Innate immune mechanisms can control disease progression in HIV-positive patients

February 24, 2010

HIV/AIDS remains one of the world's most significant public health challenges, particularly in developing countries. The Human Immunodeficiency Virus (HIV-1), the variant responsible for the pandemic, has the ability to infect different cell types such as T cells, macrophages and dendritic cells (DC). These latter cells are crucial in the defense against infectious agents and play a major role in viral pathogenesis. The present study, led by researchers from Hospital Clinic de Barcelona-IDIBAPS, within the framework of HIVACAT, shows for the first time that dendritic cells in HIV-infected patients who spontaneously control the infection produce high levels of α-defensins 1 -3. This is associated with slower disease progression, suggesting potential diagnostic, therapeutic and preventive implications. The first author of this study is Dr. Marta Rodriguez-Garcia, Emili Letang Fellowship award from Hospital Clinic of Barcelona for her work in this line of research, and currently a postdoc at The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard. The senior researchers of the study are Dr. Teresa Gallart, from the Immunology Service of Hospital Clinic and collaborator of the IDIBAPS team on Infectious Diseases and AIDS, and Dr. Josep M ª Gatell, Head of the Infectious Diseases Department at the Hospital Clinic and leader of the same IDIBAPS team.

The study was done in collaboration with the Catalan Center for HIV Vaccine Research and Development (HIVACAT), a public-private partnership involving IrsiCaixa Foundation and the Infectious Diseases Department at the Hospital Clinic of Barcelona. The research conducted within this initiative is made in coordination with Esteve and with the support of "La Caixa" Foundation and the Health and the Innovation, Universities and Enterprise Departments of the Generalitat de Catalunya.

Defensins are endogenous antimicrobial peptides with broad-spectrum antimicrobial properties and immunomodulatory effects. They have a potent anti-HIV activity, acting directly on the virus and also in target cells. According to its structure, human defensins are classified into two subfamilies: α-defensins and β-defensins, both with anti-HIV activity. The α-defensins, also known as human neutrophil peptides, are stored in neutrophils and, to a lesser extent, in other types of leukocytes. Although the anti-HIV activity of α-defensins1-3 has been clearly demonstrated in vitro, their possible protective role during HIV infection in vivo remains uncertain.

The authors recently demonstrated that α-defensins1-3 are produced by monocyte-derived immature dendritic cells (MDDC) in healthy individuals and they are able to modulate the maduration and differentiation process of MDDC. Dendritic cells (DC) are the main antigen-presenting cells and play a key role in the innate immune response against different viral infections, especially during the response generated against HIV. Due to their mucosal localization, DC are thought to be one of the first cells that encounter the HIV and, after migration to the lymph nodes, they would mediate the transmission of HIV-1 virions to CD4 T cells, the main source of HIV-1 replication and dissemination. For this study, a valid model of in vivo myeloid DC, the MDDC, was analysed. These might be one of the key cells involved in early HIV infection, and therefore their capacity to produce and release α-defensins1-3 by DC may have physiological relevance.

The study enrolled healthy, non-infected controls and HIV-1-infected subjects. These HIV-1-infected individuals were classified as: elite controllers (patients able to spontaneously control VIH infection in the absence of therapy, with plasma viral loads below 50 RNA copies/ml and that constitute the 5% of the infected population), viremic controllers (with PVLs higher than 50 and lower than 5000 RNA copies/ml without therapy), viremic non-controllers (with PVLs higher than 5000 RNA copies/ml without therapy) and patients with antiretroviral therapy (HAART). All patients had CD4 T cell counts higher than 450 cell/mm3. Results revealed that immature dendritic cells from HIV-infected patients who control the infection produced higher levels of α-defensins1-3 than the non-infected control group and these levels were associated with a better control of HIV infection and slower disease progression. The study of controller patients, especially elite controllers, is of particular relevance since these individuals demonstrate that natural control of HIV replication in the absence of antiretroviral therapy is possible.

The findings of this study show that of α-defensins1-3 may be potential prophylactic agents and open a new line of investigation to treat HIV / AIDS, although further studies will be needed to determine the possible value of these molecules as an important diagnostic and therapeutic tool to arrest or slow the replication of HIV in infected patients.

IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer

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