HLA/KIR restraint of HIV: surviving the fittest

Abstract

Multiple epidemiological studies have demonstrated associations between the human leukocyte antigen (HLA) loci and human immunodeficiency virus (HIV) disease, and more recently the killer cell immunoglobulin-like (KIR) locus has been implicated in differential responses to the virus. Genome-wide association studies have convincingly shown that the HLA class I locus is the most significant host genetic contributor to the variation in HIV control, underscoring a central role for CD8 T cells in resistance to the virus. However, both genetic and functional data indicate that part of the HLA effect on HIV is due to interactions between KIR and HLA genes, also implicating natural killer cells in defense against viral infection and viral expansion prior to initiation of an adaptive response. We review the HLA and KIR associations with HIV disease and the progress that has been made in understanding the mechanisms that explain these associations.

Figure 1

The genetic map of the human MHC. A subset of genes within the 4 Mb region of the MHC is shown. Numbers of alleles for the classical class I and class II genes (based on the information from the IMGT/HLA database, http://www.ebi.ac.uk/imgt/hla) are depicted in red.

Figure 2

Schematic representation of two prototypic human KIR haplotypes. The digit before the letter D in the KIR gene name denotes the number of Ig-like domains in the molecule, the letter following D specifies long (L) or short (S) cytoplasmic tails in a corresponding protein, or pseudogenes (P). Long tailed KIRs are inhibitory and short tailed are activating with the exception of KIR2DL4, which has potential for both inhibition and activation. Gene pairs KIR2DL2/2DL3 and KIR3DL1/3DS1 are alleles of the same loci (shown in green and orange). The four framework genes are shown as gray boxes. Genes encoding activating KIR with short tails and pseudogenes are denoted by red and blue letters, respectively. The number of alleles differing at the amino acid level is shown above each gene (based on data from the IPD-KIR database, http://www.ebi.ac.uk/ipd/kir).

Figure 3

Dynamics of peripheral blood CD4 T cell counts and plasma viral load during a typical course of HIV infection. The three major phases of infection are shown: acute, chronic, and AIDS. The eclipse phase is the initial stage of the acute infection before systemic viral dissemination. The acute phase is characterized by flu-like symptoms and a peak viral load, followed by a drop to a set point level. During the asymptomatic chronic phase, viral load gradually increases while CD4 T cell counts gradually decline to the level of 200 cells/ml of blood, a point defining AIDS onset.

Figure 4

The -35 genotype (TT, CT, or CC) correlates with surface HLA-C expression (a) and mean log viral load (b). HLA-C expression was detected on CD3⁺ T lymphocytes of normal individuals by flow cytometry using the DT9 monoclonal antibody and compared between pairs of genotypes. The association of the −35 genotypes with mean log viral load was analyzed in a cohort of 923 HIV-1-infected patients. The figure is based on data published previously (133).

Figure 5

The effect of KIR3DS1 and HLA-B Bw4-80I on HIV infection. (a) Kaplan-Meier survival analysis comparing individuals homozygous for HLA-B Bw6 and individuals with the KIR3DS1/Bw4-80I compound genotype in HIV seroconverters as described in Reference . (b) Inhibition of viral replication by NK cells derived from subjects expressing both KIR3DS1 and Bw4-80I, HLA-B Bw4 and no KIR3DS1, KIR3DS1 and no HLA-B Bw4, and neither KIR3DS1 nor HLA-B Bw4. Inhibition of viral replication in the first groups is significantly higher than in any other group (p < 0.001). The data were presented in Reference .

Figure 6

KIR3DS1 and HLA-B Bw4-80I frequencies across populations. Populations are ordered by region based on increasing distance from East Africa. Frequencies of KIR3DS1 increase with the distance from Africa, whereas frequencies of HLA-B Bw4-80I have the opposite trend. As a result, the frequency of the compound KIR3DS1/Bw4-80I genotype is maintained at an approximately similar low level across populations. The figure is modified from Reference .