viral immunity: therapeutic hiv vaccines

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© 2003 Nature Publishing Group HIGHLIGHTS NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | FEBRUARY 2003 | 91 An effective immune response to simian immunodeficiency virus (SIV) can be elicited in vivo by a new thera- peutic dendritic-cell (DC) vaccine, as reported by Lu and colleagues in Nature Medicine. Chronic infection with HIV or SIV results in progressive immuno- deficiency and ineffective antiviral immune responses. Although highly active antiretroviral therapy (HAART) can reduce the viral load and improve CD4 + T-cell counts, these drugs do not restore immune functions completely, and a therapeutic vaccine is highly sought after. Previous studies have shown that DCs that have been pulsed with chemically (aldrithiol-2,AT-2)- inactivated HIV or SIV can stimu- late the activity of antiviral cytotoxic T lymphocytes (CTLs) in vitro. Here, Lu and colleagues test the activity of an AT-2-inactivated SIV-pulsed DC vac- cine in vivo in SIV-infected rhesus monkeys. Fourteen SIV-infected monkeys were split into two groups of vacci- nated (ten) and control (four) ani- mals. Vaccinated monkeys received immunizations and boosters of AT-2- inactivated SIV-loaded DCs, whereas control monkeys received comparable injections of unloaded autologous DCs. Levels of SIV cellular DNA and plasma RNA decreased rapidly in the vaccinated animals, and the levels remained low and stable for the remainder of the study. In addition, vaccination led to higher numbers of CD4 + T cells and increased titres of neutralizing antibodies. In the control animals, the levels of viraemia, CD4 + T cells and antibodies remained unchanged throughout the study. Next, the authors assessed SIV- specific immunity. Higher numbers of SIV-specific memory T cells could be detected after vaccination, the cytolytic activity of SIV-specific CTLs was increased and the inhibitory effect of CD8 + T cells on replication of SIV was enhanced. Secondary lymph nodes are important sites for the replication of SIV and HIV, and for the development of antiviral responses. Lymph-node biopsies carried out in the last week of the study showed that the lymphoid follicular DC network was destroyed in half of the control monkeys, whereas it was intact in all of the vacci- nated monkeys. Also, the levels of cel- lular SIV DNA and SIV RNA were considerably lower in the vaccinated monkeys than in the control monkeys. Most importantly, high levels of lymph-node SIV-specific CTLs were associated with low levels of local cel- lular SIV burden, illustrating the effective control of viral spread by cell-mediated immunity in situ. This study shows that inactivated SIV-pulsed DC-based vaccines can elicit effective cellular and humoral immune responses against SIV in vivo, resulting in the control of SIV replica- tion in secondary lymphoid tissues and reduced levels of viraemia in vac- cinated monkeys. If this approach could be adapted for use in humans, then inactivated whole-virus DC vaccines could be promising thera- pies for controlling chronic infection with HIV. Jenny Buckland References and links ORIGINAL RESEARCH PAPER Lu, W. et al. Therapeutic dendritic-cell vaccine for simian AIDS. Nature Med. 9, 27–32 (2002) Therapeutic HIV vaccines VIRAL IMMUNITY IN BRIEF Activation of influenza virus-specific CD4 + and CD8 + T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Fontaneu, J. et al . Blood 2 January 2003 (DOI: 10.1182/blood-2002-10-3063) Plasmacytoid dendritic cells (pDCs) contribute to innate immune responses to viral infections by producing type I interferons, but their ability to process and present antigens to T cells has not been demonstrated. In this study, Nina Bhardwaj’s lab assessed the ability of pDCs to activate influenza-specific T cells. The results show that pDCs can process and present antigens from influenza virus to CD4 + and CD8 + T cells, and they provide the first direct evidence that pDCs contribute to the adaptive immune response to this virus. Whether such responses are protective at the level of T cells during chronic viral infection remains to be determined. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Abtahian, F. et al. Science 299, 247–251 (2003) Lymphatic vessels are derived from pre-existing blood vessels, but it is not clear which factors control the separation of emerging lymphatics from blood vessels. Mice lacking SLP76 or Syk show a failure to separate these vessels, resulting in embryonic haemorrhage and arteriovenous shunting. The transfer of bone- marrow cells derived from SLP76- or Syk-deficient animals was sufficient to recreate the abnormal vascular phenotype, which indicates that haematopoietic cells and not lymphatic endothelial cells are responsible for the defect. Further work is necessary to determine how defects in circulating cells can influence the growth of lymphatic vessels. Mycobacteria target DC-SIGN to suppress dendritic- cell function. Geijtenbeek, T. B. H. et al. J. Exp. Med. 197, 7–17 (2003) DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. Tailleux, L. et al. J. Exp. Med. 197, 121–127 (2003) Although macrophages are the main cellular target of Mycobacterium tuberculosis, dendritic cells (DCs) are important mediators of immune responses against M. tuberculosis. These studies show that M. tuberculosis infects DCs using the C-type lectin receptor DC-SIGN. This interaction prevents the maturation of DCs induced by mycobacteria or lipopolysaccharide through Toll-like receptors. Interaction of mycobacteria with DC- SIGN also results in production of the anti-inflammatory cytokine IL-10, which can modify the immune response, and might promote survival of mycobacteria. These results indicate that M. tuberculosis infects DCs and interferes with DC-mediated immune responses by targeting DC-SIGN. So, DC-SIGN is a Trojan horse for M. tuberculosis as has been shown previously for HIV-1. INFECTIOUS DISEASE DEVELOPMENT DENDRITIC CELLS

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© 2003 Nature Publishing Group

H I G H L I G H T S

NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | FEBRUARY 2003 | 91

An effective immune response tosimian immunodeficiency virus (SIV)can be elicited in vivo by a new thera-peutic dendritic-cell (DC) vaccine, asreported by Lu and colleagues inNature Medicine.

