HIV-1C dynamics and evolutionary trends in Botswana

Moyo, Sikhulile (2016-12-09)

Thesis (PhD)--Stellenbosch University, 2016

Thesis

ENGLISH ABSTRACT : Introduction: HIV incidence estimates are critical for monitoring HIV transmission dynamics, and for design and evaluation of the impact of interventions. Biomarkers and assays for cross-sectional surveillance of HIV incidence are greatly needed because of the high costs and time needed to maintain prospective cohorts to determine HIV incidence. New cross-sectional assays for estimation of HIV incidence are attractive due to their improved performance and cost-effectiveness. In this dissertation, methods for identification and characterization of recency of HIV infection are described. An in-depth review of HIV recency determination methods, including novel cross-sectional application of molecular methods, is given in “From serological assays to genomics.” Multi-assay approaches were evaluated in order to increase the sensitivity and specificity of the commercial incidence assays in the context of high treatment coverage and stable but high HIV prevalence in Botswana. A novel biomarker based on HIV viral diversity was investigated as a complementary or standalone tool to characterize HIV recency. In this thesis, an innovative use of pairwise diversity and the time to the most recent common ancestor (tMRCA) in a heterosexual HIV-1 subtype C (HIV-1C) epidemic were introduced as novel approaches for HIV incidence estimation. We evaluated the properties of the new potential tools for estimating time since infection, including their specificity and predictive performance in the context of the HIV-1C epidemic in Botswana. Methods: Characterization of HIV recency and novel biomarkers for estimation of HIV infection incidence is based on application of immunologic and molecular methods: a) Evaluation of the long-term specificity (false recent classification rates) of serological tests for recent infection, and algorithms for estimating HIV-1C incidence utilizing samples from patients with known long-standing HIV infection. b) Application of within-host viral diversity for estimation of HIV-1C recency in Botswana using samples collected from patients with known time since seroconversion in the primary HIV-1C infection cohort. c) Investigation of intra-host viral pairwise diversity and the time to the most common recent ancestor (tMRCA), as potential markers for HIV infection recency. Results: We estimated for the first time false recency rates (FRR) of the commercially available BED and Limiting Antigen (LAg) assays in Botswana. We demonstrated that combined algorithms reduce FRR to the recommended < 2%. Including viral load in the assay algorithm resulted in an FRR of 0.4% for LAg. Analysis of the within-host viral pairwise diversity provided more accurate estimation of HIV recency, as compared with the recommended LAg and BED using the receiver operator characteristic analysis (ROC). We demonstrated that intra-host viral pairwise distances reduce misclassification and increase the accuracy of serologic assays. tMRCA and intra-host viral pairwise distances correlated with time since HIV infection provide additional novel tools for reliable estimation of HIV recency. Conclusion: HIV infection recency can be determined cross-sectionally using a combination of serological and molecular biomarkers. Including viral load and an assessment of prior exposure to ARVs is critical for accurate estimation of HIV incidence. Intra-host pairwise diversity and tMRCA are able to predict time since HIV infection and can be used to improve accuracy in estimation of HIV infection recency.

AFRIKAANSE OPSOMMING : Inleiding: MIV voorkoms skattings is van kritieke belang vir die monitering van MIV-oordrag dinamika, en vir die ontwerp en evaluering van die impak van intervensies. Biomerkers en toetse vir deursnee-toesig van MIV voorkoms is baie nodig as gevolg van die hoë koste en tyd wat nodig is om voornemende kohorte in stand te hou om MIV voorkoms te bepaal. Nuwe deursnee-toetse vir skatting van MIV voorkoms is aantreklik as gevolg van hul verbeterde prestasie en koste-effektiwiteit. In hierdie verhandeling word metodes vir die identifikasie en karakterisering van resentheid van MIVinfeksie beskryf. 'N In-diepte oorsig van MIV relevante bepaling metodes, insluitend roman deursneetoepassing van molekulêre metodes, word in "Van serologiese toetse om genomika." Multi-toets benaderings is om die sensitiwiteit en spesifisiteit van die kommersiële voorkoms verhoog geëvalueer toetse in die konteks van 'n hoë dekking behandeling en stabiele maar 'n hoë voorkoms van MIV in Botswana. 'N roman biomerker wat gebaseer is op MIV virale diversiteit ondersoek as 'n aanvullende of selfstandige instrument om MIV relevante kenmerk. In hierdie tesis, 'n innoverende gebruik van paarsgewyse diversiteit en die tyd om die mees onlangse gemeenskaplike voorouer (tMRCA) in 'n heteroseksuele MIV-1 subtipe C (HIV-1 C) epidemie is ingestel as nuwe benaderings vir MIV voorkoms skatting. Ons geëvalueer die eienskappe van die nuwe potensiële gereedskap vir die beraming keer sedert infeksie, insluitend hul spesifisiteit en voorspellende prestasie in die konteks van die MIV-1C epidemie in Botswana. Metodes: Karakterisering van MIV relevante en nuwe biomerkers vir skatting van MIV-infeksie voorkoms is gebaseer op die toepassing van immunologiese en molekulêre metodes: a) Evaluering van die langtermyn-spesifisiteit (valse onlangse klassifikasie tariewe) van serologiese toetse vir onlangse infeksie, en algoritmes vir die beraming van MIV-1C voorkoms met behulp van die monsters van pasiënte met 'n bekende lang MIV-infeksie. b) Toepassing van binne-gasheer virale diversiteit vir skatting van MIV-1C resentheid in Botswana met behulp van monsters van pasiënte met 'n bekende keer sedert sero Omskakeling geconstateerd in die primêre MIV-1C infeksie vorder. c) Ondersoek van intra-gasheer virale paarsgewyse diversiteit en die tyd om die mees algemene onlangse voorouer (tMRCA), as 'n potensiële merkers vir MIV-infeksie resentheid. Resultate: Ons beraam vir die eerste keer valse relevante tariewe (FRR) van die kommersieel beskikbare BED en beperking van Antigeen (lag) toetse in Botswana. Ons het getoon dat gekombineerde algoritmes te verminder FRR om die aanbevole <2%. Insluitend virale lading in die toets algoritme tot gevolg gehad dat 'n FRR van 0,4% vir lag. Ontleding van die binne-gasheer virale paarsgewyse diversiteit verskaf meer akkurate skatting van MIV resentheid, in vergelyking met die aanbevole lag en 'n bed met behulp van die ontvanger operateur eienskap analise (ROC). Ons het getoon dat intra-gasheer virale paarsgewyse afstande te verminder foutieve classificatie en verhoog die akkuraatheid van serologic toetse. tMRCA en intra-gasheer virale paarsgewyse afstande gekorreleer met die tyd sedert MIV-infeksie bykomende roman gereedskap vir 'n betroubare beraming van MIV resentheid. Gevolgtrekking: MIV-infeksie resentheid kan kruis-sectionally bepaal met behulp van 'n kombinasie van serologiese en molekulêre biomerkers. Insluitend virale lading en 'n evaluering van vorige blootstelling aan ARV is van kritieke belang vir akkurate skatting van MIV voorkoms. Intra-gasheer paarsgewyse diversiteit en tMRCA in staat is om tyd te voorspel, aangesien MIV-infeksie en kan gebruik word om die akkuraatheid in raming van MIV-infeksie relevante verbeter.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/100312
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