HIV induced humoral immune response with specific relevance to IgA

Detta är en avhandling från Stockholm : Karolinska Institutet, Karolinska Institutet, Stockholm Söder Hospital

Sammanfattning: Human Immunodeficiency Virus (HIV) transmission occurs primarily after hetero- and homosexual contact and across mucosal surfaces. The immune response in mucosal tissues is typified by secretory immunoglobulin A (SIgA), which is the predominant lg class in human external secretions. Since the dimeric lgA molecule is stabilized by the attendant J-chain and the secretory component, it has the unique capacity to maintain its function in an environment rich in proteolytic enzymes (e.g. mucosal compartments). This study was designed to investigate the biological function of local versus systemic humoral response against HIV infection. Furthermore, to define lgA mediated neutralization against both primary and T cell line adapted HIV-1 and HIV-2 isolates. The innate local defense in the oral cavity against HIV transmission was additionally adressed by investigating the presence and biological function of secretory leukocyte proteinase inhibitor (SLPI). The locally produced anti-HIV responses were investigated both with respect to different stages of disease and with respect to the time of follow-up. Using synthetic peptides representing earlier identified antigenic sites of the HIV-1 and HIV-2 proteins for IgG antibodies in serum, we illustrated potential epitopes for salivary and serum derived lgA antibodies. lgA mediated response against HIV-1 was found to be mainly directed against epitopes in the second and fourth variable regions (V2 and V4) of gpl20. In contrast, we found strongest lgA binding activity against a region (aa 615-658) in the central part of gp36 in HIV-2. The neutralizing activity mediated by lgA antibodies could not be correlated to the total amount of lgA in saliva or serum, or to any dominance in neutralizing activity against primary isolates with a specific biological phenotype. The high degree of inter-individual variability in neutralizing capacity indicate that the presence of functional, specific anti-HIV1 lgA antibodies is not a general phenomenon and can not be associated with elevated levels of total lgA but can be observed on an individual basis, even in late stages of disease. A persistent longitudinal SIgA response was also found in salivary samples from four out of eleven HIV-1 infected patients during a follow-up period of three years. These samples contained highly specific anti-HIV-1 SIgA with neutralizing activity against both a T cell adapted strain and four primary isolates. Furthermore, serum derived lgA obtained from two different cohorts, one in Guinea Bissau and one in Portugal demonstrated neutralizing capacity against HIV-2. Among several salivary derived innate factors with antiviral effect, SLPI is the only protein proved to be efficient in physiological concentrations. We have investigated the biological function of SLPI in salivary mediated inhibition of HIV infection and in addition the inhibitory effect of recombinant SLPI on isolates with various virus tropism. No significant difference in salivary concentrations of SLPI could be found between HIV infected individuals and healthy controls. Elevated levels of salivary SLPI could be associated with an increased inhibitory effect of the whole saliva sample against HIV-1 isolates. The inhibitory effect was found to decrease with broad co-receptor usage of the virus. To further elucidate the mechanisms of SLPI in the entry stage of the lifecycle of HIV1, we used a panel of virus isolates with distinct molecular phenotype. The monotropic strains, using either CXCR4 or CCR5 were shown to be most receptive to the inhibitory effect of rSLPI, while multitropic strains displayed a lower sensitivity to the protein.

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