Mbopi-Kéou, Franҫois-Xavier

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Open Research OnlineThe Open University’s repository of research publicationsand other research outputsThe Role of Herpes simplex virus type 2 (HSV-2) as acofactor in HIV transmissionThesisHow to cite:Mbopi-Ke´ou, Franois-Xavier (2002). The Role of Herpes simplex virus type 2 (HSV-2) as a cofactor in HIVtransmission. PhD thesis The Open University.For guidance on citations see FAQs.c© 2002 The AuthorVersion: Version of RecordCopyright and Moral Rights for the articles on this site are retained by the individual authors and/or other copyrightowners. For more information on Open Research Online’s data policy on reuse of materials please consult the policiespage.oro.open.ac.ukThe Role of Herpes simplex virus type 2 (HSV-2) as a cofactor in HIV transmission Francois-Xavier Mbopi-Keou, DBiol, MPhil, MSc Ph.D 2002 The Role of Herpes simplex virus type 2 (HSV-2) as a cofactor in HIV transmission Fran~ois-Xavier Mbopi-Keou, DBiol, MPhiI, MSc A thesis submitted to the Open University in fulfIlment of the conditions governing candidates for the degree of Doctor of Philosophy Discipline: Life Sciences June 2002 Central Public Health Laboratory, Virus Reference Division, Enteric, Respiratory and Neurological Virus Laboratory, London, United Kingdom, in collaboration with: Children's Hospital Regional Medical Center, Virology Division, University of Washington, Seattle, USA & Hopital Europeen George Pompidou, Laboratoire de Virologie, INSER.1\1 U430, "Cniversite de Paris VI, France AUTHO~ NO .,.. b' I 2.5'3~ i:::>PrrE. or; su8r~\'T::$s:JorJ' '1-7 ~vl\Jt... -LOO', DPI-rt. 'V(: f\WF\fIl:~. 1Cl\. SfP1(.(Y>F.,£~ 'LOOL-A. Acknowledgements TIlis thesis mainly involved close collaboration between the Central Public Health Laboratory (CPID-) in London, UK, the Virology Division, University of Washington, Seattle, USA and the Virology Unit, Georges Pompidou University Hospital, Paris, France. Other Institutions were also part of this collaboration: (i) the CRMST of Bangui, Central African Republic and (ii) the London School of Hygiene & Tropical Medicine (LSH1M). The contribution of each is aclmowledged by joint authorship in the cited pUblications and presentations. I designed the study and analysed the data with the help of colleagues at the LSHTM (Dr Helen Weiss, Dr Philippe Mayaud, Prof. Richard Hayes, Prof David Mabey), implemented the field work in Bangui with Dr Gerard Gresenguet. I learned and performed the herpes type specific serology at the CPHL in London, the HIV and herpes quantitation work in Prof. Belec' s laboratory in Paris, and the herpes neutralizing antibody assay in Prof Rhoda Ashley's laboratory in Seattle, USA. A very special thanks to my supervisors, Dr. David Brown who initiated a Fellowship for this Ph.D at the CPHL, making a dream a reality, and Prof. Laurent Belec, my mentor for the past decade. Their continued support and understanding, provided the ongoing spark and impetus for my commitment to this work. I very much hope our friendship and collaboration will last for many years to come! I would like to thank Dr. Robin Gopal for supporting this project, Wendy Lebett for teaching me the herpes type specific serology, and the many colleagues at the CPHL for encouragement and support. I would like to express my indebtness to Drs Mathieu Matta, Ali-Si-Mohamed, Laurent Andreoletti and Marie-Claude Lang, who taught me the HIV and herpes quantitation and provided help with the bench work, and Prof. Jean-Louis Paul for the vitamin A & E work. I am very grateful to many people in Seattle, some of whom have become great friends: Prof. Rhoda Ashley and Prof. Lawrence (Larry) Corey for providing a Fellowship, Sharon Risley who did my paper work in no time. Julie Dalessio taught me the herpes neutralizing assay, help design the protocol. I'm indebted to Prof Robert Coombs, Dr, Anna Wald, Dr Connie Celum, Dr. Andrew Jolmson and Prof. James Mullins and colleagues for fruitful discussions. Thanks to many other colleagues at the University of Washington, the Fred Huchinson Cancer Research Center and at Children's Hospital who made me share their enthusiasm and passion for Medical Research. I'm very grateful to the support provided by Dr Chong G Teo and Dr Henrik Chart at CPHL, Dr. Philippe Mayaud, Dr. Helen Weiss, Prof. Richard Hayes and Prof. David Mabey as well Prof Peter Smith at the LSHTM. Thanks are also due to Prof. Harisson Spencer and Prof Richard Feachem, fomler Deans of the LSHTM, and the library staff at the LSHTM and at the CPHL. I was a Commonwealth Scholar at the LSHTM. Special thanks to His Excellency Chief Emeka Anyaoku (fomler Secretary General of the Commonwealth), Dr. Rose-M. Odiachi-Endeley and R. Galega. I'm grateful to Dr. Jamie-N.Robinson who was instrumental in securing funds from GlaxoSmithldine to support part of my research work. Finally, I was honoured to be the first winner of the GlaxoSmithKline Elion Research Award 2000-named after the Nobel prize winner Dr Elion Truly. Special thanks to Prof. Richard V,illtley Prof. Lany Corey, and the International Herpes Management Forum Board for supporti.."'1g rr..y nomination for tllis prestigious award. Above all I thank God for his multiple blessings! 