HIV-1 infection and loss of serological memory : the role of altered expression of B-cell chemokine receptors, timing of HAART and impaired antibody affinity maturation

Abstract

Currently, big efforts in HIV-1 research are devoted to the design of a HIV-1 vaccine. However, no successful vaccine is yet available, also due to the lack of basic knowledge in HIV-1 pathogenesis which is still profound. HIV-1 infected patients suffer of several abnormalities related to B-lymphocytes, which function is to produce antibodies (immunoglobulins) against common pathogenic viruses and bacteria, and experience loss of serological memory since early stages of infection. In the absence of a HIV-1 vaccine, ensuring a better protection against common diseases in infected adults and children is fundamental to prevent lethal infections of these patients.

The research presented in this thesis aimed at improving the general knowledge on HIV-1 pathogenesis and at better understanding the mechanisms behind the B-cell impairments observed during HIV-1 infection. We found that (paper I), the loss of memory B-cells is a progressive event starting early during primary infection, when a partial but irreversible depletion of specific memory B-cells occurs. A possible explanation for this phenomenon is memory B-cell exhaustion and cell death as a consequence of the general (polyclonal) B-cell activation due to the reactivation of many pathogens typical of HIV-1 infection. In this scenario, the death of specific memory B-cells could be compensated through the activation of naïve B-cells by unspecific stimuli which may lead to the production of low-quality (affinity) antibodies. Through the work presented in paper II, we found that naïve B-cells in fact undergo processes of immunoglobulin affinity maturation in the immunoglobulin genes.

Another important aspect which might be impaired during HIV-1 infection is lymphocyte trafficking between the periphery and (within) secondary lymphoid organs, for example lymph-nodes and spleen, where immunoglobulin affinity maturation takes place. In paper III, we observed that altered expression of key molecules for B-cell migration, such as the chemokine receptor CXCR5 and the chemokine CXCL13, occurs in B-cells and alters B-cell migration. This may result in defective reactions in the secondary lymphoid organs. In this respect, the application of the currently available antiretroviral therapy (HAART) early during primary infection might help minimizing these detrimental effects. In paper IV, we found that in the milieu of a developing immune system, such as the one of children infected with HIV-1 in utero, at birth or through breast feeding (vertically infected), an application of therapy within the first year of life in fact preserves both the development and the function of B-cells. This results in effective and long-lasting immunization upon common childhood vaccinations with measles, tetanus and pneumococcus.

Summarizing, the work presented in this thesis enlightens the role of altered expression of B-cell chemokine receptors and impaired immunoglobulin affinity maturation for the loss of serological memory observed during HIV-1 infection and suggests the early initiation of HAART in vertically infected children. The understanding of these phenomena, in the absence of a HIV-1 vaccine, might be the key event for ensuring a better life of HIV-1 infected patients and might help solving the problems encountered so far in the development of a HIV-1 vaccine.