16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

POTENTIAL MUCOSAL IMMUNE MECHANISMS FOR INCREASED HIV SUSCEPTIBILITY IN WOMEN INFECTED BY HERPES SIMPLEX TYPE 2

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WeAa0304

Rebbapragada A.¹, Pettengell C.¹, Sunderji S.¹, Huibner S.¹, Sheung A.¹, Moussa G.², Mazzuli A.², Wachihi C.³, Jaoko W.4, Ball B.⁵, Fowke K.⁵, Plummer F.⁵, Kaul R.^1
1 University of Toronto, Clinical Sciences Division, Toronto, Canada, ² Mount Sinai Hospital, Toronto Medical Laboratories, Toronto, Canada, ³ University of Nairobi, Department of Medical Microbiology, Nairobi, Kenya, 4 University of Nairobi, Kenya AIDS Vaccine Initiative, Nairobi, Kenya, ⁵ University of Manitoba, Department of Medical Microbiology, Winnipeg, Canada

BACKGROUND: Chronic Herpes Simplex virus type 2 (HSV2) infection is associated with a 3-fold increase in HIV susceptibility in women, although many have never had symptomatic episodes of genital ulceration. It is not known whether this enhanced susceptibility relates to asymptomatic microulceration, or to adverse changes in the mucosal immune milieu. The purpose of this study was to examine the potential mucosal immune basis of enhanced HIV susceptibility in HSV2 infected women.

METHODS: Cervico-vaginal lavage (CVL), cervical cytobrush, cervical scraper, endocervical swabs, STD diagnostics and blood were collected from FSWs attending a dedicated research clinic in Nairobi, Kenya. Endocervical CD1a+ immature dendritic cells, TLR9, DC-SIGN and CD3/CD4/CD69/CCR5 lymphocytes were quantified by flow cytometry, and ex vivo RNA expression of immune genes was assayed by RT-QPCR. Endocervical shedding of HIV RNA, HSV2 DNA and CMV DNA were assayed. FGT cytokine/chemokine levels were quantified by Cytokine Bead Array (CBA; BD Biosciences).

RESULTS: Samples were collected from 56 HIV-uninfected FSWs: 42 (75%) were HSV2 seropositive and 12 (25%) were HSV2 seronegative. There was a 10-fold increase in DC-SIGN positive CD1a immature dendritic cells in the FGT of HSV2 seropositive FSWs (P=0.005). HSV2 shedding was only detected in 3/42 (7%) HSV2+/HIV- FSWs, and tended to be associated with elevated levels of IL6, IL8 and MIG (P=0.05, P=0.07 and P=0.08, respectively). Levels of TLR9+ immature DCs were significantly reduced in the FGT of women who were shedding HSV2 (P=0.01).

CONCLUSIONS: DC-SIGN, which has been hypothesized to act as a "Trojan horse" in transporting HIV virions from mucosal sites to lymph nodes, was significantly increased in the FGT of women with chronic HSV2 infection. This suggests a potential immune mechanism for enhanced HIV susceptibility. HSV2 shedding was infrequent in HIV uninfected FSWs, and TLR9 induction may be associated with local control of HSV2 reactivation.

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2006-08-13
WeAa0304

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