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Killer immunoglobulin-like receptor genotype may distinguish immunodeficient HIV-infected patients resistant to immune restoration diseases associated with herpes virus infections.

To the Editor: A proportion of immunodeficient HIV-infected patients beginning combination antiretroviral therapy (ART) experience disease provoked by a preexisting (often quiescent) infection with an opportunistic pathogen. These can occur despite favorable virologic responses and increases in CD4 T-cell counts. Increasing evidence indicates that these diseases result from the restoration of a pathogenspecific cellular immune response that is inadequately regulated and causes immunopathologic change. They are therefore defined as immune restoration diseases (IRDs) or immune reconstitution inflammatory syndrome (IRIS). Illness associated with cytomegalovirus (CMV), Mycobacterium avium complex (MAC), Mycobacterium tuberculosis (MTB), varicella zoster virus (VZV), herpes simplex virus (HSV), hepatitis B virus (HBV), or hepatitis C virus (HCV) and exacerbation of Kaposi sarcoma attributed to human herpes virus 8 (HHV-8) have been described. IRDs associated with mycobacteria follow improved skin test responses to mycobacterial antigens and increased CD4 T cells producing interferon-g after stimulation in vitro, suggesting excessive T helper (Th) 1 responses. In contrast, IRDs provoked by various herpes viruses have been associated with a local CD8 T-cell response, persistently elevated plasma levels of CD30 and interleukin (IL)-6, and carriage of allele 1 at a locus in the 3# UTR of IL12B and allele 2 at TNFA-308. These alleles are also associated with low nadir CD4 T-cell counts (Price et al, submitted), providing a mechanism that could promote IRDs. Patients with IRDs arising from mycobacterial infection rarely carried IL6– 174*C and never carried TNFA-308*2. These findings suggest that distinct cytokine-mediated mechanisms contribute to IRDs initiated by herpes viruses and mycobacterial infections. Killer immunoglobulin-like receptors (KIRs) are a family of cell-surface molecules expressed by natural killer (NK) cells and some populations of CD8 T cells. The consequences of interactions between cytotoxic cells and virusinfected cells are determined by the expression of inhibitory and activating KIRs. Hence, KIR genotype can influence the progression of HIV disease and CMV reactivation in transplant recipients. Here, we examine the relation between carriage of genes encoding activating and inhibitory KIRs and the occurrence of herpes virus IRDs and severe CMV disease in patients with AIDS. HIV-infected patients receiving ART (triple therapy, including a protease inhibitor [PI] or nonnucleoside reverse transcriptase inhibitor [NNRTI]) at Royal Perth Hospital (Western Australia) were selected on the basis of an IRD defined by provisional diagnostic criteria. Most occurred in the first 3 months of treatment. Patients with a history of herpes virus IRDs (n = 22) comprised 6 patients with CMV retinitis (including individual patients who experienced dermatomal zoster and probable HSV-associated encephalitis or myelitis), 2 patients who experienced CMV IRD manifested as radiculomyelitis or focal cerebritis, 9 patients who experienced disease associated with VZV (dermatomal zoster [n = 8] or myelitis [n = 1]), 4 patients who had acute-onset mucocutaneous HSV lesions (including 1 who also had dermatomal zoster), and 1 patient who had an exacerbation of Kaposi sarcoma preceded by dermatomal zoster. Clinical details of most cases have been reported. Non-IRD controls were selected as a group who remained disease-free despite responding to ART after a period of extreme immunodeficiency. They had all begun ART with <50 CD4 T-cells/mL and achieved an increase of greater than 4-fold or to >200 CD4 T-cells/mL. They were excluded if their CD4 T-cell counts declined within 1 year, if there were insufficient follow-up data, or if they had experienced neoplastic or unidentified inflammatory disease during immune reconstitution, as in our previous studies. Patients without IRDs and patients with IRDs had similar nadir CD4 T-cell counts (mean 6 SEM: 16 6 2.8 cells/mL vs. 25 6 5.3 cells/mL; P = 0.18). We also genotyped patients who had experienced CMV disease as an AIDS-defining illness and died (n = 28). Results are compared those of with a local cohort of healthy donors, presumed to be HIV-seronegative (n = 202). The study was approved by the Ethics Committee of Royal Perth Hospital. Carriage of 10 KIR genes (excluding the framework genes 2DL4, 3DL2, and 3DL3) was assessed using multiplex polymerase chain reaction sequence-specific primers (PCR-SSP). Only KIR 2DS4 alleles without the 22–base pair (bp) deletion were counted. The association of genotypes with outcome was assessed using 2-sided Fisher exact tests, and continuous variables were compared by unpaired Student t tests. P < 0.05 was accepted as indicating a significant difference. Carriage of 3DS1, 2DS5 (activating KIR), and 2DL5 (inhibitory KIR) was increased in patients with IRDs relative to controls without IRDs (Table 1). Overall, patients with IRDs carried significantly more activating KIRs than controls, but numbers of inhibitory KIRs were similar. A similar increase in total numbers of activating KIRs was evident in patients who died with CMV disease as an AIDSdefining illness, with carriage of 2DS4 significantly increased. Frequencies of activating KIRs in uninfected control donors were intermediate between the controls without IRDs and the patients with IRDs or CMV/AIDS. Martin et al showed that carriage of 3DS1 in the absence of a human leukocyte antigen (HLA)-B allele with isoleucine at position 80 (denoted HLA-B Bw4 80Ile) accelerates progression to AIDS. Most patients with herpes virus IRDs carry HLA-B44 (which has threonine at position 80); thus, HLA-B Bw4 80Ile was less common in patients with herpes virus IRDs