HSV2 infection of dendritic cells amplifies a highly

HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target: implications for mucosal transmission Elena Martinelli Center for Biomedical Research Population Council © [2011] The Population Council, Inc.

HSV-2 infection increases the risk of HIV-1 acquisition ★ HIV-1 targets persist at the site of HSV-2 reactivation in absence of HSV-2 replication ★ Co-infection HIV/HSV-2 is associated with reduced HIVspecific response and immune activation ★ Macaque HSV-2 -infected DCs stimulate weaker SIVspecific responses than uninfected in-vitro November 2009 Vol. 4 No 11 A macaque model to study vaginal HSV 2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy Crostarosa et al

Which host-related factors are associated with higher susceptibility to HIV/SIV mucosal infection?

NHP Model of Rectal HSV-2 infection LIVE vs UVinactivated HSV-2 DAYS 0 Rectal Swabs Necropsy 3 6 ★ HSV-2 shedding in 9 of 11 animals challenged with live HSV-2 ★ No HSV-2 shedding in UV- HSV-2 treated animals (n=8)

Potential Role of α 4β 7 high CD 4+ T cells CD 4 α 4β 7 HIGH MEM CD 3 CD 95

HIV/SIV and α 4β 7 ★ ★ 4 7 is essential for cell homing to the gut and colocalizes with CD 4 and CCR 5 on T cells and gp 120 binds 4 7 via the LDV motif of the V 2 loop (earl -transmitted has higher reactivity for α 4β 7) 4 7 high CD 4+ T cells are preferentially infected In vivo blockade of α 4β 7: (i) reduces SIV load and pro-viral DNA (ii) preserves blood and gut CD 4+ T cell (iii) dampens p. DC recruitment to the colorectum, reducing immune activation

Increased frequency of α 4β 7 high CD 4+ T cells in HSV-2 infected animals Blood Rectum ** ** LIVE UV LIVE ** ** high α 4β 7 high %% α 4β 7 high BL * ** **** high % αα 4β 7 % 4β 7 ** LNs UV AX M ** ** ING ILIAC LIVE UV

HSV-2 -infected DCs up-regulate α 4β 7 on CD 4+ T cells *** α 4 β 7 *** CD 4+ T E LIV CD 4+ T UV CD 4 MO CK CCR 5 Y mo. DC *** TO NL % α 4β 7 high (Fold) HSV

HSV-2 infected DCs enhance HIV replication in the DC-T milieu HSV *** HIV-1 /cell (Fold) *** mo. DC HIV α 4 β 7 MOCK CCR 5 CD 4+ T UV LIVE

Memory α 4β 7 high CD 4+ T cells: % of CD 95+ that are α 4β 7 high CD 4 α 4β 7 HIGH MEM CD 3 CD 95

Frequency of memory α 4β 7 high CD 4+ T cells in blood appears to correlate with SIV acquisition DAY 0 DAY 3 POS = positive by SIVgag PCR at DAY 10 POS at DAY 14

Summary ★ ★ ★ Rectal HSV-2 infection of increases the frequency of 4 7 high CD 4+ T cells locally and systemically HSV-2 -infected DCs up-regulate 4 7 on CD 4+ T cells and increase HIV replication in the DC-T milieu Macaques with higher frequency of 4 7 high CD 4+ T cells in blood appear more susceptible to SIV rectal infection

Acknowledgements Center for Biomedical Research Population Council Melissa Robbiani Meropi Aravantinou Nina Derby Ines Frank Joselin Galvez Mayla Hsu Edith Jasny Jessica Kenney Pavel Pugach Hugo Tharinger Filippo Veglia Loreley Villamide-Herrera This work was supported by NIH grant R 37 AI 040877 Aaron Diamond AIDS Research Center Agegnehu Gettie Tulane National Primate Research Center James Blanchard Laboratory of Immunoregulation, NIAID James Arthos AIDS and Cancer Virus Program, NCI-Frederick Jeffrey D Lifson Michael Piatak Jr Julian Bess