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Open Research Online Oro.Open.Ac.Uk Open Research Online The Open University’s repository of research publications and other research outputs The Role of Viral Load in the Pathogenesis of HIV-2 Infection in West Africa Thesis How to cite: Ariyoshi, Koya (1998). The Role of Viral Load in the Pathogenesis of HIV-2 Infection in West Africa. PhD thesis The Open University. For guidance on citations see FAQs. c 1998 Koya Ariyoshi https://creativecommons.org/licenses/by-nc-nd/4.0/ Version: Version of Record Link(s) to article on publisher’s website: http://dx.doi.org/doi:10.21954/ou.ro.000101f4 Copyright and Moral Rights for the articles on this site are retained by the individual authors and/or other copyright owners. For more information on Open Research Online’s data policy on reuse of materials please consult the policies page. oro.open.ac.uk THE ROLE OF VIRAL LOAD D< THE PATHOGENESIS OF HTV-2 INFECTION IN WEST AFRICA BY KOYAARIYOSHI MRC Laboratories, Fajara, The Gambia, West Africa ^ ew • I A thesis submitted to the Open University in fulfilment for the degree of Doctor of Philosophy 1998 Collaborating Establishments: University College Medical School (London) Statens Serum Institute (Copenhagen) Institute of Molecular Medicine (Oxford) Institute of Cancer Research (London) _ ProQuest Number:C706741 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuestC706741 Published by ProQuest LLO(2019). Copyright of the Dissertationis held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346 Dedication This thesis is dedicated to my parents. u I Thanks to the people of West Africa. (Caio, Guinea-Bissau. March 1997). Acknowledgements. Tills thesis would not have been possible without the support of the West African people living with HIV who participated in the studies and of numerous other people. I would like to express my sincere gratitude to all who have directly and indirectly helped me and especially to acknowledge: Dr Hilton Whittle, who is my principle supervisor, has introduced me to the field of HIV research in Africa, has enthusiastically guided and has patiently supported me throughout these studies. Professor Andrew McMichael who is my external supervisor, has introduced me to CTL immunology and on a number of occasions given me invaluable advice. Dr Neil Berry and Professor Richard Tedder, who have generously provided advice and technical support for all virology experiments. Professor Peter Aaby who has guided me during the study in Guinea-Bissau. Shabbar Jaffar who has done most statistical analysis in this thesis. Drs Sehu Sabally and Tumani Corrah who have done the clinical part of this study. Drs Andrew Wilkins, Maarten Schim van der LoeflF, Dominique Ricard, and Diamuid O’Donovan who have conducted the epidemiological part of this study. Fatim Cham who has assisted in much of CTL and PCR work. Elizabeth Harding and Bakary Sanneh who have done all serology assays. Dr Abraham Alabi who has carried out part ofHTV viral load work. Par Tamba N’Gum and Alhagi Bayang who have run the FACScan. Mamady N ’ji and Buba Kdm for their assistance in the laboratory. Dr Margaret Finder and Keba Jammeh for analysing the malaria blood films. Ken Joof, Ramou Jargue for their field work. Dr Carlos De Costa, Glyn Taylor, Brian Savage and the Guniean field workers in Caio for their hard work in Caio, Guinea-Bissau. iv Ami Saijue and P Bass for their help. Ben Sam for his help as a general laboratory manager. Drs P Tuke, Frances Gotch, Sarah Rowland-Jones for their technical support and advice. Professor Brian Greenwood and Professor KPWJ McAdam for their support. Professor Rikuo Doi, at Yokohama City University, Japan who originally advised me to register for a PhD and has spiritually supported me from a distance. Last, my whole family. This study was supported by grants from the British Medical Research Council and Japanese Human Science Foundation. Abstract The role of Human Immunodeficiency Virus type 2 (HTV-2) viral load has been studied in West Africa in order to understand how this infection differs from HTV-1 and why the majority of HIV-2 infected individuals live for long. Using a polymerase chain reaction (PCR) based-assay, it was found that the level of HTV-2 provirus was surprisingly high in HTV-2 seropositive people who live long without sign of immunosuppression; in contrast the rate of HTV-2 replication reflected by RNA viral load was found low. However, HIV-2 replicates to a high titre in some HTV-2-infected people whose disease progresses rapidly to death. Longitudinal follow-up demonstrated that base­ line HTV-2 RNA viral load predicts the rate of CD4^ T cell decline and death but the level of proviruses is a less sensitive predictor. Cytotoxic T-lymphocyte activity (CTL) against HTV-2 structural proteins, especially Gag, was found in most HTV-2 infected people and was inversely correlated with HTV-2 proviral load. Strong CTL activity was consistently found in people who did not have progressive disease, suggesting that CTL play an important role in controlling HTV-2 replication. Co-infection with human T-lymphotropic virus type I (HTLV-I) occurred frequently in HTV-2-infected people in a village in Guinea-Bissau but did not seem to enhance HTV-2 viral load. However an increase in HTV-2 viral load was found in an HTV-2-infected individual with malaria parasitaemia, suggesting that malaria infection enhances HTV-2 viral load. The majority of people who are dually seroreactive for both HTV-1 and HTV-2 arc infected with both viruses but some subjects are dually seroreactive because antibodies against one vi type cross-react with the other type of HIV. These cross-reactive antibodies may be distinguished by antibody dilution analysis. Other dually seroreactive people harbour an undetectable level of HTV-2 provirus and HTV-2 proviral load tended to be low in advanced disease while HTV-1 proviral load was high. vu List of Contents. Title page.......................... i Dedication ....................................................................................................................... ü Acknowledgements............................................................................................................ iv Abstract.................................................. vi List of Contents................................................................................................................ viii List of Figures................................................................................................... xiii List of Tables................................... xv Chapter 1. General Introduction ..................................................................................... 1 1 .a. General review of HTV-2 research ................................................................................ 1 1 .a. 1. History of HTV-2 discovery .......................................................................... 1 l.a.2. HTV-2 Epidemiolo^ .................................................................................... 2 i. Geogrcphic distribution .......................................................... 2 a. HIV-2 epidemic in The Gambia and surrounding countries 2 Hi. Age-specific prevalence of HIV-2.................................................... 5 IV. Transmission o f HIV-2............................................................... 5 l.a.3. Clinical features and natural history of HTV-2 infection.......................... 5 l .a.4. HTV-2 virology ............................................................................................. 8 I. Structure o f HIV-2............................................................................ 8 II. Significance o f the vpx and the vpu genes...................................... 8 III. Genotypic and phylogenetic analysis o fHIV-2 .............................. 8 IV. Regulationof HTV-2 gene expression............................................. 11 V. In vitro biological characteristics o f HIV-2.................................... 15 , VI. Cell tropism o fHTV-2 ...................................... 16 1 .a.5. Host-immune response to HIV-2................................................................ 17 I. Humoral immunity......................................................................... 17 II. Cell-mediated immunity................................................................. 18 l.b. Review of serodiagnosis of HTV-infections in West Africa ....................................... 19 I.e. The role of HTV-1 viral load in HTV-1 pathogenesis .....................................................20 l.c.l. HIV-1 pathogenesis ..................................................................................... 20 l .c.2. HTV-1 virus population dynamics in vivo................................................... 21 l.c.3. Measurement of HTV-1 viral load................................................................ 24 I. Viral load in peripheral blood versus lymphoid tissue.................. 24 II. Methods used to measure viral load.............................................. 24 I .C.4. HTV-1 viral load as
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