Recombinant, attenuated Salmonella typhimurium stimulate lymphoproliferative responses to SIV capsid antigen in rhesus macaques.

Recombinant bacteria are useful vectors for delivering foreign antigens to mucosal surfaces and may elicit immune protection against sexually-transmitted pathogens. Recombinant, attenuated Salmonella typhimurium expressing the Simian Immunodeficiency Virus capsid protein (p27) were given to rhesus macaques by intragastric intubation. This route of immunization was compared with intramuscular injection of soluble p27 in adjuvant, and with immunization protocols that combined intragastric and intramuscular antigen exposures. Recombinant Salmonella stimulated p27-specific lymphoproliferative responses that were present transiently in peripheral blood, and were recalled easily by booster immunizations. Intramuscular p27 injection elicited strong serum antibody responses, but only low level capsid-specific proliferative responses. Recombinant Salmonella immunization elicited low levels of p27-specific antibodies in serum and did not suppress subsequent responses to parenteral immunization. Intragastric immunization of macaques with recombinant Salmonella typhimurium was safe and induced immune responses specific for the expressed, foreign antigen.

Acute effects of pathogenic simian-human immunodeficiency virus challenge on vaccine-induced cellular and humoral immune responses to Gag in rhesus macaques.

Simian-human immunodeficiency virus (SHIV) infection in macaques provides a convenient model for testing vaccine efficacy and for understanding viral pathogenesis in AIDS. We immunized macaques with recombinant, Salmonella typhimurium (expressing Gag) or soluble Gag in adjuvant to generate T-cell-dependent lymphoproliferative or serum antibody responses. Immunized animals were challenged by intrarectal inoculation with SHIV89.6PD. Virus infection was accompanied by rapid losses of lymphoproliferative responses to Gag or phytohemagglutinin. By 8 weeks, mitogen responses recovered to near normal levels but antigen-specific immunity remained at low or undetectable levels. Serum antibody levels were elevated initially by virus exposure but soon dropped well below levels achieved by immunization. Our studies show a rapid depletion of preexisting Gag-specific CD4(+) T cells that prevent or limit subsequent antiviral cellular and humoral immune responses during acute SHIV infection.

CD4+-T-cell and CD20+-B-cell changes predict rapid disease progression after simian-human immunodeficiency virus infection in macaques.

Simian-human immunodeficiency virus 89.6PD (SHIV89.6PD) was pathogenic after intrarectal inoculation of rhesus macaques. Infection was achieved with a minimum of 2,500 tissue culture infectious doses of cell-free virus stock, and there was no evidence for transient viremia in animals receiving subinfectious doses by the intrarectal route. Some animals experienced rapid progression of disease characterized by loss of greater than 90% of circulating CD4+ T cells, sustained decreases in CD20+ B cells, failure to elicit virus-binding antibodies in plasma, and high levels of antigenemia. Slower-progressing animals had moderate but varying losses of CD4+ T cells; showed increases in circulating CD20+ B cells; mounted vigorous responses to antibodies in plasma, including neutralizing antibodies; and had low or undetectable levels of antigenemia. Rapid progression led to death within 30 weeks after intrarectal inoculation. Plasma antigenemia at 2 weeks after inoculation (P < or = 0.002), B- and T-cell losses (P < or = 0.013), and failure to seroconvert (P < or = 0.005) were correlated statistically with rapid progression. Correlations were evident by 2 to 4 weeks after intrarectal SHIV inoculation, indicating that early events in the host-pathogen interaction determined the clinical outcome.

Immunization of Macaca mulatta with aroA attenuated Salmonella typhimurium expressing the SIVp27 antigen.

Attenuated bacteria expressing foreign antigens stimulate both systemic and mucosal immune responses to the recombinant protein. We studied the infection of rhesus macaques with an attenuated Salmonella typhimurium expressing the simian immunodeficiency virus p27 capsid protein. Juvenile rhesus macaques were inoculated by intragastric intubation with doses ranging from 3 to 9 x 10(9) viable aroA attenuated S. typhimurium. The bacterial infection was self-limiting with no overt clinical signs. Salmonella were shed in the feces of macaques for approximately five days. Salmonella were isolated from fecal material to examine the in vivo stability of both the attenuating mutation and the integrated SIVp27 expression cassette. All Salmonella isolates retained both the attenuating mutation and the recombinant expression construct. In vitro analysis showed that a minimum of 7.2 microg of p27 was delivered by a single oral dose with attenuated, recombinant S. typhimurium.

Seeing and knowing: knowledge attribution versus stimulus control in adult humans (Homo sapiens).

Interest in cognition in nonhuman animals has inspired new approaches to discovering animals' ability to attribute knowledge to others (e.g., D. J. Povinelli, K. E. Nelson, & S. T. Boysen, 1990). The assumptions of such experiments were tested in this study by training a group of humans (Homo sapiens) to use accurate information provided by a confederate who was watching as 1 container among 4 was baited; a 2nd group was similarly trained to use accurate information provided by a confederate whose back was turned during baiting. On a single reversal trial, the roles of the 2 confederates were switched. Subjects were able to learn their respective tasks but attended to different aspects of the confederates, as revealed by the reversal trial. Although attributional interpretations can be applied to such data, many of the choices in this experiment can be explained more readily with the basic principles of contingency-based learning.