Glycerol monolaurate prevents mucosal SIV transmission.
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.
Li
Qingsheng
Q
Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA.
Estes
Jacob D
JD
Schlievert
Patrick M
PM
Duan
Lijie
L
Brosnahan
Amanda J
AJ
Southern
Peter J
PJ
Reilly
Cavan S
CS
Peterson
Marnie L
ML
Schultz-Darken
Nancy
N
Brunner
Kevin G
KG
Nephew
Karla R
KR
Pambuccian
Stefan
S
Lifson
Jeffrey D
JD
Carlis
John V
JV
Haase
Ashley T
AT
D000208:Acute Disease; D000818:Animals; D001826:Body Fluids / Q000378:metabolism / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002584:Cervix Uteri / Q000187:drug effects / Q000276:immunology / Q000821:virology; D054418:Chemokine CCL20 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000502:physiology; D016209:Interleukin-8 / Q000378:metabolism; D007848:Laurates / Q000494:pharmacology*; D008253:Macaca mulatta / Q000821:virology*; D008565:Membrane Proteins / Q000378:metabolism; D050178:Monoglycerides / Q000494:pharmacology*; D009092:Mucous Membrane / Q000187:drug effects* / Q000276:immunology / Q000821:virology*; D012367:RNA, Viral / Q000097:blood; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000517:prevention & control* / Q000635:transmission* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D013997:Time Factors; D014621:Vagina / Q000187:drug effects / Q000821:virology
C108355:CCL20 protein, human; D018797:Cell Cycle Proteins; D054418:Chemokine CCL20; C102519:GML protein, human; D058851:GPI-Linked Proteins; D016209:Interleukin-8; D007848:Laurates; D008565:Membrane Proteins; D050178:Monoglycerides; D012367:RNA, Viral; D019713:Receptors, CCR5; C020777:monolaurin