A suspected delayed hemolytic transfusion reaction mediated by anti-Joa.

CONCLUSIONS: A 32-year-old African-American woman with a history of sickle cell disease presented for surgical evaluation of left total hip arthroplasty due to avascular necrosis of the femoral head. In anticipation of a complex orthopedic procedure, pre-surgical blood work was ordered. The patient's Fenwal blood sample typed as group O, D+. Although the patient had a history of anti-Fya, the antibody identification was inconclusive, so the workup was sent to a reference laboratory. The patient was last transfused with red blood cells (RBCs) 2 years earlier, but had no history of transfusion reactions. Due to surgery, the patient's hemoglobin (Hb) decreased from 10.2 g/dL (preoperative) to 8.6 g/dL (postoperative). One unit of weakly crossmatch-incompatible Fy(a-), C-, E-, K-, and sickle cell hemoglobin S (HbS)-negative RBCs was transfused without incident, and the patient was discharged. Several days later, the reference lab reported two new specificities, anti-Joa and anti-Jkb. Fortunately, the transfused RBC unit was Jk(b-). Therefore, the crossmatch incompatibility was attributed to anti-Joa, which targets a high-prevalence antigen found in 100 percent of most populations. Two weeks after discharge, the patient returned in sickle vaso-occlusive pain crisis. The patient was clinically stable, but her Hb was 6.7 g/dL. One unit of Fy(a-), Jk(b-), C-, E-, K-, HbS- RBCs, which was weakly crossmatch-incompatible, was transfused. The following day, her Hb was unchanged, lactic acid dehydrogenase increased from 951 to 2464 U/L, potassium increased from 3.7 to 4.6 mEq/L, creatinine increased from 0.60 to 0.98 mg/dL, and the patient developed a 38.4°C fever. These findings are consistent with a delayed hemolytic transfusion reaction (DHTR), mediated by anti-Joa, occurring 2 weeks after the first RBC transfusion. Further care could not be provided because the patient left the hospital against medical advice. The purpose of this case study is to report findings consistent with a DHTR attributed to anti-Joa, an antibody with relatively unknown clinical significance.

Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients.

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade-infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703-restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. In HLA-B*5703-mismatched recipients, the previously described early benefit of transmitted HLA-B*5703-associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.

Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients.

In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)-associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele-restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.