AIDSWEEKLY Plus; Monday, June 6, 2005
Staff Medical Writers

Study 1: Scientists examine the processing and presentation of exogenous HLA class I peptides by dendritic cells from human immunodeficiency virus type 1-infected patients in a recent issue of the Journal of Virology.

"Dendritic cells (DCs) loaded with viral peptides are a potential form of immunotherapy of human immunodeficiency virus type 1 (HIV-1) infection. We show that DCs derived from blood monocytes of subjects with chronic HIV-1 infection on combination antiretroviral drug therapy have increases in expression of HLA, T-cell coreceptor, and T-cell activation molecules in response to the DC maturation factor CD40L comparable to those from uninfected persons. Mature DCs (mDCs) loaded with HLA A*0201-restricted viral peptides of the optimal length (9-mer) were more efficient at activating antiviral CD8+ T cells than were immature DCs or peptide alone," investigators in the United States report.

"Optimal presentation of these exogenous peptides required uptake and vesicular trafficking and was comparable in DCs derived from HIV-1-infected and uninfected persons," stated Xiao-Li Huang and colleagues at the University of Pittsburgh. "Furthermore, DCs from HIV-1-infected and uninfected persons had similar capacities to process viral peptides with C-terminal and N-terminal extensions through their proteasomal and cytosolic pathways, respectively. We conclude that DCs derived from HIV-1-infected persons have similar abilities to process exogenous peptides for presentation to CD8+ T cells as those from uninfected persons. This conclusion supports the use of DCs loaded with synthetic peptides in immunotherapy of HIV-1 infection."

Huang and associates published their study in the Journal of Virology (Processing and presentation of exogenous HLA class I peptides by dendritic cells from human immunodeficiency virus type 1-infected persons. J Virol. 2005 Mar;79(5):3052-62.

For additional information, contact C.R. Rinaldo, Department of Infectious Disease and Microbiology, University of Pittsburgh Graduate School of Public Health, 419C Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261, USA. E-mail: rinaldo@pitt.edu.

Study 2: DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells.

According to published research from Switzerland and the Netherlands, "Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC-T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors; are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient."

"Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA-expressing lentiviral vectors to specifically knockdown DC-SIGN," stated Jean-Francois Arrighi at the University Hospital of Geneva and collaborators in Switzerland and the Netherlands. "We demonstrate that DC-SIGN- DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC-T cells conjugates."

The researchers concluded, "Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis."

Arrighi and associates published their findings in the Journal of Experimental Medicine (DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J Exp Med. 2004 Nov 15;200(10):1279-88.

Additional information can be obtained by contacting Vincent Piguet, Department of Dermatology and Venereology, University Hospital of Geneva, 4-752, 24 Rue Micheli-du-Crest, 1211 Geneva, Switzerland. E-mail: vincent.piguet@medecine.unige.ch.

Study 3: Investigators have found gender differences in human immunodeficiency virus type 1-specific CD8 responses in the reproductive tract and colon following nasal peptide priming and modified vaccinia virus Ankara boosting.

According to recent research published in the Journal of Virology, "Induction of mucosal anti-human immunodeficiency virus type 1 (HIV-1) T-cell responses in males and females will be important for the development of a successful HIV-1 vaccine. An HIV-1 envelope peptide, DNA plasmid, and recombinant modified vaccinia virus Ankara (rMVA) expressing the H-2D^d-restricted cytotoxic T lymphocyte P18 epitope were used as immunogens to test for their ability to prime and boost anti-HIV-1 T-cell responses at mucosal and systemic sites in BALB/c mice."

"We found of all prime-boost combinations tested, an HIV-1 Env peptide subunit mucosal prime followed by systemic (intradermal) boosting with rMVA yielded the maximal induction of gamma interferon (IFN-gamma) spot-forming cells in the female genital tract and colon," stated James W. Peacock and collaborators at Duke University, Harvard University, and Therion Biologics Corporation. "However, this mucosal prime-systemic rMVA boost regimen was minimally immunogenic for the induction of genital, colon, or lung anti-HIV-1 T-cell responses in male mice. We determined that a mucosal Env subunit immunization could optimally prime an rMVA boost in female but not male mice, as determined by the magnitude of antigen-specific IFN-gamma responses in the reproductive tracts, colon, and lung."

"Defective mucosal priming in male mice could not be overcome by multiple mucosal immunizations," reported Peacock and his coauthors. "However, rMVA priming followed by an rMVA boost was the optimal prime-boost strategy for male mice as determined by the magnitude of antigen-specific IFN-gamma responses in the reproductive tract and lung. Thus, prime-boost immunization strategies able to induce mucosal antigen-specific IFN-gamma responses were identified for male and female mice. Understanding the cellular and molecular basis of gender-determined immune responses will be important for optimizing induction of anti-HTV-1 mucosal immune responses in both males and females."

Peacock and his colleagues published their study in the Journal of Virology (Gender differences in human immunodeficiency virus type 1-specific CD8 responses in the reproductive tract and colon following nasal peptide priming and modified vaccinia virus Ankara boosting. J Virol. 2004 Dec;78(23):13163-72.

For additional information, contact Herman F. Staats, Department of Medicine, Human Vaccine Institute, Duke University Medical Center, Box 3712, Durham, NC 27710, USA. E-mail: hfs@acpub.duke.edu.

The information in this article comes under the major subject areas of AIDS and HIV Vaccine, Vaccine Efficacy, Human Immunodeficiency Virus, Gender Studies, Women's Health, Men's Health, Immunology, Immunotherapy, Mucosal Immunization, and Virology.

This article was prepared by AIDS Weekly editors from staff and other reports.

Reference

Huang XL, Fan Z, Colleton BA, et al., Processing and presentation of exogenous HLA class I peptides by dendritic cells from human immunodeficiency virus type 1-infected persons., J Virol. 2005 Mar;79(5):3052-62.   PubMED Related articles Search

Arrighi JF, Pion M, Garcia E, et al., DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells., J Exp Med. 2004 Nov 15;200(10):1279-88.   PubMED Related articles Search

Peacock JW, Nordone SK, Jackson SS, et al., Gender differences in human immunodeficiency virus type 1-specific CD8 responses in the reproductive tract and colon following nasal peptide priming and modified vaccinia virus Ankara boosting., J Virol. 2004 Dec;78(23):13163-72.   PubMED Related articles Search

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