This is a new R29 submission to study the roles of co-stimulatory molecules B7.1 and B7.2, as well as cytokines IL4 and IL10, in the regulation of CTL activity toward HIV. The proposal is based on a series of observations, which illustrate that while vigorous CTL responses to HIV are detected in acute and chronically infected subjects, they are unable to completely inhibit virus replication and eradicate disease. The hypothesis advanced is that CTL to HIV may be suppressed in early to mid stage disease due to the lack of co-stimulatory molecule B7.1 expression in lymphoid germinal centers. The lack of B7.1 engagement of CTL is proposed to result in enhanced production of IL4, which fosters an environment where naive CD8+ cells are unable to develop into functional/activated CTL. There are three specific aims: (1) to quantitative t he expression of B7.1 and B7.2, and the production of IL4 and IL10 in lymph node germinal centers at various stages of HIV infection; (2) to determine the effect of HIV replication on the expression of co-stimulatory molecules and cytokine production; and (3) to investigate the relationship between co-stimulatory molecule expression, cytokine production and CTL function in vitro.
