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Journal of Virology, September 2005, p. 11553-11554, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11553-11554.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Glycoprotein B (gB), along with gD, gH, and gL, is essential for herpes simplex virus (HSV) entry. Except for gD, which interacts with a cognate receptor, functions of the other glycoproteins are not known. Bender et al. (p. 11588-11597) found that the gB ectodomain (gBt) interacts with cell-surface heparan sulfate proteoglycan (HSPG) as expected but also binds to another cell-surface receptor that is not HSPG. Entry into cells deficient in HSPG synthesis was blocked equally well by both gBt and gDt. These results suggest that HSV entry requires interaction with receptors for both glycoproteins.

Viral 7-Transmembrane Receptor Important for Human Herpesvirus 6 Replication

Many herpesviruses encode 7-transmembrane (7-tm) receptor homologs. Several of these bind to host chemokines, which may contribute to viral immune evasion. Human herpesvirus 6 (HHV-6) encodes two such receptors, U12 and U51, but technical limitations have precluded the generation of viral mutants bearing deletions in the genes encoding these molecules. Zhen et al. (p. 11914-11924) used RNAi technology to selectively diminish U51 expression. The results show that U51 facilitates virus replication and cell-cell fusion. This study suggests a novel role for viral 7-tm receptors in facilitating the replication and spread of HHV-6 and other cell-associated herpesviruses.

Virus-Induced Rearrangement of Vimentin Requires Activation of Calcium Calmodulin Kinase II

Vimentin filaments are redistributed in cells infected with viruses and in cells containing aggresomes filled with misfolded protein. Redistribution of vimentin may represent a protective cellular response to the accumulation of unusual proteins in cells, which may aid in formation of viral assembly complexes. Stefanovic et al. (p. 11766-11775) show that the vimentin cages surrounding assembly complexes generated by African swine fever virus are phosphorylated by calcium calmodulin kinase II. Activation of the kinase is also essential for virus replication. These results suggest a link between activation of calcium calmodulin kinase II, virus replication, and consequent rearrangement of vimentin within viral assembly complexes.

Amino Acid Residues Critical for Mason-Pfizer Monkey Virus Env Incorporation and Function

The efficient incorporation of fusion-active Env proteins into retroviruses is essential for their infectivity. Song et al. (p. 11559-11568 and p. 11569-11579) demonstrate that individual residues in the cytoplasmic domain of Mason-Pfizer monkey virus Env can dramatically modulate fusion activity of the protein and relate these effects to predicted coiled-coil interactions in this region. Three cytoplasmic residues, two of which influence endocytosis, are shown to play critical roles in both Env incorporation and virion release. This work identifies a novel linkage between vesicular trafficking of Env, intracellular transport of Gag, and glycoprotein incorporation into virions.

Utilization of Rab9 in Enveloped Virus Replication

Late endosomes are important in the initiation of HIV assembly. HIV buds from the cell surface or into multivesicular bodies, depending on the cell type. Using insertional mutagenesis and RNA interference, Murray et al. (p. 11742-11751) show that the cellular Rab9 GTPase and its binding partners are essential for HIV-1 replication. Rab9 is also important for the enveloped Ebola, Marburg, and measles viruses but not the nonenveloped reovirus, suggesting an egress pathway conserved between diverse enveloped viruses. The identification of Rab9 and the endosomal trafficking pathway it defines (late endosome to trans-Golgi) may provide new cellular targets for antiviral therapeutics.

Interleukin-2 Autocrine Stimulation Establishes Benign Oncoretrovirus Infection

While human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL), a closely related virus, HTLV-2, is not associated with ATL or any other leukemia. Niinuma et al. (p. 11925-11934) demonstrate that interleukin-2 (IL-2) autocrine stimulation through activation of NFAT by HTLV-2 Tax is essential for cell growth of HTLV-2-infected T-cell lines but not those infected with HTLV-1. This work suggests that IL-2 secretion establishes a benign and life-long HTLV-2 infection.

Prion Entry into Nervous System Bypasses Lymphoid System Infection

Peripheral prion infection requires replication in secondary lymphoid tissues prior to entry into the nervous system and spread to the brain. Bartz et al. (p. 11858-11863) demonstrate that the prion agent can directly enter the nervous system from the tongue without replicating in lymphoid tissue. This study demonstrates a pathway of prion neuroinvasion, from a densely innervated peripheral site, that may be relevant to ruminant prion disease in which infection of the lymphoid system is not detected.

Anatomy of an HIV-1 Superinfection

Studying a high-risk cohort in Tanzania, McCutchan et al. (p. 11693-11704) have caught an HIV-1 superinfection in the act. A single homogeneous HIV-1 strain was present preseroconversion and for the first 6 months of infection, but by 9 months, an explosion of diversity had occurred. A superinfecting strain and many new recombinants appeared and persisted, in various proportions, for at least 2 years. Given other reports of higher viral loads in dual infections, these myriad recombinants may arise in the very individuals most able to transmit them.

Recent H5N1 Viruses Exhibit Increased Virulence in Mammals

Avian (H5N1) influenza viruses continue to cause outbreaks in poultry and disease in humans across Asia. Maines et al. (p. 11788-11800) have evaluated the virulence of recent human and avian H5N1 viruses in mice and ferrets and compared them to 1997 human H5N1 strains. The levels of virulence of the H5N1 viruses in these models are in general agreement, but the ferret model demonstrates increased virulence of the 2004 human H5N1 isolates compared with 1997 human isolates. These models may allow us to predict the potential of newly emerging H5N1 viruses to infect and cause disease in mammals.

The LC16m8 Smallpox Vaccine Protects Mice against Lethal Challenge

Generating safe and efficacious smallpox vaccines is a top priority in current biodefense efforts. Low-virulent vaccinia virus LC16m8 was developed from the Lister vaccine used in the WHO smallpox eradication program, but its efficacy has not been definitely established. Morikawa et al. (p. 11873-11891) show that the LC16m8 and Lister vaccines have a comparable gene structure and organization. Mice immunized with LC16m8 were protected against lethal challenge with vaccinia virus. These results have implications for worldwide vaccination strategies against smallpox bioterrorism.

A Bioinformatics Approach for the Identification of HCMV miRNAs

A number of viruses have recently been shown to express micro-RNAs (miRNAs). In this study, Grey et al. (p. 12095-12099) used a comparative bioinformatics approach to successfully identify miRNAs encoded by human cytomegalovirus (HCMV). This comparative approach will be useful for identification of viral miRNAs, especially those refractory to cloning methods. The expression of these viral miRNAs also suggests an important role of RNAi in control of HCMV replication.

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