DNA Encapsidation as a Target for Anti-Herpesvirus Drug Therapy

Antiviral Research, Volume 59: 73-87, 2003
Robert J. Visalli and Marja van Zeij

ABSTRACT: The current repertoire of approved anti-herpesviral drugs consists primarily of nucleoside analogues that inhibit viral replication by targeting the virus-encoded DNA polymerase. This class of agents has been critical in controlling infections by herpes simplex, varicella zoster, and cytomegalovirus. However, because nucleoside analogues share a similar mechanism of action, treatment options are limited once resistance develops. This becomes an important medical issue with respect to the treatment of disease caused by resistant viral strains, particularly in immunocompromised individuals. Furthermore, several of the currently available therapies can result in mild to severe side effects making the discovery of less toxic drugs desirable. Efforts over the last decade have focused on the identification and development of improved therapies including less toxic compounds with novel mechanisms of action. Here we review the progress that has been made in targeting the DNA packaging and encapsidation process as a novel target for chemotherapy. Several recently identified compounds may warrant further development as a medically important group of herpesviral encapsidation inhibitors.

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Restriction Factors: a Defense Against Retroviral Infection

Trends in Microbiology, Volume 11: 286-291, 2003
Paul D. Bieniasz

ABSTRACT: Susceptibility to retroviral infection is determined, in part, by host genes with antiviral activity. The Fv1 gene, which inhibits murine leukemia virus infection in mice, encodes one such resistance factor, and was long thought to be unique in that it restricts post-entry, preintegration steps of retroviral replication. However, recent findings suggest the existence of similar restriction factors in primates, including humans. These factors, termed Lv1 and Ref1, can inhibit a range of retroviruses, including human immunodeficiency virus type 1 and its relatives. Fv1, Lv1 and Ref1 target capsid determinants to block infection but can be saturated by incoming virions. Primate- and murine-retrovirus restriction factors have diverse and overlapping specificities, and some variants of Lv1, as well as Ref1, apparently recognize and inhibit infection by widely divergent retroviruses.

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The Interaction of HIV-1 with the Host Factors

Japanese Journal of Infectious Diseases, Volume 58: 125-130, 2005
Jun Komano, Yuko Futahashi, Emiko Urano, Kosuke Miyauchi, Tsutomu Murakami, Zene Matsuda, and Naoki Yamamoto

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) is a causative agent of acquired immunodeficiency syndrom (AIDS) in humans. In the last decade, the functions of HIV-1-encoded genes have been intensively studied. These studies have contributed to the development of the effective anti-AIDS drugs directing against the HIV-1-encoded enzymes, namely reverse transcriptase and protease. However, even the combination of these drugs is not sufficient enough to stop the progression of AIDS partly due to the emergence of drug-resistant HIV-1 mutants as well as the severe side effects. Understanding the molecular mechanisms by which cellular factors support the efficient replication of HIV-1 should contribute to develop means to control the progression of AIDS. This field is now expanding rapidly. Here we review the host factors involved in the replication of HIV-1 and highlight some findings that have a substantial impact on the retroviral research.

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Why Old World Monkeys Are Resistant to HIV-1

Science, Volume 318: 1565-1566, 2007
Matthew Stremlau

ABSTRACT: Premature disassembly of the HIV-1 capsid is caused by the rhesus monkey protein, TRIM5α, and a single amino acid change in human TRIM5α confers similar anti–HIV-1 activity.

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Targeting Host Factors: a Novel Rationale for the Management of Hepatitis C Virus

World Journal of Gastroenterology, Volume 15: 3472-3479, 2009
Mahmoud Aboelneen Khattab

ABSTRACT: Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor tolerability, and significant expense. New treatment options that are more potent and less toxic are much needed. Moreover, more effective treatment is an urgent priority for those who relapse or do not respond to current regimens. A major obstacle in combating hepatitis C virus (HCV) infection is that the fidelity of the viral replication machinery is notoriously low, thus enabling the virus to quickly develop mutations that resist compounds targeting viral enzymes. Therefore, an approach targeting the host cofactors, which are indispensable for the propagation of viruses, may be an ideal target for the development of antiviral agents because they have a lower rate of mutation than that of the viral genome, as long as they have no side effects to patients. Drugs targeting, for example, receptors of viral entry, host metabolism or nuclear receptors, which are factors required to complete the HCV life cycle, may be more effective in combating the viral infection. Targeting host cofactors of the HCV life cycle is an attractive concept because it imposes a higher genetic barrier for resistance than direct antiviral compounds. However the principle drawback of this strategy is the greater potential for cellular toxicity.

