Browsing by Author "Mugisha, Joseph Y. T."

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    Estimation of the HIV-1 Backward Mutation Rate From Transmitted Drug-Resistant Strains
    (Theoretical Population Biology, 2016-12) Kitayimbwa, John M.; Mugisha, Joseph Y. T.; Saenz, Roberto A.
    One of the serious threats facing the administration of antiretroviral therapy to human immunodeficiency virus (HIV-1) infected patients is the reported increasing prevalence of transmitted drug resistance. However, given that HIV-1 drug-resistant strains are often less fit than the wild-type strains, it is expected that drug-resistant strains that are present during the primary phase of the HIV-1 infection are replaced by the fitter wild-type strains. This replacement of HIV-1 resistant mutations involves the emergence of wild-type strains by a process of backward mutation. How quickly the replacement happens is dependent on the class of HIV-1 mutation group. We estimate the backward mutation rates and relative fitness of various mutational groups known to confer HIV-1 drug resistance. We do this by fitting a stochastic model to data for individuals who were originally infected by an HIV-1 strain carrying any one of the known drug resistance-conferring mutations and observed over a period of time to see whether the resistant strain is replaced. To do this, we seek a distribution, generated from simulations of the stochastic model, that best describes the observed (clinical data) replacement times of a given mutation. We found that Lamivudine/Emtricitabine-associated mutations have a distinctly higher, backward mutation rate and low relative fitness compared to the other classes (as has been reported before) while protease inhibitors-associated mutations have a slower backward mutation rate and high relative fitness. For the other mutation classes, we found more uncertainty in their estimates.
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    The Role of Backward Mutations on the Within-Host Dynamics of HIV-1
    (Journal of Mathematical Biology, 2012-09-06) Kitayimbwa, John M.; Mugisha, Joseph Y. T.; Saenz, Roberto A.
    The quality of life for patients infected with human immunodeficiency virus (HIV-1) has been positively impacted by the use of antiretroviral therapy (ART). However, the benefits of ART are usually halted by the emergence of drug resistance. Drug-resistant strains arise from virus mutations, as HIV-1 reverse transcription is prone to errors, with mutations normally carrying fitness costs to the virus. When ART is interrupted, the wild-type drug-sensitive strain rapidly out-competes the resistant strain, as the former strain is fitter than the latter in the absence of ART. One mechanism for sustaining the sensitive strain during ART is given by the virus mutating from resistant to sensitive strains, which is referred to as backward mutation. This is important during periods of treatment interruptions as prior existence of the sensitive strain would lead to replacement of the resistant strain. In order to assess the role of backward mutations in the dynamics of HIV-1 within an infected host, we analyze a mathematical model of two interacting virus strains in either absence or presence of ART. We study the effect of backward mutations on the definition of the basic reproductive number, and the value and stability of equilibrium points. The analysis of the model shows that, thanks to both forward and backward mutations, sensitive and resistant strains co-exist. In addition, conditions for the dominance of a viral strain with or without ART are provided. For this model, backward mutations are shown to be necessary for the persistence of the sensitive strain during ART.