The long range objective of the proposed study is to understand the microbiologic, serologic and molecular epidemiologic basis of infection with opportunistic Rochalimaea species in individuals with HIV infection. The four Rochalimaea species are among the newest emerging pathogens, having been identified in the US only in the 1990s, and producing syndromes including bacillary angiomatosis and peliosis hepatis. HIV antibody-positive individuals are at markedly increased risk of developing severe, even lethal, infection with the Rochalimaea species, yet these infections are curable if diagnosed in a timely manner, and may be preventable if sources of infection can be identified. The immediate objective of these studies will be: 1. Identification of epidemiologic risk factors associated with infection by the different Rochalimaea species: A case-control epidemiologic study to determine various exposures associated with developing infection with the different Rochalimaea species, including mammalian reservoirs and arthropod vectors implicated in transmission of each species, will be performed. Prevention of infection is dependent on identifying the risk factors for these infections. 2. Characterization of the Rochalimaea species isolated from humans, reservoirs and vectors: Preliminary data suggest that the reservoir and vector exposures differ for infection with the different species. Because so few data exist regarding these infections, a) cultures will be performed from all patients, reservoirs and vectors with suspected Rochalimaea infection, b) molecular techniques will be utilized to speciate isolates, and to determine genetic relationships between isolates and c) the new species or subspecies of Rochalimaea which we have isolated will be characterized. 3. Characterization of the serologic response of the HIV-infected individual to Rochalimaea infection: We will utilize an IFA test to investigate a) duration of antibody response, b) species-specificity of the IFA test and c) if this test can be used to predict relapse. A sensitive and specific serologic test will substantially facilitate diagnosis and management of this infection in HIV-infected people. 4. Preliminary characterization of the angiogenic response to Rochalimaea infection: Rochalimaea infection in HIV-infected patients causes a unique vascular proliferative response. Using isolates derived from the above studies, we will evaluate several different assay systems to determine the angiogenic potential of these species. The elucidation/characterization of these parameters of human infection with Rochalimaea species will provide a basis for diagnostic, therapeutic and preventive strategies which will decrease morbidity and mortality among individuals with HIV infection. R01AI36086 The overall aim of the studies described in this proposal is to relate alterations in patterns of cytokine expression to the course of HIV infection and disease, by quantifying cytokine production in specific subpopulations of men in the Multicenter AIDS Cohort (MACS). In preliminary studies, cytokines that determine immune function were found to be substantially altered in HIV infection. the proposed studies are designed to determine: 1) whether high levels of those cytokines fostering cell-mediated immunity (the TH1 cytokines IFN(gamma) and IL-2, as well as IL-12, a cytokine that induces TH1 cells) are associated with relatively stable CD4 T cell levels and with the absence of opportunistic infections (OI), in HIV infection; 2) if the predominance of TH2 cytokines (IL-4 and IL-10) is associated with falling CD4 T cell levels and with the occurrence of OI, in HIV infection; 3) if increases in TNF(alpha) and IL-6 gene expression/levels are associated with an adverse disease course in HIV infected people, and to determine whether these cytokines are a better predictor of disease progression than the over- expression of TH2 cytokines (IL-4 and IL-10); 4) the relevance to prognosis (relative hazard) of individual and complex changes in cytokine expression and to find if these changes provide prognostic information not available from the measurement of CD4 T cell number of serum activation markers (such as neopterin or beta-2-M). Populations for investigation include cohorts from the MACS studies: a) HIV seroconverters, b) HIV-seropositive (HIV+) men with different rates of decline of CD4T cell number, c) HIV+ men progressing to AIDs within 3 years, d) long term HIV+ survivors with little or no measurable loss of CD4 T cells, e) HIV+ men who have had low CD4 numbers for an extended time without the occurrence of opportunistic infection, and f) a population in which selected cytokines can be evaluated for relative hazard of AIDS occurrence. We will measure: 1) serum levels of these cytokines, 2) levels of cytokine gene expression (mRNA) in peripheral blood mononuclear cells (PBMC) by RNA PCR, 3) cytokine production, and levels of cytokine mRNA, in response to in vitro stimulation of PBMC, in HIV+ subjects and in HIV seronegative people. These studies will provide valuable new information on the role of cytokines in the progression of HIV disease, as well as determining the patterns of cytokine expression that are associated with HIV disease progression and the pathogenesis of AIDS.
Showing the most recent 10 out of 15 publications
