Although no curative or preventive remedy has yet been developed, newer and better forms of treatment for HIV infection, ARC and AIDS permit extended lifespans and more occasions for infectious complications. Although many infections are due to the expected T-cell opportunists, two thirds of the septicemias are with extracellular pathogens. Traditional first line defenses against extracellular pathogens are antibody, complement and neutrophils. Defects in HIV+ patients are described in all three of these parameters. Changes in these parameters with time and as a consequence of specific therapy are not well understood. Therefore, parameters modulating host defense against extracellular pathogens need systematic study in patients undergoing anti-HIV treatment with special attention to the effects of therapy. More recently described components of the inflammatory response, such as mannose binding protein, are also likely to participate in the host response to infectious agents. This may be particularly relevant in HIV+ patients who are often infected with pathogens bearing mannose-rich surfaces - Mycobacteria, Salmonellae, most fungi, and Pneumocystis carinii - as well as HIV, itself coated with mannose-rich glycoprotein 120. It is not known if mannose-binding protein is deficient or dysfunctional in HIV infections. Thus, the role of mannose-binding protein in immunity of HIV+ patients needs to be explored. The overall objective of this proposal is to evaluate effects on humoral immunity of clinical therapeutic regimens given specifically to treat HIV infection (asymptomatic infection, ARC, and AIDS) or infectious complications of HIV infection. We will longitudinally evaluate complement-mediated serum microbicidal activity in patients on anti-HIV therapy and will test serum bactericidal and opsonic activity for blood isolates of bacteria and fungi from HIV-infected individuals. In particular, we will inquire into the role of complement and mannose-binding protein in these immune functions. Finally, we will evaluate the effects of subtherapeutic concentrations of antimicrobial agents on the interaction of complement and MBP with bloodstream isolates from HIV+ patients. These studies will provide a comprehensive yet focused analysis of the interaction between complement, MBP and antimicrobial therapy in host defense against extracellular pathogens in the HIV+ patient population.
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