Genetic diversity in Hla Kir and HIV strategies for survival

Viral co-evolution with molecules of the immune system is thought to have been a major force in shaping the genetic diversity observed today in genes involved in our immune defence. The consequences of this are seen in the human leukocyte antigen (HLA) genes where particular alleles have been found to be associated with differences in disease progression after infection with HIV-1. Research in this field has provided evidence to support the hypothesis of 'heterozygous advantage' (also called 'overdominant selection') - the concept that individuals heterozygous for HLA loci were at an immunological advantage compared to homozygotes as they were able to present a greater variety of antigenic peptides (Section 12.3.1) (Doherty and Zinkernagel 1975b). Carrington and coworkers studied patients who became HIV antibody positive after enrolling in at-risk AIDS cohort studies, and in whom rates of progression to AIDS endpoints could be carefully defined (Carrington et al. 1999). They found that among 498 seroconverters, those individuals maximally heterozygous at MHC class I loci had significantly delayed onset of AIDS compared to individuals homozygous at one or more loci (Fig. 14.10) - class I loci encoding proteins responsible for presentation of viral antigen to cytotoxic T lymphocytes (Section 12.2.1).

Are specific class I alleles associated with disease progression? Carrington and colleagues found that six of 63 class I alleles tested were associated with disease progression, notably HLA-B*35 and Cw*04 among Caucasians (Carrington et al. 1999). These were large effects: people homozygous for HLA-B*35 progressed to AIDS in half the median time of those without HLA-B*35. A more detailed examination of the role of specific HLA-B*35 subtypes provided clues about the underlying mechanisms involved (Gao et al. 2001). Presentation of viral peptides by the B*35 encoded class I molecules on CD4+ T lymphocytes to cytotoxic T cells showed highly specific peptide recognition. Among the five different HLA-B*35

Years since seroconversion

Figure 14.10 Homozygosity at HLA class I and progression to AIDS. A Kaplan-Meier survival curve for 498 seroconverters showing the influence of HLA class I genotype on progression to AIDS (defined as AIDS-1987, namely HIV-1 infection plus an AIDS-defining illness or death). For individuals with one locus homozygous, the relative hazard (RH) was 1.8 (P = 0.0005; n = 74), for two or three loci homozygous the RH was 4.1 (P = 1 X 106; n = 18). P values are calculated by the Cox proportional hazards model and analyses are stratified by age and race. From Carrington et al. (1999), reprinted with permission from the AAAS.

Years since seroconversion

Figure 14.10 Homozygosity at HLA class I and progression to AIDS. A Kaplan-Meier survival curve for 498 seroconverters showing the influence of HLA class I genotype on progression to AIDS (defined as AIDS-1987, namely HIV-1 infection plus an AIDS-defining illness or death). For individuals with one locus homozygous, the relative hazard (RH) was 1.8 (P = 0.0005; n = 74), for two or three loci homozygous the RH was 4.1 (P = 1 X 106; n = 18). P values are calculated by the Cox proportional hazards model and analyses are stratified by age and race. From Carrington et al. (1999), reprinted with permission from the AAAS.

subtypes, two groups could be resolved with different peptide binding specificities. The HLA-B*35-PY group (mainly comprising B*3501, the commonest subtype of B*35) and the HLA-B*35-Px group differ in the ability to recognize particular amino acids at position 9 in the HIV-1 peptide (the PY group are specific to tyrosine at position 9, the Px group are specific to different amino acids but not tyrosine). All the effect found for HLA-B*35 was due to the HLA-B*35-Px group: a change in preference of a single amino acid in a class I molecule sufficient to dramatically alter disease progression (Gao et al. 2001). The observed association with Cw*04 was felt to be attributable to linkage disequilibrium with HLA-B*35-Px alleles.

The strong selective pressure exerted by HLA on the genetic diversity of HIV-1 has also been documented. There is a selective advantage for variant viral epitopes that may escape the cytotoxic T lymphocyte (CTL) response by failing to bind to class I molecules or interact with T cell receptors. Moore and colleagues analysed the reverse transcriptase sequences from 473 people enrolled in the Western Australian HIV Cohort Study

(Moore et al. 2002). They chose to look at the reverse transcriptase protein given the high level of expression in virions and immunogenicity in the early host response to HIV-1. Immune escape was found to be common and restricted by a range of different class I molecules. An excess of mutations was found in regions with motifs recognized by HLA alleles associated with rapid progression. Is there evidence that HLA types specific to regions of viral proteins important to viral survival (and therefore harder to mutate without deleteriously affecting function) are advantageous? HLA-B*27 and B*57 encoded molecules are specific to epitopes in conserved parts of p24 viral capsid protein for which at least two mutations are required for immune escape; both HLA types are associated with a survival advantage (Migueles et al. 2000; Gao et al. 2001; Kelleher et al. 2001).

The lysis of HIV-1 infected cells by CD8+ T cells through recognition of viral peptides presented by class I molecules on the infected cell surface is critical to the control of HIV-1 infection. The virus is able to combat this by downregulating expression of class I molecules on the infected cell surface and so make cells less likely to be recognized and lysed (Collins et al. 1998). There is a potential problem with such a strategy: downregulation of class I molecules carries the risk of destruction by natural killer (NK) cells. NK cells play a critical role in combating viral infection through killing infected cells, secreting anti-inflammatory cytokines such as interferon gamma (IFNy), and coordinating, with dendritic cells, the adaptive immune response. NK cells express activating and inhibitory receptors for HLA class I molecules which are critical to determining the NK response between the tolerance of healthy cells and destruction of infected ones (Box 14.6).

