Immunogenetics: Safety in numbers

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A recent report from Enrique Gonzalez et al provides a striking example of the influence that duplications of immune receptor genes can have on HIV susceptibility and progression to AIDS. The HIV virus utilises three major receptors of the immune system to beat this system from within. These are the CD4 coreceptor on CD4þ T-helper cells, the CCR5 chemokine receptor on T-cells and the DC sign receptor on antigenpresenting dendritic cells (DCs). The virus utilises these receptors to attack to, penetrate into and replicate in mainly CD4þ T cells and it eventually destroys and depletes them. In the case of DC sign, this appears to allow DCs to transport HIV towards central lymphoid organs to gain better access to T lymphocytes. Polymorphisms in the HIV components that interact with these receptors and polymorphisms in the host receptors themselves, as well as duplications of these genes can therefore be expected to influence susceptibility to HIV infection and progression to AIDS. In this new study, the authors show that duplications of the gene that encodes CCL3L1, the most potent known ligand for CCR5, confers marked resistance to HIV infection and progression towards AIDS, independent of ethnic background. CCL3L1 presumably has potent anti-HIV activity because its chemokine activity might block the interaction between HIV gp120 envelope protein and CCR5. As the authors speculate, another alternative is that CCL3L1 may induce ligand-mediated internalisation of CCR5, thereby reducing its availability for use by gp120. More research is obviously needed to clarify the precise mechanism(s) by which CCL3L1 low copy number predisposes to HIV persistence following infection and to progression towards AIDS in those persistently infected. Not surprisingly, CCL3L1 copy number and CCR5 genotypes were shown to have interactive effects. Earlier work had shown before that CCR5 haplotypes, including CCR5 promoter polymorphisms as well as coding polymorphisms in CCR2 (CCR2-V64I) and CCR5 (D32), influence the risk of acquiring HIV and the rate of disease progression. – 5 In the current work, CCR5 detrimental (det), that is, disease accelerating and nondetrimental (non-det) CCR5 genotypes, were further analysed with respect to low or high CCL3L1 copies (CCL3L1 or CCL3L1 ) in an HIV-positive adult cohort. This analysis allowed this cohort to be stratified into four mutually exclusive genetic risk groups. Interestingly, the theoretically highest risk group (CCL3L1 CCR5) showed a greater than three-fold greater risk of progressing rapidly to eight of 12 AIDS-defining illnesses. The important role that genetics has in susceptibility to retrovirus-induced disease has been well-known for decades, ever since the pioneering work of Frank Lilly and co-workers – 8 on murine viral leukemogenesis. The genes involved were found to affect viral host range and replication as well as the immune response. The earliest gene locus (cluster) found to affect susceptibility to murine viral leukemogenesis was in fact MHC. Even at this early stage, a gene dose effect was evident, because in animals with homozygous MHC-resistant haplotypes a protection against viral leukemogenesis was more profound than in heterozygous animals with a single MHC-resistant haplotype. MHC haplotypes are known to affect a variety of specific immune responses, including antiviral antibodies, CD4þ Thelper cell responses and cytotoxic T lymphocyte (CTL) responses. For example, the HLA B*5701 allele frequently shows up in cohorts of long-term asymptomatic HIV-infected individuals: a pattern that probably reflects CTL recognition of dominant and conserved HIV peptides that HLA B*5701 presents. In most individuals infected with HIV, the virus manages to immuno-escape from CTL responses by generating mutations in the viral peptides presented by HLA molecules. Viral structural constraints in the conserved HIV peptides presented by HLA B*5701 apparently do not allow the virus to escape from immune attack by mutations in these particular sequences. So now we have a good idea of the importance of polymorphisms in CCR5, CCL3L1 and HLA genes for susceptibility to retroviral diseases. However, many more genetic effects are lurking in the dark, awaiting exploration. Nonetheless, the susceptibility loci that have already been identified point towards the mechanisms that underlie this susceptibility and, moreover, suggest ways of therapeutically exploiting the chemokine and chemokine receptor pathways. Also, in vaccine design experience with the HLA B57 resistance allele indicates that HIV vaccines should aim at induction of T-cell responses against conserved epitopes that the HIV virus cannot afford to evade by generating escape mutants. Clearly, the challenges for geneticists, virologists and immunologists alike are enormous, to not only further document genetic control of HIV infection and progression towards AIDS, but also to design novel therapeutic interventions based on these insights’