Viruses2014, 6(10), 4095-4139; doi:10.3390/v6104095 - published 24 October 2014 Show/Hide Abstract
Abstract: Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired drug resistance. In this review, the viral fitness and its correlation to HIV-1 mutation rates and drug resistance are discussed while emphasizing the concept of lethal mutagenesis as an alternative therapy. The development of resistance to the different classes of approved drugs and the importance of monitoring antiretroviral drug resistance are also summarized briefly.
Viruses2014, 6(10), 4080-4094; doi:10.3390/v6104080 - published 23 October 2014 Show/Hide Abstract
Abstract: Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable due to its pivotal position in the dNTP-binding pocket, its involvement in nucleoside analog resistance and polymerase fidelity. This review focuses on K65 residue and summarizes a substantial body of biochemical and structural studies of its role in RT function and the functional consequences of the K65R mutation.
Viruses2014, 6(10), 4047-4079; doi:10.3390/v6104047 - published 23 October 2014 Show/Hide Abstract
Abstract: The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers.
Viruses2014, 6(10), 4024-4046; doi:10.3390/v6104024 - published 23 October 2014 Show/Hide Abstract
Abstract: Virus entry is a complex process characterized by a sequence of events. Since the discovery of KSHV in 1994, tremendous progress has been made in our understanding of KSHV entry into its in vitro target cells. KSHV entry is a complex multistep process involving viral envelope glycoproteins and several cell surface molecules that is utilized by KSHV for its attachment and entry. KSHV has a broad cell tropism and the attachment and receptor engagement on target cells have an important role in determining the cell type-specific mode of entry. KSHV utilizes heparan sulfate, integrins and EphrinA2 molecules as receptors which results in the activation of host cell pre-existing signal pathways that facilitate the subsequent cascade of events resulting in the rapid entry of virus particles, trafficking towards the nucleus followed by viral and host gene expression. KSHV enters human fibroblast cells by dynamin dependant clathrin mediated endocytosis and by dynamin independent macropinocytosis in dermal endothelial cells. Once internalized into endosomes, fusion of the viral envelope with the endosomal membranes in an acidification dependent manner results in the release of capsids which subsequently reaches the nuclear pore vicinity leading to the delivery of viral DNA into the nucleus. In this review, we discuss the principal mechanisms that enable KSHV to interact with the host cell surface receptors as well as the mechanisms that are required to modulate cell signaling machinery for a successful entry.
Viruses2014, 6(10), 4005-4023; doi:10.3390/v6104005 - published 23 October 2014 Show/Hide Abstract
Abstract: Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNAs are encoded in the latency-associated region. Knockdown of KSHV miR-K12-3 and miR-K12-11 increased expression of lytic genes in BC-3 cells, and increased virus production from latently infected BCBL-1 cells. Furthermore, iSLK cells infected with miR-K12-3 and miR-K12-11 deletion mutant viruses displayed increased spontaneous reactivation and were more sensitive to inducers of reactivation than cells infected with wild type KSHV. Predicted binding sites for miR-K12-3 and miR-K12-11 were found in the 3’UTRs of the cellular transcription factors MYB, Ets-1, and C/EBPα, which activate RTA, the KSHV replication and transcription activator. Targeting of MYB by miR-K12-11 was confirmed by cloning the MYB 3’UTR downstream from the luciferase reporter. Knockdown of miR‑K12-11 resulted in increased levels of MYB transcript, and knockdown of miR-K12-3 increased both C/EBPα and Ets-1 transcripts. Thus, miR-K12-11 and miR-K12-3 contribute to maintenance of latency by decreasing RTA expression indirectly, presumably via down‑regulation of MYB, C/EBPα and Ets-1, and possibly other host transcription factors.
Viruses2014, 6(10), 3991-4004; doi:10.3390/v6103991 - published 23 October 2014 Show/Hide Abstract
Abstract: The term arbovirus denotes viruses that are transmitted by arthropods, such as ticks, mosquitoes, and other biting arthropods. The infection of these vectors produces a certain set of evolutionary pressures on the virus; involving migration from the midgut, where the blood meal containing the virus is processed, to the salivary glands, in order to transmit the virus to the next host. During this process the virus is subject to numerous bottlenecks, stochastic events that significantly reduce the number of viral particles that are able to infect the next stage. This article reviews the latest research on the bottlenecks that occur in arboviruses and the way in which these affect the evolution and fitness of these viruses. In particular we focus on the latest research on three important arboviruses, West Nile virus, Venezuelan equine encephalitis virus and Chikungunya viruses and compare the differing effects of the mosquito bottlenecks on these viruses as well as other evolutionary pressures that affect their evolution and transmission.