2 B. Dedication To the memory of my father who gave me a very good start in life, the values which have driven me, and above all, the confidence to believe in my self. To my mother for honesty and warmth, To my large Family for love and support, To Dame Claude, Marilyn, Amanda .. .just beyond words ... . . . and to all those who care to listen to the illnesses, whispering the tales of the voiceless -particularly the women - in the developing world. .., -' c. Declaration The work described in this thesis has not previously been submitted for a degree at the Open University or any other University. Data in several sections have been published (see list of scholarly contributions-copies attached in appendix). With the following exceptions, I have carried out all the work described in this thesis: a) Dr P. Mayaud, Dr H. Weiss, ProfD. Mabey and ProfR. Hayes help with study design. b) Dr G. Gresenguet did the clinical evaluations of the patients in Bangui. c) Prof R. Ashley and J. Dalessio help design the HSV neutralizing antibody study. Dr L. Andreoletti, Dr. A. Si-Mohamed and M. Matta help design the herpes quantitation study. Prof J-L Paul's laboratory performed the Vitamin A & E evaluation. d) Dr D. Brown and profL. Belec supervised the whole study. I confmn that the above is a true statement and that, subject to any comment above, the thesis is my own original work. London, February 15th , 2002 Franc;ois-Xavier Mbopi-Keou 4 D. Scholarly contributions from this thesis D.1. Publications in peer review journals Mbopi-Keou, FX., Gresenguet, G., Mayaud, P., Weiss, H.A, Gopal, R., Brown, D., Hayes, R.l, Mabey, D.C.W. and Belec, 1. (1999) Genital Herpes simplex virus type 2 shedding is increased in HIV-infected women in Africa. AIDS 4,536-537. Mbopi-Keou, FX., Gresenguet, G., Mayaud, P., Weiss, H.A, Gopal, R., Brown, D., Hayes, R.l, Mabey, D.C.W. and Belec, L. (2000) Interactions between Herpes simplex virus type 2 and HIV infection in African women: opportunities for intervention. J Infect Dis 182, 1090-1096. Belec, L., Gresenguet, G., Mbopi-Keou, F.X., Mayaud, P. (2000) High frequency of asymptomatic shedding of herpes simplex virus type 2 in African women. Clin Microbiol Infect 6,56-57. B6lec, L., Mbopi-Keou, FX., Roubache, J.F., Mayaud, P., Paul, lL., Gresenguet, G. (2002) Vitamin A deficiency and genital tract infections in women living in Central Africa. J Acquir Immune D~fic Syndr 29, 203-204. Mbopi-Keou, F.X., Robinson, N.J., Mayaud, P., Belec, L. and Brown D.W. (2002) Herpes simplex virus type 2 and heterosexual spread of human immunodeficiency virus infection in developing countries: hypotheses and research priorities. Clin Microbial Infect in press. Mbopi-Keou, F.X., Legoff, l, Gresenguet, G., Si-Mohamed, A, Matta, M., Mayaud, P., Andreoletti, L., Brown, D., Belec, L. (2002) Genital shedding of HSV-2 DNA and HIV-I proviral D~A in HIV- and HSV- co-infected women. JAIDSin press. D.2. Paper submitted for Publication in peer review journals: 5 Mbopi-Keou, FX., Dalessio, l, Gresenguet, G., Brown, D.W.G., Belec, L. Ashley, R.L. (2002) Cervicovaginal neutralizing antibodies to Herpes simplex virus type-2 (HSV-2) in cervicovaginal secretions of African women. (Submitted) D.3. Presentations at International meetings (presenting author name underlined): *Chair of the herpesviruses session at 41 til Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, IL, USA, December 16-19, 2001, and presenter of the paper: Mbopi-Keou, FX., Andreoletti, L., Gresenguet, G., Matta, M., Mayaud, P., Weiss, H.A., Gopal, R., Si-Mohamed, A., Lang, M.e., Hayes, R.J., Brown, D., Mabey, D.C.W., Belec, L. (2001) Association of genital replication of HSV-2 with increasing HIV-I RNA, but not HIV-l proviral DNA, genital shedding in HIV - and HSV - co-infected women [oral presentation]. 41 th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, December 16-19, Abstract no 1113. Mbopi-Keou, FX. Interactions between HSV-2 and HIV-l infection in African women: "Pefa me Si dasi meji" [oral presentation]. Annual Virology and Infectious Diseases Research Conference, University of Washington, Fred Hutchinson Cancer Research Center, Children's Hospital and Regional Medical Center, Seattle, USA, 9th March 2000. Mbopi-Keou, FX, Gresenguet G, Mayaud P, Weiss HA, Gopal R, Matta M, Brown D, Hayes RJ, Mabey DCW, Belec L. Increased shedding of HSV-2 in HIV-I infected women in Africa [oral presentation]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAA.C), San Francisco, California, USA, September 26-29, 1999, Abstract no 1407. Mbopi-Keou, FX, Gresenguet G, Mayaud P, Weiss HA, Gopal R, Matta M, Brown D, Hayes RJ, Mabey DCW, Belec L. High seroprevalence and shedding of HSV-2 in HIV-l infected women in Aflica [oral presentation]. "Research in Progress" Royal Society of Tropical Medicine & Hygiene, London, Ll(, 1 t h November 1999 (highly commended presentation see Transacrions of the Royal Society of Tropical Medicine and Hygiene 2000,94,128-134). 