Mechanisms underlying impaired humoral immunity in primary and chronic HIV-1 infection

Abstract

B cells of HIV-1-infected patients have both phenotypic and functional dysfunctions which may be important in HIV-1 pathogenesis. Immune activation during HIV infection is an essential part of the body s defense against the virus, but may be the root cause of B cell dysfunctions. Evidence of B cell dysfunctions during HIV-1 infection include altered expression of activation markers, spontaneous apoptosis, and polyclonal activation. These may occur very early in infection, and may have important effects on the outcome of infection and treatment of the patient. Interaction between B cells and other cells of the immune system is essential to the proper functioning of the B cells and may also be altered during HIV-1 infection.

With this thesis I wanted to investigate if: (1) B cell dysfunctions are initiated during primary HIV-1 infection (2) Patients treated during primary infection may stand a better chance of controlling infection (3) Immune activation induces and enhances B cell dysfunctions in primary and chronic HIV infection; (4) Interactions between B cells and other lymphocytes may be altered in HIV infection, leading to malfunction of the B cells (5) HIV-infected patients respond poorly to vaccination and infections because they have impaired serological memory.

The results obtained indicate that: Majority of B lymphocyte dysfunctions are initiated early in primary infection and persist throughout the course of the disease; Naive B lymphocytes are abnormally activated in HIV-1 infection and may contribute to excessive hypergammaglobulinemia; Loss of memory (CD27+) B cells is a feature of chronic infection, but is not observed in primary infection thus may be an effect of persistent immune activation; The Fas-FasL pathway may play a key role in the deletion of B cells in HIV infection; Antigen-specific humoral immunity is also impaired early during primary HIV-1 infection as shown by reduced levels of specific antibodies to HIV, and non-HIV antigens such as measles and pneumococcus polysaccharide antigens; Measles-specific memory B cells are deleted in HIV-1 infection; Immune activation, assessed by plasma sCD27, IgG and beta-2 microglobulin, is lower in HIV-2 than in HIV-1 infection.

HIV infection leads to important B cell dysfunctions and impaired humoral immunity which in turn impair the ability of the patient to control the infection and/or mount an effective response to the virus. An ideal HIV vaccine would be one that is able to elicit strong humoral immune as well as cell-mediated responses and understanding the role of B cell dysfunctions in immunopathogenesis of HIV infection is important in refining strategies for effective therapies and vaccines.