Chronic infection with HIV orSIV results in progressive immuno-deficiency and ineffective antiviralimmune responses. Although highlyactive antiretroviral therapy (HAART)can reduce the viral load and improveCD4+ T-cell counts, these drugs do notrestore immune functions completely,and a therapeutic vaccine is highlysought after. Previous studies haveshown that DCs that have been pulsedwith chemically (aldrithiol-2, AT-2)-inactivated HIV or SIV can stimu-late the activity of antiviral cytotoxic T lymphocytes (CTLs) in vitro. Here,Lu and colleagues test the activity of anAT-2-inactivated SIV-pulsed DC vac-cine in vivo in SIV-infected rhesusmonkeys.

Fourteen SIV-infected monkeyswere split into two groups of vacci-nated (ten) and control (four) ani-mals. Vaccinated monkeys receivedimmunizations and boosters of AT-2-inactivated SIV-loaded DCs, whereascontrol monkeys received comparableinjections of unloaded autologousDCs. Levels of SIV cellular DNA andplasma RNA decreased rapidly in thevaccinated animals, and the levelsremained low and stable for theremainder of the study. In addition,vaccination led to higher numbers ofCD4+ T cells and increased titres ofneutralizing antibodies. In the controlanimals, the levels of viraemia, CD4+

T cells and antibodies remainedunchanged throughout the study.

Next, the authors assessed SIV-specific immunity. Higher numbersof SIV-specific memory T cells couldbe detected after vaccination, thecytolytic activity of SIV-specific CTLswas increased and the inhibitory effectof CD8+ T cells on replication of SIVwas enhanced.

Secondary lymph nodes areimportant sites for the replication ofSIV and HIV, and for the developmentof antiviral responses. Lymph-nodebiopsies carried out in the last week ofthe study showed that the lymphoidfollicular DC network was destroyedin half of the control monkeys,whereas it was intact in all of the vacci-nated monkeys.Also, the levels of cel-lular SIV DNA and SIV RNA wereconsiderably lower in the vaccinatedmonkeys than in the control monkeys.Most importantly, high levels oflymph-node SIV-specific CTLs wereassociated with low levels of local cel-lular SIV burden, illustrating theeffective control of viral spread bycell-mediated immunity in situ.

This study shows that inactivatedSIV-pulsed DC-based vaccines canelicit effective cellular and humoralimmune responses against SIV in vivo,resulting in the control of SIV replica-tion in secondary lymphoid tissuesand reduced levels of viraemia in vac-cinated monkeys. If this approachcould be adapted for use in humans,then inactivated whole-virus DCvaccines could be promising thera-pies for controlling chronic infectionwith HIV.

Jenny BucklandReferences and links

ORIGINAL RESEARCH PAPER Lu, W. et al.Therapeutic dendritic-cell vaccine for simian AIDS.Nature Med. 9, 27–32 (2002)

Therapeutic HIV vaccines

V I R A L I M M U N I T Y IN BRIEF

Activation of influenza virus-specific CD4+ and CD8+

T cells: a new role for plasmacytoid dendritic cells inadaptive immunity.Fontaneu, J. et al. Blood 2 January 2003 (DOI: 10.1182/blood-2002-10-3063)

Plasmacytoid dendritic cells (pDCs) contribute to innate immuneresponses to viral infections by producing type I interferons, buttheir ability to process and present antigens to T cells has not beendemonstrated. In this study, Nina Bhardwaj’s lab assessed the abilityof pDCs to activate influenza-specific T cells. The results show thatpDCs can process and present antigens from influenza virus toCD4+ and CD8+ T cells, and they provide the first direct evidencethat pDCs contribute to the adaptive immune response to thisvirus. Whether such responses are protective at the level of T cellsduring chronic viral infection remains to be determined.

Regulation of blood and lymphatic vascular separationby signaling proteins SLP-76 and Syk.Abtahian, F. et al. Science 299, 247–251 (2003)

Lymphatic vessels are derived from pre-existing blood vessels, butit is not clear which factors control the separation of emerginglymphatics from blood vessels. Mice lacking SLP76 or Syk show a failure to separate these vessels, resulting in embryonichaemorrhage and arteriovenous shunting. The transfer of bone-marrow cells derived from SLP76- or Syk-deficient animals wassufficient to recreate the abnormal vascular phenotype, whichindicates that haematopoietic cells and not lymphatic endothelialcells are responsible for the defect. Further work is necessary todetermine how defects in circulating cells can influence the growthof lymphatic vessels.

Mycobacteria target DC-SIGN to suppress dendritic-cell function.Geijtenbeek, T. B. H. et al. J. Exp. Med. 197, 7–17 (2003)

DC-SIGN is the major Mycobacterium tuberculosisreceptor on human dendritic cells.Tailleux, L. et al. J. Exp. Med. 197, 121–127 (2003)

Although macrophages are the main cellular target ofMycobacterium tuberculosis, dendritic cells (DCs) are importantmediators of immune responses against M. tuberculosis. Thesestudies show that M. tuberculosis infects DCs using the C-typelectin receptor DC-SIGN. This interaction prevents thematuration of DCs induced by mycobacteria or lipopolysaccharidethrough Toll-like receptors. Interaction of mycobacteria with DC-SIGN also results in production of the anti-inflammatory cytokineIL-10, which can modify the immune response, and mightpromote survival of mycobacteria. These results indicate that M. tuberculosis infects DCs and interferes with DC-mediatedimmune responses by targeting DC-SIGN. So, DC-SIGN is a Trojanhorse for M. tuberculosis as has been shown previously for HIV-1.

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