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AIDS Research and Human Retroviruses (1)
Shell, Elisabeth J. (2)
Estes, D. Mark (1)
Ferguson, Monique R. (1)
Fokam, Eric B. (1)
Hanley, Kathryn A. (1)
Mason, Peter W. (1)
Montes-Walters, Miguel (1)
O'Brien, William A. (1)
Parkin, Neil (1)
Rojo, Daniel R. (1)
Trivedi, Vinod (1)
Vasilakis, Nikos (1)
Von Lindern, Jana (1)
Weaver, Scott C. (1)
Year of Publication
Potential of ancestral sylvatic dengue-2 viruses to re-emerge
Fokam, Eric B.
Mason, Peter W.
Hanley, Kathryn A.
Estes, D. Mark
Weaver, Scott C.
Dengue viruses (DENV) are the most important arboviral pathogens in tropical and subtropical regions throughout the world. DENV transmission includes both a sylvatic, enzootic cycle between nonhuman primates and arboreal mosquitoes of the genus Aedes, and an urban, endemic/epidemic cycle between Aedes aegypti, a mosquito with larval development in peridomestic water containers, and human reservoir hosts. All 4 serotypes of endemic DENV evolved independently from ancestral sylvatic viruses and have become both ecologically and evolutionarily distinct; this process may have involved adaptation to (i) peridomestic mosquito vectors and/or (ii) human reservoir hosts. To test the latter hypothesis, we assessed the ability of sylvatic and endemic DENV-2 strains, representing major genotypes from Southeast Asia, West Africa and the Americas, to replicate in two surrogate human model hosts: monocyte-derived, human dendritic cells (moDCs), and mice engrafted with human hepatoma cells. Although the various DENV-2 strains showed significant inter-strain variation in mean replication titers in both models, no overall difference between sylvatic and endemic strains was detected in either model. Our findings suggest that emergence of endemic DENV strains from ancestral sylvatic strains may not have required adaptation to replicate more efficiently in human reservoir hosts, implying that the potential for re-emergence of sylvatic dengue strains into the endemic cycle is high. The shared replication profiles of the American endemic and sylvatic strains suggest that American strains have maintained or regained the ancestral phenotype.
Dengue virus (DENV); Dengue virus type 2 (DENV-2); Sylvatic; Endemic; Re-emergence; Monocyte-derived dendritic cells (moDCs); Severe combined immune deficiency (SCID) mouse
Impact of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Drug Resistance Mutation Interactions on Phenotypic Susceptibility
Von Lindern, Jana
Rojo, Daniel R.
O'Brien, William A.
Ferguson, Monique R.
AIDS Research and Human Retroviruses
The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals.
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