We speculate that if Vpu can be presented in a manner that elicits functional and effective ADCC responses, then the Vpu ADCC epitopes that we describe AZD4547 could be interesting vaccine antigens. Interestingly, a study by Chen et al. in 2003 suggested that Vpu-specific antibody responses detected by Western blot were associated with slower disease progression. An important caveat of this work is that our mapping of ADCC responses was limited to linear peptide epitopes that could be defined with individual
peptides. Conformational ADCC epitopes within Vpu and other HIV proteins recognized by LTSP subjects would also be of considerable interest, but such epitopes are more difficult to map. Further, the number of LTSP subjects that generated Vpu peptide-specific ADCC responses was modest (seven of the 65 subjects, 10·8%). However, this might be expected because multiple other mechanisms, such as HLA
class I molecules and CCR5 deletions, have been associated with slow HIV progression.[39, 40] Indeed, 35% of the LTSP subjects tested were CCR5Δ32 heterozygotes and 41% of the LTSP subjects tested had either HLA B27 or B57 alleles. It is possible that ADCC responses targeting common epitopes in Env or other HIV-1 proteins are also associated with slowly progressive HIV. The C1 region of Env has recently been shown to be a common target of ADCC antibodies and we recently showed that ADCC epitopes within C1 can force immune escape. Our ability to fully map Env-specific ADCC in the LTSP cohort was limited by the volumes of sera available from the LTSP cohort and the large number of overlapping peptides spanning Env. this website This is a subject of ongoing research. The large diversity of infecting Env strains, the ability of Env to readily escape antibody responses, and the limited apparent fitness costs of Env variants potentially makes Env a less attractive target than more conserved HIV proteins.[42-45] Although this study identifies an immune response associated with slow
HIV progression, this does not prove that this response is causally linked to slow progression. LTSP subjects are by definition infected for long periods of time and the anti-HIV ADCC responses may broaden over Suplatast tosilate time unrelated to the control of viraemia. Previous smaller studies suggest broadening of ADCC responses over time.[46, 47] However, we are now in a position to definitively test the protective effects of these Vpu ADCC antibodies in passive transfer studies in macaques subsequently challenged with chimeric SHIV expressing HIV-1 Vpu. Previous passive transfer experiments using neutralizing antibodies have suggested an important additive role for ADCC functions,[10, 48] but the utility of ADCC antibodies without neutralizing activity in protecting macaques from SHIV infection is not known. In conclusion, we studied HIV-specific ADCC responses in a large cohort of LTSP subjects.