HIV-associated bactericidal and inhibitory immunity to Salmonella in Africans

It has been recognized for almost thirty years that nontyphoidal strains of Salmonella are a leading cause of death in HIV-infected Africans. The mechanisms underlying this susceptibility to invasive Salmonella disease have only recently started to be identified. Firstly, it became apparent that antibody-induced complement-mediated bacterial killing can protect healthy Africans adults and children by preventing the spread of the Salmonella through the blood. More recently we reported that in many HIV-infected African adults, antibodies against Salmonella lipopolysaccharide (LPS) block the antibody-induced complement-mediated killing of these bacteria, thus allowing the extracellular spread of infection. Here, we show that the blocking effect of anti-LPS antibodies is a factor of antibody concentration, rather than antibody structure or specificity. Thus, antibodies from HIV-infected subjects that block killing of Salmonella at plasma concentrations induce complement-mediated killing of Salmonella in diluted plasma. Equally, bactericidal anti-LPS antibodies of all isotypes from individuals not infected with HIV inhibit the killing of Salmonella when concentrated to levels grossly above those found in plasma. These findings indicate that underlying susceptibility of HIV-infected individuals to Salmonella, and potentially other pathogens, relates to hypergammaglobulinemia associated with impaired immune homeostasis