6 Mbopi-Keou, F.x., Robinson, N.J., Gresenguet, G., Weiss, H.A., Mayaud, P., Gopal, R., Hayes, R.I., Mabey, D.C.W., Belec, 1. and Brown, D. Case for control of genital herpes infection in developing countries [poster presentation]. Joint Meeting of the ASTDA and the MSSVD, Baltimore, MD, USA, May 3-6, 2000, Abstract no 117. Mbopi-Keou F.X., Dalessio, 1., Gresenguet, G., Gopal, R., Mayaud, P., Weiss, H.A., Hayes, R.1., Mabey, D.C.W., Corey, 1., Brown, D.W.G., Belec, L. , Ashley RL. Relationship between HSV-2 shedding and cervical antibody responses in African women at risk of or \vith HIV [poster presentation]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 17-20,2000, Abstract No 771. 7 Table of Contents A. Acknowledgements ...................................................................................................... 2 B. Dedication ............................................. : .. ~ ...... ~ ............................................................. 3 c. Declaration ................................................................................................................... 4 D. Scholarly contributions from this thesis ................................................................... 5 E. Abstract ...................................................................................................................... 13 F. Abreviations ................................................................................................................ 14 G. List of Tables .............................................................................................................. 16 H. List of Figures ............................................................................................................. 18 Olapter 1. General introduction to Herpes simplex virus type 2 and heterosexual spread of human immunodeficiency virus 1 .1. TIle history of genital herpes ................................................................. 20 1 .2. Herpes simplex virus structure and replication ............................................ 21 1.3. HSV-2 infection: a growing public health problem ....................................... 23 1.3 .1. Natural history of genital herpes ........................................................... 24 1.3.2. Epidemiology of HSV and HSV -related genital ulcers ............................... 30 1.3.3. HSV -2 as a marker of sexual behaviour .................................................. 34 1.4. HSV-2 type specific serology .................................................................................... 35 1 .4.1. Gold standard non -commercial tests for HSV type specific antibody ................... 36 1.4.2. Conmlercially gG-based type-specific tests ............................................................ 38 1.4.3. Limitations of gG-based tests ................................................................................. 39 8 1.5. Genital HSV-2 as a possible cofactor in HIV infection ............................................. 41 1.5.1. STI: Cofactors of sexual transmission ofHIV ........................................................ 41 1.5.2. Bi-directional interaction between HSV-2 and HIV ............................................... 42 1.6.HSV and HIV interaction: the role of vitamin A ........................................................ 49 1.6.1. The role of vitamin A in immunity to infectious diseases ...................................... 49 1.6.2. Vitamin A deficiency in HIV seropositive persons ................................................ 51 1.7. Research priorities for developing world ................................................................... 53 1.7.1. Biological interactions between HSV-2 and HIV ................................................... 53 1.7.2. HSV-2 treatrnenttrials ............................................................................................ 53 1.7.3. Genital mucosal immunity to HSV-2 infection ...................................................... 57 1.7.4. Vaccination against HSV-2 ..................................................................................... 58 Chapter 2. Aims and settings of the study ........... ......................................................... 