Dynamics of the HIV-2-specific immunoglobulin A(IgA) response

Detta är en avhandling från Stockholm : Karolinska Institutet, Microbiology and Tumor Biology Center (MTC)

Sammanfattning: Millions of lives are affected by infection with HIV, which causes AIDS if untreated. HIV transmission occurs primarily through sexual contact across mucosal surfaces. In the mucosal immune response, IgA is considered the first defense line against HIV invasion. Furthermore, a recent study suggests that serum IgA can initiate phagocytosis by Kuppfer cells in vivo to avoid bacteria spreading via the blood system, which further suggests that serum IgA can serve as a second defense line. HIV-2, the second lentivirus known to cause AIDS, appears to be less pathogenic with a lower transmission rate than HIV-1. It provides an important opportunity to study immune control and pathogenesis of lentivirus infections in humans. The overall goal of our investigations was to elucidate the role of IgA in HIV-2 infection and immunity. Four studies were performed. The first study was designed to investigate the antigenic sites of HIV-2 that are important for the binding of serum IgA. We showed that serum IgA in HIV-2 infected individuals had the capacity to neutralize HIV-2. Additionally, a strong serum IgA binding activity against a peptide (aa 644-658, MYELQKLNSWDVFGN) in the region of the central part of transmembrane envelope of HIV-2 (gp36) was displayed. In the second study, we found that serum IgA in HIV-2-exposed IgG seronegative (EGSN) individuals had more potent capacity to neutralize HIV-2 than their known HIV-2 positive partners. The ratios of neutralizing titers/mg IgA (T/mg IgA) between EGSN individuals (580) and their known partners (480) was statistically significant (p<0.05). Given that IgA had potent neutralizing capacity in vitro, it may confer protection in the populations at high risk of HIV-2 exposure. This study may have important implications in understanding HIV-2 pathogenesis and transmission. In the third study, sera were collected longitudinally from a group of HIV-2 infected individuals during three-to-eight years of follow-up. We demonstrated that HIV-2-specific serum IgA has as broad binding reactivity pattern to the different antigens as IgG. Importantly, our data indicate that HIV-2 specific serum IgA may be induced independently of CD4T cells or by long lived memory B cells, since loss of CD4 T cells did not give a reduction of serum IgA. Moreover, a sustained serum IgA neutralizing capacity against HIV-2 was displayed during 8 years of follow-up. Thus, serum IgA may be associated with the lower pathogenesis and lower transmisson rates seen in HIV-2 infected individuals. Based on our prior findings, we were stimulated to explore in depth the serum IgA targeted neutralizing sites on HIV-2. Thus in a fourth study we explored the neutralization capacity of serum IgA against multiple HIV-2 strains and investigated targets for HIV-2 neutralizing IgA within the transmembrane protein (gp36) of HIV-2 in an effort to further understand the mechanism of IgAmediated immunity. We showed broad HIV-2 serum IgA-mediated neutralization against three primary isolates representing HIV-2 subtype A and B. Furthermore, our results demonstrated that two epitopes in gp36, GCAFR (aa 588-592) and MYELQ (aa 644-648), were important in mediating serum IgA antigenic binding. However, none of the selected six peptides having either the amino acid sequence GCAFR or MYELQ exhibited inhibition of IgA neutralization of HIV-2 in peptide blocking experiments. In summary, we have shown long-lived virus neutralizing HIV-2-specific serum IgA responses, which may be associated with the lower pathogenesis and lower transmisson rates seen in HIV-2 infected individuals. The importance of serum IgA was further implicated when HIV-2 exposed seronegative individuals were found to have strong serum IgA-mediated HIV-2 neutralizing activity. These studies have provided significant information important for the understanding of immune responses against HIV, particularly HIV-2, and may lay important information for the foundation of the design of an HIV vaccine.

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