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The Capsid Protein of Human Immunodeficiency Virus: Interactions of HIV-1 Capsid with Host Protein Factors

FEBS Journal, Volume 276: 6118-6127, 2009
Anjali P. Mascarenhas and Karin Musier-Forsyth

ABSTRACT: HIV-1 is a retrovirus that causes AIDS in humans. The RNA genome of the virus encodes a Gag polyprotein, which is further processed into matrix, capsid and nucleocapsid proteins. These proteins play a significant role at several steps in the viral life cycle. In addition, various stages of assembly, infection and replication of the virus involve necessary interactions with a large number of supplementary proteins ⁄ cofactors within the infected host cell. This minireview focuses on the proteomics of the capsid protein, its influence on the packaging of nonviral molecules into HIV-1 virions and the subsequent role of the molecules themselves. These interactions and their characterization present novel frontiers for the design and advancement of antiviral therapeutics.

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Host Proteins Involved in HIV Infection: New Therapeutic Targets

Biochimica et Biophysica Acta, Volume 1802: 313-321, 2010
Nathalie Arhel and Frank Kirchhoff

ABSTRACT: Current treatment of HIV/AIDS consists of a combination of three to five agents targeting different viral proteins, i.e. the reverse transcriptase, protease, integrase and envelope, and aims to suppress viral replication below detectable levels. This “highly active antiretroviral therapy” (HAART) has brought an enormous benefit for life expectancy and quality in HIV-1-infected individuals, at least in industrialized countries. However, significant limitations with regard to efficiency, drug resistance, side effect and costs still exist. Recent data suggest that cellular factors also represent useful targets for therapy. Here, we summarize findings from several genome-wide screens that identified a large number of cellular factors exploited by HIV-1 at each step of its life cycle. Furthermore, we discuss the evidence that humans are equipped with powerful intrinsic defense mechanisms against retroviruses but that HIV-1 has evolved elaborate ways to counteract or evade them. Preventing the use of host cell proteins obligatory for viral replication or strengthening the cellular defense mechanisms may help to reduce viral replication to harmless levels. A better understanding of the host factors that promote or restrict HIV-1 replication may thus lead to the development of novel therapeutics against HIV/AIDS.

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A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection

Cell, Volume 139: 1255-1267, 2009
Sagi D. Shapira, Irit Gat-Viks, Bennett O.V. Shum, Amelie Dricot, Marciela M. de Grace, Liguo Wu, Piyush B. Gupta, Tong Hao, Serena J. Silver, David E. Root, David E. Hill, Aviv Regev, and Nir Hacohen

ABSTRACT: During the course of a viral infection, viral proteins interact with an array of host proteins and pathways. Here, we present a systematic strategy to elucidate the dynamic interactions between H1N1 influenza and its human host. A combination of yeast two-hybrid analysis and genome-wide expression profiling implicated hundreds of human factors in mediating viral-host interactions. These factors were then examined functionally through depletion analyses in primary lung cells. The resulting data point to potential roles for some unanticipated host and viral proteins in viral infection and the host response, including a network of RNA-binding proteins, components of WNT signaling, and viral polymerase subunits. This multilayered approach provides a comprehensive and unbiased physical and regulatory model of influenza-host interactions and demonstrates a general strategy for uncovering complex host-pathogen relationships.

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Human host factors required for influenza virus replication.

Nature. 2010 Feb 11;463(7282):813-7.
König R, Stertz S, Zhou Y, Inoue A, Hoffmann HH, Bhattacharyya S, Alamares JG, Tscherne DM, Ortigoza MB, Liang Y, Gao Q, Andrews SE, Bandyopadhyay S, De Jesus P, Tu BP, Pache L, Shih C, Orth A, Bonamy G, Miraglia L, Ideker T, García-Sastre A, Young JA, Palese P, Shaw ML, Chanda SK.

ABSTRACT: Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle1. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host–pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-β. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIβ (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.