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HIV-1 TRANSMISSION FROM SEMEN TO CERVICO-VAGINAL TISSUE EX VIVO

HIV-1 TRANSMISSION FROM SEMEN TO CERVICO-VAGINAL TISSUE EX VIVO. Andrea Introini 1 , Christophe Vanpouille 1 , Andrea Lisco 1 , Jean-Charles Grivel , Arshi Munawwar 2 , Sarman Singh 2 , and Leonid Margolis 1

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HIV-1 TRANSMISSION FROM SEMEN TO CERVICO-VAGINAL TISSUE EX VIVO

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  1. HIV-1 TRANSMISSION FROM SEMEN TO CERVICO-VAGINAL TISSUE EX VIVO Andrea Introini1, Christophe Vanpouille1, Andrea Lisco1, Jean-Charles Grivel, Arshi Munawwar2, Sarman Singh2,and Leonid Margolis1 1National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States, 2All India Institute of Medical Sciences, New Delhi, India

  2. Vaginal intercourse is the main route of HIV-1 sexual transmission

  3. HIV- infection of human cervico-vaginal tissue ex vivo tonsillar rectosigmoid HIV-1 in seminal fluid exocervical

  4. Semen and blood from 50 HIV-1-infected and 33 HIV-uninfected men

  5. SEMEN AND BLOOD ARE SEPARATE IMMUNOLOGICAL COMPARTMENTS Semen: Blood plasma ratio (S:B ratio) Blood Semen IFN-γ GM-CSF MIP-1β MIP-3α SDF-1β TNF-α TGF-β IL-1β IL-6 IL-7 IL-8 IL-16 MCP-1 Eotaxin MIG MIP-1α IL-1α IL-2 IL-15 IP-10 HIV-1-UNINFECTED INDIVIDUALS

  6. The 2-way hierarchical cluster analysis confirms that blood and semen have 2 distinct cytokine profiles (HIV-1-uninfected) IL-1a IL1-a IL-7 MCP-1 IP-10 IL-8 MIG MIP-3a SDF-1b IL-6 TGF-b IL-15 IL-1b MIP-1a GM-CSF IL-2 IGN-g IL-16 Eotaxin MIP-1b TNF-a blood plasma seminal plasma Cytokine levels: high; low

  7. Correlations between cytokine levels in seminal plasma +0.5 ≤  ≤ +0.7 HIV+ -0.25 ≤  ≤ -0.5 HIV- 71 correlations HIV¯  ≥ +0.7 20 correlations +0.25 ≤  ≤ +0.5 No correlation -0.5 ≤  ≤-0.7  ≥-0.7

  8. HERPESVIRUSES REACTIVATION IN SEMINAL PLASMA HIV-1-infected % of positive samples 80 60 40 20 0

  9. CMV EBV 6 9 8 5 7 4 6 5 3 4 2 3 2 1 1 EBV and CMV reactivation is compartmentalized Viral load [log10 copies/mL] Viral load [log10 copies/mL] blood semen blood semen CMV and EBV seminal shedding occurs in absence of plasma viremia in 75 and 54% of the patients, respectively

  10. IL-7 is increased in semenof chronically HIV-1-infected individuals Blood Semen IL-7 (pg/ml) IL-7 (pg/ml)

  11. IL-7 Naïve T-cell Stromal cell IL-7 IL-7 IL-7 • Survival •  Proliferation Thymus Memory T-cell IL-7 role in HIV-1 transmission to cervico-vaginal tissue?

  12. HIV-1 infection of human tissue ex vivo IL-7 HIV-1 Collagen raft

  13. IL-7 enhances HIV-1 replication in cervico-vaginal tissue ex vivo [BaL+IL-7] [BaL] HIV-1 p24gag (ng/ml) HIV-1BaL HIV-1BaL + IL-7

  14. IL-7 increases the number of HIV-1-infected CD4 T-cells Day 6 HIV-1BaL HIV-1BaL+ IL-7 CD4 HIV-1 p24gag

  15. IL-7 decreases HIV-1-induced CD4 T-cells depletion HIV-1LAI.04 Day 9 - + IL-7

  16. IL-7 decreases apoptosis of HIV-1-infected CD4 T-cells HIV-1LAI.04 Day 6 p=0.0049 p24gag+ APO2.7+ (% of CD4+) - + IL-7

  17. IL-7 decreases apoptosis of HIV-1-infected CD4 T-cells Day 9 HIV-1LAI.04 HIV-1LAI.04 + IL-7 Cumulative distribution function Bcl-2

  18. Conclusions • Semen and blood are immunologically separate compartment which differ in their cytokine spectra. • HIV-1 infection enhances this difference changing the entire pattern of cytokine networks. • IL-7 is one of the seminal cytokines greatly upregulated in HIV-1 infected men • Upon deposition on cervico-vaginal tissue IL-7 enhances HIV-1 transmission • Enhancement of HIV-1 infection is associated with IL-7-mediated prevention of death of HIV-1-infected CD4 T-cells, due to suppression of apoptosis

  19. Speculations • Cervico-vaginal tissue contains much less CD4 T cells than lymph nodes or other lymphoid organs, which may be one of the reasons for a relatively low probability of male-to-female HIV-1 sexual transmission. By preventing the death of the small initial pool of infected cells, IL-7 gives HIV more time to find and infect target cells in cervix/vagina and to start dissemination • Concentration of IL-7 in the semen of an HIV-1 infected man may be a determinant of infectiousness for his uninfected female partner.

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