title: HSV-2-driven increase in the expression of α4β7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection.
abstract: The availability of highly susceptible HIV target cells that can rapidly reach the mucosal lymphoid tissues may increase the chances of an otherwise rare transmission event to occur. Expression of α4β7 is required for trafficking of immune cells to gut inductive sites where HIV can expand and it is expressed at high level on cells particularly susceptible to HIV infection. We hypothesized that HSV-2 modulates the expression of α4β7 and other homing receptors in the vaginal tissue and that this correlates with the increased risk of HIV acquisition in HSV-2 positive individuals. To test this hypothesis we used an in vivo rhesus macaque (RM) model of HSV-2 vaginal infection and a new ex vivo model of macaque vaginal explants. In vivo we found that HSV-2 latently infected RMs appeared to be more susceptible to vaginal SHIVSF162P3 infection, had higher frequency of α4β7high CD4+ T cells in the vaginal tissue and higher expression of α4β7 and CD11c on vaginal DCs. Similarly, ex vivo HSV-2 infection increased the susceptibility of the vaginal tissue to SHIVSF162P3. HSV-2 infection increased the frequencies of α4β7high CD4+ T cells and this directly correlated with HSV-2 replication. A higher amount of inflammatory cytokines in vaginal fluids of the HSV-2 infected animals was similar to those found in the supernatants of the infected explants. Remarkably, the HSV-2-driven increase in the frequency of α4β7high CD4+ T cells directly correlated with SHIV replication in the HSV-2 infected tissues. Our results suggest that the HSV-2-driven increase in availability of CD4+ T cells and DCs that express high levels of α4β7 is associated with the increase in susceptibility to SHIV due to HSV-2. This may persists in absence of HSV-2 shedding. Hence, higher availability of α4β7 positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission.
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Goode
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Rosaline
authors.initials: R
authors.lastname: Truong
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Villegas
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Giulia
authors.initials: G
authors.lastname: Calenda
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Guerra-Perez
authors.affiliation: AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Tulane National Primate Research Center, Tulane University Sciences Center, Covington, Louisiana, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: Tulane National Primate Research Center, Tulane University Sciences Center, Covington, Louisiana, United States of America; Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
authors.affiliation: Center for Biomedical Research, Population Council, New York, New York, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Martinelli
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D060085:Coinfection / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006678:HIV / Q000302:isolation & purification / Q000502:physiology; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006558:Herpes Genitalis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D018258:Herpesvirus 2, Human / Q000302:isolation & purification / Q000502:physiology*; D016023:Integrins / Q000378:metabolism*; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification / Q000502:physiology; D015854:Up-Regulation; D014621:Vagina / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D039521:CD11c Antigen; D016023:Integrins; C071777:integrin alpha4beta7