Intrapatient Evolutionary Dynamics of Human Immunodeficiency Virus Type 1 in Individuals Undergoing Alternative Treatment Strategies with Reverse Transcriptase Inhibitors
نویسندگان
چکیده
Structured treatment interruption (STI) has been trialed as an alternative to lifelong antiretroviral therapy (ART). We retrospectively performed single genome sequencing of the HIV-1 pol region from three patients representing different scenarios. They were either failing on continuous therapy (CT-F), failing STI (STI-F), or suppressing on STI (STI-S). Over 460 genomes were generated from three to five different time points over a 2-year period. We found multiple-linked-resistant mutations in both treatment failures. However, the CT-F patient showed a stepwise accumulation of diverse, linked mutations whereas the STI-F patient had lineage turnover between treatment periods with recirculation of wild-type and resistant variants from reservoirs. The STI-F patient showed a 7-fold increase in the third codon position substitution rate relative to the first and second positions compared to a 2-fold increase for CT-F and increased purifying selection in the pol gene (62 vs. 22 sites, respectively). An understanding of intrapatient viral dynamics could guide the future direction of treatment interruption strategies.
منابع مشابه
Resistance mechanism of human immunodeficiency virus type-1 protease to inhibitors: A molecular dynamic approach
Human immunodeficiency virus type 1 (HIV-1) protease inhibitors comprise an important class of drugs used in HIV treatments. However, mutations of protease genes accelerated by low fidelity of reverse transcriptase yield drug resistant mutants of reduced affinities for the inhibitors. This problem is considered to be a serious barrier against HIV treatment for the foreseeable future. In this st...
متن کاملCurrent antiretroviral drugs for human immunodeficiency virus infection: review article
Currently, there are about 37 million people worldwide living with human immunodeficiency virus (HIV) /AIDS, with an estimated two million new cases per year globally. According to estimates from the World Health Organization (WHO), only 75% of the population with HIV know their status. Initially, HIV infection was associated with significantly increased rates of mortality and morbidity. Howeve...
متن کاملInsertions in the human immunodeficiency virus type 1 protease and reverse transcriptase genes: clinical impact and molecular mechanisms.
Treatment of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals with antiretroviral (ARV) drugs is highly effective in inhibiting viral replication, increasing both the duration and the quality of life (71). Regimens consisting of combinations of protease (PR), reverse transcriptase (RT), and fusion inhibitors are the current standard of care and typically reduce the circula...
متن کاملComputational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors
Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with othe...
متن کاملPrevalence of protease and reverse transcriptase drug resistance mutations over time in drug-naïve human immunodeficiency virus type 1-positive individuals in Rio de Janeiro, Brazil.
The prevalence of mutations that confer resistance to protease inhibitors and to nucleoside and nonnucleoside reverse transcriptase inhibitors in 49 blood samples from drug-naïve human immunodeficiency virus type 1-infected blood donors living in Rio de Janeiro state, Brazil, in 1998 was evaluated genotypically and phenotypically.
متن کامل