Publication Date:
2009-03-06
Description:
Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry. Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3alpha (also known as CCL20), plasmacytoid dendritic cells and CCR5(+ )cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4(+) T cells to fuel this obligate expansion. We then show that glycerol monolaurate-a widely used antimicrobial compound with inhibitory activity against the production of MIP-3alpha and other proinflammatory cytokines-can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785041/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785041/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Qingsheng -- Estes, Jacob D -- Schlievert, Patrick M -- Duan, Lijie -- Brosnahan, Amanda J -- Southern, Peter J -- Reilly, Cavan S -- Peterson, Marnie L -- Schultz-Darken, Nancy -- Brunner, Kevin G -- Nephew, Karla R -- Pambuccian, Stefan -- Lifson, Jeffrey D -- Carlis, John V -- Haase, Ashley T -- G20 RR022780/RR/NCRR NIH HHS/ -- G20 RR022780-01A1/RR/NCRR NIH HHS/ -- HHSN266200400088C/PHS HHS/ -- N01-CO-12400/CO/NCI NIH HHS/ -- P01 AI066314/AI/NIAID NIH HHS/ -- P01 AI066314-040003/AI/NIAID NIH HHS/ -- P51 RR000167/RR/NCRR NIH HHS/ -- P51 RR000167-440109/RR/NCRR NIH HHS/ -- P51 RR000167-440189/RR/NCRR NIH HHS/ -- P51 RR000167-46S27592/RR/NCRR NIH HHS/ -- R21 AI071976/AI/NIAID NIH HHS/ -- R21 AI071976-02/AI/NIAID NIH HHS/ -- RR020141-01/RR/NCRR NIH HHS/ -- RR15459-01/RR/NCRR NIH HHS/ -- England -- Nature. 2009 Apr 23;458(7241):1034-8. doi: 10.1038/nature07831. Epub 2009 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262509" target="_blank"〉PubMed〈/a〉
Keywords:
Acute Disease
;
Animals
;
Body Fluids/metabolism/virology
;
CD4-Positive T-Lymphocytes/immunology/virology
;
Cell Cycle Proteins/metabolism
;
Cervix Uteri/drug effects/immunology/virology
;
Chemokine CCL20/immunology/metabolism
;
Dendritic Cells/immunology/metabolism
;
Female
;
GPI-Linked Proteins
;
Gene Expression Profiling
;
HIV-1/physiology
;
Interleukin-8/metabolism
;
Laurates/*pharmacology
;
Macaca mulatta/*virology
;
Membrane Proteins/metabolism
;
Monoglycerides/*pharmacology
;
Mucous Membrane/*drug effects/immunology/*virology
;
RNA, Viral/blood
;
Receptors, CCR5/immunology/metabolism
;
Simian Acquired Immunodeficiency Syndrome/genetics/*prevention &
;
control/*transmission/virology
;
Simian Immunodeficiency Virus/drug effects/genetics/growth &
;
development/physiology
;
Time Factors
;
Vagina/drug effects/virology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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