New Target For HIV/AIDS Drugs And Vaccine Discovered
Researchers from Rome, Italy, describe a finding in the August 2007 print issue of The FASEB Journal that could lead to new drugs to fight the HIV/AIDS virus, as well as new vaccines to prevent infection. It has been known that HIV proteins disable the antibody-forming part of the immune system (the “homeland defense” or acquired immune system).
In this report, researchers demonstrate for the first time how the HIV-1 Nef viral protein delivers a one-two punch to the body’s innate immune system (our “early warning system” composed of dendritic and natural killer cells). First, Nef hijacks dendritic cells (DCs) to upset the function of natural killer (NK) cells. Second, after blocking this first line of defense against the immune system, Nef uses DCs and NK cells to create a microenvironment that actually makes it easier for HIV/AIDS to replicate.
According to Maria Giovanna Quaranta of Instituto Superiore de Sanità and first author of the article, “The findings described in this work may have several implications for AIDS treatment: the understanding of Nef function, mechanism of action, and cellular partners might aid the discovery of suitable drugs able to block the activity of this smart protein.” Quaranta added, “An exciting possibility is the design of a vaccine including a mutated Nef protein unable to assist the virus in the control of its host.”
The research findings also raise another intriguing possibility: Nef proteins may be able to boost or suppress DC and NK cell activity. If so, it may prove to be a valuable new therapeutic approach for people with diseases and disorders that involve overactive or underactive immune responses. DCs and NK cells play critical roles in the body’s initial defense against infection.
DCs are instrumental in identifying foreign invaders to the body and then orchestrating an immune response that ultimately removes them. NK cells are among the first cells summoned by DCs to help isolate and contain the infection until more potent reinforcements can be manufactured to eradicate the virus or bacteria. When DC cells can no longer adequately “manage” the immune response and when NK cells can no longer contain infections, the likelihood of survival without medical intervention is relatively low.
“HIV’s relatively rapid evolution has given it an ability to handle all our bodies can throw at it and more,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “Now that we know how the viral protein disables the innate as well as the acquired arm of our immune system, we can begin to design decoy proteins or to devise new vaccines. Millions of lives depend on our finding a way to restore both aspects of our immune defense against HIV/AIDS—this study should go a long way toward that goal.”
FASEB J. 2007 Apr 12; [Epub ahead of print]
HIV-1 Nef impairs the dynamic of DC/NK crosstalk: different outcome of CD56dim and CD56bright NK cell subsets.
Quaranta MG, Napolitano A, Sanchez M, Giordani L, Mattioli B, Viora M.
*Department of Drug Research and Evaluation,Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immunity and play a critical role in the first phase of host defense against infection. Interactions between DCs and NK cells have been demonstrated in a variety of settings, with evidence emerging of complex bidirectional crosstalk between the two cell types. The accessory HIV-1 Nef protein is a crucial determinant for viral replication and pathogenesis. We previously demonstrated that Nef, hijacking DC functional activity, subverts the DC arm of immune response to escape the adaptive immune attack. Here, we monitor the effect of Nef on the outcome of the innate immune response, focusing on the impact of Nef on DC/NK crosstalk. We demonstrate that Nef up-regulates the ability of DCs to stimulate the immunoregulatory NK cells (CD56(bright)) as assessed by the activated phenotype, up-regulation of their proliferative response and INF-gamma release. On the other hand, Nef-pulsed DCs inhibit cytotoxic NK cells (CD56(dim)), as assessed by the reduced HLA-DR surface expression, reduced proliferation and cytotoxic activity. Moreover, in the presence of Nef-pulsed DCs, we found a significant up-regulation of TNF-alpha secretion and a significant reduction of IL-10, GM-CSF, MIP-1alpha and RANTES secretion. Our findings suggest that the Nef-induced dysregulation in the DC/NK cell crosstalk may represent a potential mechanism through which HIV escapes innate immune surveillance.–Quaranta, M.G., Napolitano, A., Sanchez, M., Giordani, L., Mattioli, B., Viora, M. HIV-1 Nef impairs the dynamic of DC/NK crosstalk: different outcome of CD56(dim) and CD56(bright) NK cell subsets.
PMID: 17431094 [PubMed – as supplied by publisher]