Zhang L, Yu W, He T, et al. Science. 2002;298:995–1000
Purpose of the Study.
Since 1986, it has been known that CD8+ T-cells from human immunodeficiency virus (HIV)-infected, immunologic stable long-term survivors secrete a soluble factor that has been termed CD8 antiviral factor (CAF). The molecular identity of CAF has remained elusive. Some of the antiviral activity in CAF appears to be mediated by β−chemokines, MIP-1α, MIP-1 β and RANTES; however, these factors do not account for all of the anti-HIV activity in CAF. The purpose of this study was to describe the anti-HIV activity of human α-defensins.
Protein chip technology was used to identify a cluster of proteins that were secreted when CD8+ T-cells from long-term nonprogressors were stimulated in vitro. After identification of these proteins, HIV suppressive activity was measured and the source of these molecules was identified.
The proteins were identified as α-defensins 1, 2, and 3 on the basis of specific antibody recognition and amino acid sequencing. A significant proportion of CAF activity was eliminated or neutralized by antibody specific for human α-defensins. Synthetic and purified preparation of α-defensins inhibited the replication of HIV isolates in vitro. Finally, a subset of CD8+ T-cells express and secrete α-defensins.
These results indicate that α-defensins 1, 2, and 3 collectively account for much of the anti HIV activity in CAF that is not attributable to β-chemokines. The potential usefulness of α-defensins as therapeutic agents in patients with HIV remains to be demonstrated.
Defensins are members of a family of antimicrobial peptides that are particularly abundant in neutrophils. The demonstration that defensins constitute a component of CAF has important implications. Perhaps these defensins are causally involved in the reduction of HIV progression. If so, the administration of extrinsic defensins or the stimulation of in vivo production of defensins would be appropriate therapeutic goals. Alternatively, the presence of a subset of T cells capable of generating α-defensins may simply reflect the preservation of selected immune functions in individuals in which other mechanisms are responsible for this preservation. Importantly the amount of α-defensins produced by CD8+ T cells is tiny relative to the amount routinely expressed in neutrophils, including those of progressing HIV-infected patients.