HIV Induced Damage of B Cells and Production of HIV Neutralizing Antibodies

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Background

Scientists operating in HIV research concentrate their efforts in designing effective HIV vaccines. These vaccines may also be important within the frame of a possible cure for HIV, to reinvigorate the immunological capacity of an HIV infected individual to control HIV infection.

The few trials conducted with candidate HIV vaccines showed that it is difficult to elicit high titers of HIV neutralizing antibodies in vaccinated individuals and that the low levels of antibodies mounted against HIV vaccines soon declined. Memory B cells (MBCs) and long lived plasma cells are responsible for maintenance of serological memories to vaccines and infections. Studies in HIV infected children and adults have shown that blood MBCs are reduced in number during HIV infection and that the decline in MBCs correlated to reduction of Ab titers against children vaccinations; initiation of antiretroviral therapy (ART) within the first year of life improves development and maintenance of MBCs.

As B cells do not carry receptors for HIV binding and entry, it is unlikely that MBCs may be damaged through direct HIV infection. The mechanism of B cell damage during HIV infection remains poorly characterized. One interesting aspect of immunopathology is that a population of exhausted memory B cells is increased in circulation during HIV infection; these cells are denominated as tissue-like memory (TLM) B cells in view of their phenotypic similarities with tonsillar B cells. TLM B cells have an exhausted phenotype, including expression of PD-1 and of the inhibitory receptor Fc-receptor-like-4 (FCRL4), and are more susceptible to Fas-mediated apoptosis. It is possible that the expression of inhibitory receptors on the surface of TLM B cells during HIV infection may engage specific pathway leading to inhibition of B cell proliferation and antibody production.

Reverting in vivo the damage which HIV exerts on B cells could result in increased production of HIV neutralizing antibodies. This task may be complex to pursue as potential immunotherapy approaches aimed at improving B cell responses may have the important caveat of broadening the process of antibody production towards an autoimmune phenotype. Thus it is important to identify in more details the mechanisms and molecular pathways involved in B cell damage during HIV infection with the goal of ameliorating B cell functions. The possibility of inducing HIV neutralizing antibodies in vivo through therapeutical vaccination should be considered and highly innovative approaches need to be applied to this field. Integrated knowledge from vaccine design for other pathogens may accelerate the design of preventive or therapeutic HIV-1 vaccines with the property of inducing potent neutralizing antibody.

For immunotherapy development, a safe approach is to concentrate on neutralizing HIV antibodies with high potency and broad spectrum isolated from HIV infected patients; this innovation process is proceeding rapidly and if not too costly, the administration of cocktails of highly effective HIV neutralizing antibodies to infected patients for the purpose of controlling viral disseminations may become a reality within short term.

Keywords: HIV, B cell differentiation, neutralizing antibodies, mucosal immunology, response to vaccination

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