The answer for the virus appears to have been selective downregulation of class I molecules by the HIV-1 accessory protein Nef. HLA-A and HLA-B molecules were found to be removed but not HLA-C or HLA-E (Cohen et al. 1999). A systematic study of 221 cell lines created to stably express CD4 and specific class I proteins were analysed after infection with HIV-1. HLA-C and HLA-E encoded proteins were protected from viral downregu-lation by single specific residues in the cytoplasmic tails of the proteins differing between alleles. Retention of expression of HLA-C was sufficient to make the HIV-1 infected cells 'invisible' to most NK cells.

Box 14.6 Polymorphism of KIRs in health, evolution, and disease

NK cell receptors for MHC class I molecules include lectin-like receptors encoded by the NK complex gene cluster on chromosome 12p12-p13 and immunoglobulin-like receptors encoded by genes in the leukocyte receptor complex on 19q13.4, which includes the killer immunoglobulin-like receptors (KIRs). KIRs directly recognize the polymorphic determinants of the class I molecules and are themselves remarkably polymorphic and rapidly evolving (Vilches and Parham 2002). Extreme diversity in gene number and composition is seen between KIR haplotypes, a degree of diversity comparable to that found for HLA class I alleles. Among KIR haplotypes the distribution of Alu repetitive elements (Section 8.4) indicates rapid expansion of the gene family (Martin et al. 2000). The KIR genes are highly homologous, as are the highly conserved 2 kb intergenic sequences between them; this is thought to have facilitated non-reciprocal recombination leading to deletion, duplication, and recombination of genes (Parham 2005). One of the intergenic sequences is unique: it is 14 kb, lies in the centre of the cluster (between KIR3DP1 and KIR2DL4), and is the preferred site of reciprocal recombination of the centromeric and telomeric motifs leading to further haplotypic diversity (Martin et al. 2003). HLA-A molecules such as A3 and A11 are recognized by receptors encoded by KIR3DL2 and KIR2DS1 at the telomeric end of the KIR locus, HLA-B Bw4 is a ligand for KIR3DL1, and in the centromeric part receptors for HLA-C molecules are encoded. HLA-C1 allotypes with Asn at position 80 are recognized by receptors encoded by KIR2DL3 and KIR2DL2; KIR2DL1 encodes KIR receptors with a methionine rather than lysine at position 44 and these recognize HLA-C2 allotypes with lysine at position 80. As well as the disease associations with HIV-1 infection, genetic diversity at the KIR and HLA class I is important in other infections, autoimmunity, reproduction, and cancer. For example, maternal KIR genotype and fetal HLA-C type are important in pre-eclampsia (Hiby et al. 2004); homozygosity of KIR2DL3 and of HLA-C1 allotypes modulate hepatitis C infection (Khakoo et al. 2004); and KIR2DS1 and Cw*06 are associated with psoriasis (Suzuki et al. 2004).

A recent study has highlighted how a combination of specific KIR subtypes and their complementary HLA-B alleles can modulate HIV-1 disease progression and viral load (Martin et al. 2007). Martin and colleagues sought to investigate the role of the inhibitory KIR receptor allotypes KIR3DL1 and the class I molecules to which they bind, HLA-B molecules containing the Bw4 motif with isoleucine at position 80 (Bw4-80I). HLA-B Bw4 alleles include HLA-B*27 and B*57, and are known to be highly protective in terms of HIV disease progression. Specific KIR3DL1 allotypes vary in their surface expression on NK cells and thus in their ability to bind class I molecules. Analysis of over 1500 HIV-1 infected individuals revealed that those people with HLA-B alleles Bw4-80I and high expressing KIR3DL1 allotypes had significantly slower disease progression than those individuals with either the low expression allotype or lacking the Bw4 allele (Martin et al. 2007). Resequencing KIR3DL1 among diverse human populations has demonstrated remarkable levels of variation with at least 38 alleles and evidence of positive selection notably in the extracellular immunoglobu-lin domains (Norman et al. 2007).

Genome-wide association studies are providing dramatic insights into many common diseases (Section 9.3). For HIV-1 infection, such a study was recently performed to investigate genetic determinants of viral set point, the amount of circulating virus found in the plasma during the asymptomatic phase prior to progression to AIDS (Fellay et al. 2007). Over 500 000 SNPs were successfully genotyped for 486 accurately phenotyped patients. The analysis found that genetic variation in the MHC was most significant, in particular that polymorphisms near HLA-B

and HLA-C explained 9.6% and 6.5% of the total variation in HIV-1 set point, respectively. Further replication and fine mapping is required but the most strongly associated SNP was in HCP5, 100 kb centromeric of HLA-B and in strong linkage disequilibrium with HLA-B*5701, an allele strongly associated with protection against disease progression (Migueles et al. 2000) and control of HIV-1 viraemia (Altfeld etal. 2003).

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