Transplantation

Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Kuwaki, K. et al. Nature Med. 11, 29–31 (2005).

Marked prolongation of porcine renal xenograft survival in baboons through the use of α1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Yamada, K. et al. Nature Med. 11, 32–34 (2005).

Natural antibodies specific for α1,3-galactose (Gal), which is present on the surface of all pig cells, are the main cause of hyperacute xenograft rejection in non-human primates. Cardiac and renal transplants from α1,3-galactosyltransferase gene-knockout pigs, which do not express Gal, have extended survival in baboons, with a maximum of 83 days for the renal transplant and 179 days for the cardiac transplant. These are the longest recorded xenograft survival times of this type.

HIV

The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Gonzalez, E. et al. Science 6 Jan 2005 (10.1126/science.1101160).

Variation between individuals in the copy number of CC-chemokine ligand 3 (CCL3)-like 1 (CCL3L1), a duplicated isoform of CCL3, has a significant effect on immunity to HIV. Individuals with a lower than average CCL3L1 copy number have an increased risk of becoming infected with HIV and of progressing rapidly to AIDS, and vice versa. High levels of CCL3L1, which is the most potent known ligand for the HIV co-receptor CCR5, are thought to block the association between CCR5 and HIV gp120 required for virus internalization. Individuals with a low CCL3L1 copy number were more susceptible to the disease-accelerating effects of detrimental CCR5 genotypes, supporting the crucial involvement of CCR5 and its ligands in determining HIV pathogenesis.

Antigen processing

Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Paludan, C. et al. Science 9 Dec 2004 (10.1126/science.1104904).

Although MHC class II molecules mainly present peptides of exogenous origin, some peptides are derived from endogenous proteins. Paludan et al. showed that inhibition of lysosomal acidification leads to accumulation of the endogenous antigen Epstein-Barr virus nuclear antigen 1 (EBNA1) in cytosolic vesicles. Some of these vesicles also contained a lysosomal marker, and most had ultrastructural features of autophagosomes. Consistent with this, interferon-γ production by EBNA1-specific CD4+ T cells was decreased after stimulation with either cells treated with an inhibitor of autophagy or cells in which expression of the essential autophagy gene Atg12 had been reduced. The authors suggest that lysosomal processing after autophagy allows MHC-class-II-restricted immune surveillance of some endogenous proteins.