and sporozoite transmission. These approaches for determining factors regulating the ability of Anopheles mosquitoes to serve as malaria vectors will yield new information for investigating malaria parasite transmission in nature, and for developing and evaluating malaria control measure. GRANT-R01AI32885 A number of biochemical features of the AIDS virus hamper efforts to control the disease or prevent the spread of infection. Included among them is the high degree of viral genetic variation, and therefore antigenic variation, within the envelope protein. A multifaceted study is proposed to correlate findings from a careful clinical and immunological analysis of HIV1 in an infected male homosexual (referred to as subject MA or 145) and an in-depth analysis of the diversity and functional consequences of this diversity in viral envelope genes. Virus isolates and cytotoxic T-lymphocyte (CTL) cell lines derived from cerebrospinal fluid (CSF) and PBL will be generated and PBMC, serum and semen samples will be obtained at frequent intervals. These will be combined with an extensive list of materials and information already available from this subject, including CTL lines, virus isolates. CSF and other tissue samples and DNA sequence information, including samples which bracket the onset of AZT therapy. Complete envelope genes will be subjected to PCR amplification and cloning into a vaccinia virus expression vector. PCR products will be subjected to heteroduplex, restriction fragment length polymorphism and DNA sequence analyses over the 3'700 bp of the gp120 coding sequence. Whole envelope proteins will be expressed in vaccinia virus and evaluated for CTL recognition and neutralization susceptibility, and inserted into a provirus backbone for analysis of virus cell tropism, syncytium inducing capacity, and cytopathogenicity. Extensive computer-aided analyses will be performed to track viral genotypes and identify genetic features which correlate with structural and functional differences. Detailed analysis of this and subsequent subjects provides a unique opportunity to study the natural history of infection and disease progression as well as provide valuable insight into the response to antiviral therapy and potentially vaccine design.
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