Dizygotic twins discordant for HIV-1 despite vertical transmission prophylaxis: was human leukocyte antigen homozygosity of disadvantage to the infected twin?
Neubert, Jennifera; Enczmann, Juergenb; Krux, Franka; Hower, Martinc; Borkhardt, Arndta; Laws, Hans-Juergena
aClinic of Pediatric Oncology, Hematology and Clinical Immunology, Germany
bBone Marrow Donor Center with Eurocord Bank and Transplantation Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
cDepartment of Immunodeficiency, Klinikum Dortmund, Dortmund, Germany.
Received 17 May, 2010
Accepted 5 June, 2010
Correspondence to Dr Jennifer Neubert, MD, Clinic of Pediatric Oncology, Hematology and Immunology, University Hospital Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany. Tel: +49 211 811 8297; fax: +49 211 811 6539; e-mail: firstname.lastname@example.org
Genetic polymorphisms in human leukocyte antigen (HLA) influence the susceptibility and disease progression in HIV-infected adults and children [1–4]. Furthermore, HLA homozygosity at any class I loci has been associated with rapid disease progression [4–6], presumably because homozygotes present a less diverse collection of epitopes to the immune system than heterozygotes, allowing HIV to more easily escape the immune response.
We report a case of dizygotic twins discordant for HIV-1 despite vertical transmission prophylaxis. The infected twin was homozygous at two HLA loci (HLA-A, HLA-DQ), whereas the noninfected twin was heterozygous at all loci.
Non-identical HIV-1 exposed female twins were referred to our centre at the age of 3 months. Maternal HIV was acquired heterosexually during pregnancy and diagnosed around gestation week 25. A prior test at gestation week 6 had revealed a negative HIV status. Maternal HIV-1-RNA at diagnosis was 190 000copies/ml and CD4 cell count was 564 μl (25%). Antiretroviral therapy was initiated with nevirapine, zidovudine, tenofovir and emtricitabine. HIV-1-RNA dropped to 2140 copies/ml and the CD4 cell count increased to 726 μl (39%) 4 weeks before delivery.
Caesarean section was performed at gestation week 32 owing to preterm labour without preterm rupture of the membranes. Zidovudine was given during labour, the twins were treated with lamivudine and zidovudine for 6 weeks and received a single dose of nevirapin. Maternal HIV-1-RNA 4 weeks after delivery was 520 copies/ml and the CD4 cell count was 982 μl (44%). Blood was taken from both twins at the age of 6 weeks. The volume of the blood taken from twin A was insufficient for HIV-1-RNA PCR; unfortunately, the blood draw was not repeated. In twin B, HIV-1-RNA PCR was negative. HIV antibody tests in both twins were negative.
Virology tests were repeated at our centre at the age of 3 months. HIV-1-RNA PCR in twin A was positive and the HIV-1-RNA load was 3197 444 copies/ml. HIV-1-RNA PCR in twin B was negative. HIV antibody tests were positive in only twin A. CCR5 receptor analysis of both twins revealed wild type CCR5 receptor. PCR-based HLA typing of the twins and the mother revealed homozygous HLA class I and class II loci in the infected twin whereas the HIV negative twin was heterozygous at all loci (Table 1).
The only study addressing HIV-1 mother-to-child transmission (MTCT) in twins in the era of transmission prophylaxis found no increased risk for twins (0.9% transmission rate for twins versus 1.8% singletons) . In our case, the primary HIV-1 infection of the mother during pregnancy most probably led to in utero infection of twin A and differences in host genetic factors most probably accounted for the discordant HIV-1 status.
HLA encode molecules that differentially present endogenous viral peptides to CD8+T cells [cytotoxic T lymphocytes (CTLs)] and CD4+ T cells. HLA class I and class II haplotypes thus determine which HIV-1 epitopes bind and how effectively those epitopes are presented. CTLs exert significant immune pressure on HIV-1 , suggesting that this response might modulate transmission. The impact of CTLs in HIV-infected pregnant mothers on transmission has been demonstrated . HIV-specific CTLs are also detected from birth in HIV-infected children  and there is evidence documenting HIV-specific T-helper and CTL responses, among HIV exposed but uninfected infants [9,10]. Evidence demonstrating viral escape from infant immune responses as the cause of HIV-1 acquisition is lacking.
HLA homozygosity at any class I locus has been associated with more rapid disease progression presumably owing to the decreased number of HLA haplotypes that may limit the breadth of peptide recognition and immune response against HIV. There is evidence demonstrating that maternal HLA homozygosity and HLA concordance between a mother and her infant increases the risk of MTCT , although data demonstrating that infant HLA homozygosity increases the risk of acquisition are lacking. Associations between HIV transmission, disease progression and HLA class II alleles have been reported but not as consistent as those observed for class I. Interestingly, the HIV negative twin was heterozygous at all class II loci and carried DRB1*13 and DQB1*06. DRB1*13 alleles have been associated with decreased susceptibility to vertical HIV transmission and long-term survival in HIV-infected children [12,13]. It is noteworthy that, in a study done in acutely HIV-1-infected adults receiving antiretroviral treatment, the HLA class II haplotype DRB1*13-DQB1*06 was present only among individuals who maintained virus suppression at all times measured post treatment .
In conclusion, we hypothesize that the HLA class I and II heterozygosity and favourable class II alleles might have protected one twin from HIV infection, whereas HLA homozygosity made the other twin more susceptible to HIV infection.
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