M. Boeckh, R. Coombs, D. Koelle, M. Huang
Interaction of CMV and HIV in the female genital tract. Studies are being conducted in collaboration with Robert Coombs and David Koelle [ HD 40540, PI Robert Coombs (PO-1) 4/01/01-03/31/06 NIH, CMV and HIV-1 Interactions in the Female Genital Tract ] to determine whether CMV upregulates HIV-1 replication in the female genital tract and whether suppression of CMV load by antiviral chemotherapy may decrease HIV-1 load in the female genital tract. Women will be monitored daily for two months for quantitative CMV DNA, HSV DNA, HIV-1 RNA, HIV-1 DNA, along with CMV-specific systemic and local immune responses. To study the causal relationship between cervical CMV and/or HSV shedding and HIV-1 cervical shedding, a prospective randomized treatment study will be conducted. HIV-infected women who are on stable antiretroviral therapy, shed CMV in cervical secretions, and have no cervicovaginal bacterial infection will be randomized to valganciclovir, valacyclovir, or placebo in a double-blind, cross-over fashion. The primary endpoint of the study is a reduction of cervical HIV RNA load. Additional laboratory studies are aimed at determining if infection with multiple CMV strains has an effect on CMV and HIV load. A heteroduplex mobility assay has been developed to address this question.
The aims of the project are:
1. Define the pattern of cervical CMV DNA and HSV DNA shedding relative to cervical HIV-1 RNA and DNA levels in HIV infected women.
We hypothesize that local infection with CMV or HSV may lead to upregulation of HIV-1 replication in the female genital tract or shedding of HIV-infected cells. This aim will be addressed in a prospective cohort study of HIV-1-infected women. Women will be monitored daily for two months. The general study design is similar to that outlined in Project 1. During the 2 months of prospective monitoring, parameters tested include daily tests for quantitative CMV DNA, HSV DNA, HIV-1 RNA, HIV-1 DNA, along with CMV-specific systemic and local immune responses and clinical information obtained by questionnaires.
2. Determine whether suppression of CMV and HSV with valganciclovir or suppression of HSV alone with valayclovir reduces HIV-1 RNA or DNA shedding in the female genital tract.
Since local replication of CMV is a contributory factor of local HIV-1 replication, we hypothesize that intervention with anti-CMV chemotherapy may lead to a decrease in local detection of HIV-1 RNA. To study the causal relationship between cervical CMV and/or HSV shedding and HIV-1 cervical shedding, a prospective randomized treatment study will be conducted. HIV-infected women who are on stable antiretroviral therapy, shed CMV in cervical secretions, and have no cervicovaginal bacterial infection will be randomized to valganciclovir, valacyclovir, or placebo in a double-blind, cross-over fashion. The primary endpoint of the study is a reduction of cervical HIV RNA load.
3. Determine the relationship between the number of strains of CMV infecting the cervix, immune responses to CMV, and cervical HIV and CMV viral load .
We will determine if cervical infection with multiple strains of CMV, or cervical infection with specific genotypes of CMV, is associated with HIV shedding. HIV-infected women may be infected with multiple CMV strains due to susceptibility to exogenous re-infection secondary to immunologic defects, or to behavioral/demographic factors also associated with HIV acquisition. We will investigate local and systemic CMV-specific immune responses in Specific Aim 1. We hypothesize that cervical infection with multiple CMV strains will be associated with higher overall cervical CMV shedding, and with higher overall HIV shedding. Many genetic polymorphisms between CMV strains are predicted to encode differences in protein amino acid sequences. We hypothesize that differences in the biological activities of variants of these proteins could effect the replication of CMV in the reproductive tract, the ability to up-regulate HIV shedding, or both.
CMV in HIV: Recent Publications
Mutimer, H.P., Akatsuka, Y., Manley, T., Chuang, E.L., Boeckh, M ., Jones, T., Greenberg P.,Riddell, S.R. Immune recovery vitritis is associated with a diverse intra-ocular CMV-specific cytotoxic T cell response. J Infect Dis 186 ; 701-5 2002 .
Boeckh, M. , Huang, M.L., Ferrenberg, J., Stevens-Ayers, T., Stensland, L., Nichols, W.G., Corey L. Optimization of Quantitative Detection of Cytomegalovirus DNA in Plasma by Real-Time PCR. J Clin Microbiol 42 :1142-8, 2004 .
Manley, T.J., Luy, L., Jones, T., Boeckh, M ., Mutimer, H., Riddell, S.R. Immune evasion proteins of cytomegalovirus do not prevent diverse CD8 + cytotoxic T cell responses. Blood 104 :1075-82, 2004 .
