Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.

BACKGROUND: Killer-cell Immunoglobulin-like Receptors (KIR) interact with Human Leukocyte Antigen (HLA) to modify natural killer- and T-cell function. KIR are implicated in HIV acquisition by small studies that have not been widely replicated. A role for KIR in HIV disease progression is more widely replicated and supported by functional studies. METHODS: To assess the role of KIR and KIR ligands in HIV acquisition and disease course, we studied at-risk women in South Africa between 2004-2010. Logistic regression was used for nested case-control analysis of 154 women who acquired vs. 155 who did not acquire HIV, despite high exposure. Linear mixed-effects models were used for cohort analysis of 139 women followed prospectively for a median of 54 months (IQR 31-69) until 2014. RESULTS: Neither KIR repertoires nor HLA alleles were associated with HIV acquisition. However, KIR haplotype BB was associated with lower viral loads (-0.44 log10 copies/ml; SE = 0.18; p = 0.03) and higher CD4+ T-cell counts (+80 cells/µl; SE = 42; p = 0.04). This was largely explained by the protective effect of KIR2DL2/KIR2DS2 on the B haplotype and reciprocal detrimental effect of KIR2DL3 on the A haplotype. CONCLUSIONS: Although neither KIR nor HLA appear to have a role in HIV acquisition, our data are consistent with involvement of KIR2DL2 in HIV control. Additional studies to replicate these findings are indicated.

Killer-cell immunoglobulin-like receptor genotyping and HLA killer-cell immunoglobulin-like receptor-ligand identification by real-time polymerase chain reaction.

The effector function of natural killer (NK) cells is modulated by surface expression of a range of killer-cell immunoglobulin-like receptors (KIRs) that interact with human leukocyte antigen (HLA) class I ligands. We describe the use of real-time polymerase chain reaction (PCR) assays that allow easy and quick detection of 16 KIR genes and the presence/absence of KIR-ligands based on allelic discrimination at codon 80 in the HLA-A/B Bw4 and HLA-C C1/C2 genes. These methods overcome the tedious and expensive nature of conventional KIR genotyping and HLA class I typing using sequence-specific primer (SSP) PCR, sequence-specific oligonucleotide (SSO) hybridization or sequence-based typing (SBT). Using these two cost-effective assays, we measured the frequencies of KIRs, KIR-ligands and KIR/KIR-ligand pairs in a cohort of Black women recruited in South Africa.

Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.