Role of alloimmunity in susceptibility to HIV-1 infection

Abstract

Allo-immunity is defined as immunity of one individual against another of the same species. In humans allo-immunity can be measured as antibodies against human leucocyte antigens (HLA), termed HLA antibodies. HLA antibodies are naturally occurring antibodies present in an individual with specificity against the HLA proteins of another individual. HLA antibodies may develop following exposure to HLA proteins of another individual. HLA antibodies may arise during pregnancy but may also be present in women who have never been pregnant as well as in men and children.

The overarching hypothesis of this thesis was that HLA antibodies may play a physiological role in the human immune system and protect against infection with certain pathogens. Enveloped viruses, including Human Immunodeficiency Virus-1 (HIV), incorporate host proteins such as HLA into their envelope. Pre-existing HLA antibodies may bind to these extraneous surface proteins and impact viral infectivity. Macaque studies using simian immunodeficiency virus have confirmed that xenoimmunization with HLA antigens protect against infection. Since HIV gp120 shows homology with class 2 HLA, including shared affinity for binding to CD4, antibodies against class 2 HLA proteins (class 2 HLA antibodies) have the potential to influence HIV acquisition via binding to gp120 on the viral envelope.

To explore whether naturally occurring HLA antibodies in humans protect against HIV acquisition, in the first part of this work I characterized the HLA allele and haplotype frequencies of HIV-1 serodiscordant couples. In the second part of the work I analysed class 1 and class 2 HLA antibodies in originally HIVuninfected partners. I interrogated whether the prevalence of HLA antibodies varied between nonseroconverting and seroconverting individuals. First I assessed whether the prevalence of antibodies against any class 1 or class 2 locus varied between non-seroconverting and seroconverting individuals. I then analysed only those antibodies directed against the HLA type of the HIV-infected sexual partner, which I termed matching antibodies. I enquired whether matching antibodies differed between nonseroconverters and seroconverters. In the third section of this work, I investigated the natural history of HLA antibody development in the physiological situations of pregnancy and infancy. I analysed whether maternal HLA antibody specificities were shared between mothers and their infants. This work serves as background for future studies in infants examining whether infant HLA antibodies impact the risk of viral infections in the infant.