1. Center for Biomedical Research
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.

2. 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 HIV-specific response and immune activation
★ Macaque HSV-2-infected DCs stimulate weaker SIV-specific responses than uninfected in-vitro
A macaque model to study vaginal HSV-2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy
Crostarosa et al
November 2009
Vol. 4 No 11

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

4. NHP Model of Rectal HSV-2 infection
LIVE vs UV-inactivated HSV-2
Rectal Swabs
Necropsy
DAYS 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)

5. Potential Role of α4β7high CD4+ T cells
MEM
CD3
CD95

6. HIV/SIV and α4β7 reduces SIV load and pro-viral DNA
★ 47 is essential for cell homing to the gut and co-localizes with CD4 and CCR5 on T cells and
★ gp120 binds 47 via the LDV motif of the V2 loop (early-transmitted has higher reactivity for α4β7)
★ 47high CD4+ T cells are preferentially infected
★ In vivo blockade of α4β7:
reduces SIV load and pro-viral DNA
preserves blood and gut CD4+ T cell
dampens pDC recruitment to the colorectum, reducing immune activation

7. Increased frequency of α4β7high CD4+ T cells in HSV-2 infected animals
Blood
Rectum
LNs ** ** * ** ** ** ** ** ** ** **
% α4β7high
% α4β7high
% α4β7high
% α4β7high
% α4β7 BL
LIVE UV
LIVE UV AX M
ING
ILIAC
LIVE UV

8. HSV-2-infected DCs up-regulate α4β7 on CD4+ T cells
***
% α4β7high (Fold)
HSV
moDC
CD4+ T
α4β7
CCR5
MOCK UV
LIVE
T ONLY
CD4
CD4+ T

9. HSV-2 infected DCs enhance HIV replication in the DC-T milieu
***
***
moDC
HIV-1 /cell (Fold)
HIV
α4β7
CCR5
MOCK UV
LIVE
CD4
CD4+ T

10. Memory α4β7high CD4+ T cells:
% of CD95+ that are α4β7high
HIGH
CD4
α4β7
MEM
CD3
CD95

11. Frequency of memory α4β7high CD4+ T cells in blood appears to correlate with SIV acquisition
DAY 0
DAY 3
DAY 10
POS at DAY 14
POS = positive by SIVgag PCR at DAY 10

12. Summary
★ Rectal HSV-2 infection of increases the frequency of 47high CD4+ T cells locally and systemically
★ HSV-2-infected DCs up-regulate 47 on CD4+ T cells and increase HIV replication in the DC-T milieu
★ Macaques with higher frequency of 47high CD4+ T cells in blood appear more susceptible to SIV rectal infection

13. Acknowledgements Melissa Robbiani 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
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
This work was supported by NIH grant R37 AI040877