Until recently, it was a mystery why some individuals infected with HIV-1 do not become immunodeficient (long-term non-progressors, LTNPs). CD8+ T cells are known to be important, but why are they more effective in some individuals than others? A recent paper in Nature Immunology showed that the increased expression of perforin by CD8+ T cells from LTNPs is important for their cytolytic activity (see the Highlight 'Quality control' in our November issue). But, since the first description of CD8 antiviral factor (CAF) — which is secreted by stimulated CD8+ T cells from certain infected individuals — it has been recognized that soluble factors can inhibit virus replication also. Now, Zhang et al. report in Science the identification of human α-defensins 1, 2 and 3 as one of the main components of CAF.

Previous studies had indicated that β-chemokines (CCL3, CCL4 and CCL5) might account for the antiviral activity of CAF by competing with virus for binding to CCR5, which is used as a co-receptor for virus entry. However, this can only inhibit R5 viruses, and not X4 viruses, which use CXCR4 as a co-receptor. Using protein-chip technology, Zhang et al. have shown that the α-defensins carry out much of the anti-HIV activity of supernatants from stimulated CD8+ T cells that is not attributable to β-chemokines.

The authors compared the protein mass spectra of supernatants from stimulated and unstimulated CD8+ T cells of LTNPs, normal progressors and controls. Marked differences between stimulated and unstimulated spectra were observed — specifically, three peaks between 3.3 and 3.5 kD that were present in stimulated cultures from LTNPs and some controls, but not progressors. The three peaks correspond to the molecular masses of human α-defensins 1, 2 and 3, and this result was confirmed by protein sequencing.

Depletion of these molecules from culture supernatants eliminated activity against X4 viruses and markedly reduced activity against R5 viruses. Residual activity against R5 viruses could be neutralized by the addition of antibodies specific for the β-chemokines. Furthermore, synthetic and purified α-defensins were shown to reduce HIV-1 replication in vitro.

So, we are one step closer to understanding the mystery of LTNPs, which can only aid the development of new therapeutics. It remains to be determined how the α-defensins mediate their antiretroviral effects, and whether they are involved directly in non-progression.