62 2.1. Aims of the study ....................................................................................................... 63 2.2. Setting of the study .................................................................................................... 64 2.2.1. Background information on Central African Republic ........................................... 64 2.2.2. HIV epidemic in Central African Republic ............................................................ 67 2.2.3. Sexually Transmitted Diseases in CAR .................................................................. 68 2.2.4. Health services in CAR ........................................................................................... 68 2.2.5. The CNRMST/SIDA of Bangui .............................................................................. 69 Chapter 3. Patients and Methods .................................................................................. 73 3.1. Study population ........................................................................................................ 74 3.2. San1ple size ................................................................................................................ 74 3.3. Samples taken and laboratory methods ...................................................................... 75 3.3.1. Serology .................................................................................................................. 75 3.3.2. HSV-l and HSV-2 type specific serology .............................................................. 75 3.3.3. Vitamin A and vitamL."'1 E ........................................................................................ -:-6 9 3.3.4. Vaginal and cervical infections ............................................................................... 77 3.3.5. Cervico-vaginallavages .......................................................................................... 77 336 HIV-l RNA· 1· d . . . 1 . . . ill P asma an rn cervJ.covagma samples ........................................... 78 3.3.7. Cell associated HIV provirus DNA quantitation in cervicovaginal samples .............................................................................................................................. 79 3.3.8. HSV in Genital secretions ....................................................................................... 79 3.3.9. PCR controls ........................................................................................................... 82 3.3.10. HSV -specific binding antibodies .......................................................................... 82 3.3.11. Total IgG and IgA in CVL .................................................................................... 83 3.3.12. Neutralizing activity assay ........................ : ............................................................ 84 3.3.13. Specific activity ..................................................................................................... 84 3.3.14. Quantitation ofHSV DNA in genital secretions by real time PCR ...................... 85 3.3.15. Statistical analysis ................................................................................................. 86 Chapter 4. Results ................................................................................. 88 4.1. Interactions between Herpes simplex virus type 2 and HIV-1 infection i11 African women: opportunities for intervention ............................................................ 89 4.1.1. Population characteristics ....................................................................................... 89 4.1.2. Information on sexual and reproductive health ....................................................... 89 4.1.3. Clinical frndings and SID prevalence .................................................................... 90 4.1.4. HIV -1 viral loads in plasma and genital secretions ................................................ 91 4.1.5. HSV-2 genital shedding .......................................................................................... 92 4.1.6. Association of genital shedding ofHIV-1 and HSV-2 ........................................... 92 4.1.7. Discussion ............................................................................................................... 93 4.2. Vitamin A deficiency and genital tract infection in women living in Central ~AJiican Republic ............................................................................................................. 106 4.2.1. Discussion ............................................................................................................. ]. 06 ~o 

The Role of <i>Herpes simplex</i> virus type 2 (HSV-2) as a cofactor in HIV transmission

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