HIV infection results in multiple defects in B cell function, as well as in chronic polyclonal B cell activation. HIV- related B cell dysfunction contributes both to immune deficiency, which may include the loss of protective antibodies to vaccine antigens, and to an elevated risk for developing B cell non-Hodgkin lymphoma (NHL). Although B cell responses improve in HIV+ persons receiving highly active anti-retroviral therapy (HAART), the B cell compartment does not generally return fully to normal; individuals on HAART can continue to show elevated levels of B cell-stimulatory cytokines, hypergammaglobulinema, reduced levels of memory B cells, and reduced responses to specific antigens, when compared to HIV-uninfected persons. In preliminary studies, we saw that exposure of resting B cells to simvastatin and/or lovastatin resulted in decreased B cell activation, after exposure to CD40L-expressing HIV virions, or to the Epstein-Barr virus (EBV) in vitro. Exposure to these statins also reduced the spontaneous production of Ig by B cells obtained from individuals with advanced HIV disease. Pilot studies in the Multicenter AIDS Cohort Study (MACS) have shown that statin use in HIV+ men receiving HAART was associated with decreased serum levels of cytokines (IL10, IL12, IP10/CXCL10) that are known to be associated with B cell activation and/or inflammation.
The specific aims of this study are designed to provide proof of concept to the idea that statins might be useful in reducing residual dysfunction in the B cell compartment in HIV infection.
The specific aims are to determine: 1) how statins can attenuate HIV- or EBV-induced B cell activation in vitro, and the apoptosis of memory B cells that is induced by exposure to LPS and HIV in vitro, and 2) if statin use is associated with reduced B hyperactivation, improved levels of B cell function (antibody production), and improved levels of circulating memory B cells and T follicular-helper cells in HIV+ persons in the MACS receiving HAART. These studies will provide valuable new information on the potential of statins to reduce B cell dysfunction in HIV infection, which may thereby reduce the risk of AIDS-lymphoma and improve responses to vaccines, including therapeutic vaccines for HIV. If statins do improve B cell function and dampen chronic B cell activation, they could readily be included in treatment regimens for HIV infection, as these drugs are safe, affordable, and are in wide use.
B cell dysfunction, including chronic B cell hyperactivation and reduced responses to common vaccine antigens, is commonly seen in HIV-infected persons, and is only partially corrected by highly active antiretroviral therapy (HAART). Statin drugs show promise to further decrease B cell activation and improve B cell function in HIV+ persons receiving HAART. By better defining how, and which, statins improve B cell function and dampen chronic B cell activation in vitro and in vivo, these studies will provide valuable new information on the potential of statins for use in HIV+ persons receiving antiretroviral therapy, which could potentially lead to new treatments to reduce the risk of AIDS-associated malignancies and increase the effectiveness of vaccines, including therapeutic vaccines for HIV, in this population.
