An effective means to eradicate latent reservoirs in HIV-1-infected individuals remains elusive. Attempts to purge these reservoirs were undertaken over a decade ago without success. The subsequent lapse in further clinical attempts since may have been justified as our knowledge of the mechanisms which underpin the latent state still evolves. Although additional novel molecular antagonists of HIV-1 latency have subsequently been reported, these candidate agents have not been tested in human trials for reservoir ablation. This review provides an overview of the protein kinase C (PKC) pathway which can be modulated by small molecular agents to induce the expression of latent HIV-1 from within infected reservoir cells. Some of these agents have been tested against select cancers with seemingly tolerable side effects. As such, modulation of the PKC pathway may yet be a viable mechanism toward HIV-1 reservoir eradication.

Lisa N. McKernan

David Momjian

Joseph Kulkosky

Protein Kinase C: One Pathway towards the Eradication of Latent HIV-1 Reservoirs

<i  >Background</i>. It has been suggested that chronic hepatitis B infection leads to growth impairment, but data are inconsistent and underlying factors are not defined. <i  >Methods</i>. Children and adolescents with chronic hepatitis B (HBV) or C (HCV) were retrospectively evaluated for growth, weight, antiviral treatment, biochemical signs of liver inflammation, route of infection, and HBV DNA, respectively. <i  >Results</i>.  In all, 135 children (mean age 6.1 years, 81 male, 54 female) with HBV (<svg style="vertical-align:-0.1638pt;width:44.400002px;" id="M1" height="11.125" version="1.1" viewBox="0 0 44.400002 11.125" width="44.400002"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.863)"><path id="x1D45B" d="M495 86q-46 -47 -87 -72.5t-63 -25.5q-43 0 -16 107l49 210q7 34 8 50.5t-3 21t-13 4.5q-35 0 -109.5 -72.5t-115.5 -140.5q-21 -75 -38 -159q-50 -10 -76 -21l-6 8l84 340q8 35 -4 35q-17 0 -67 -46l-15 26q44 44 85.5 70.5t64.5 26.5q35 0 10 -103l-24 -98h2&#xD;&#xA;q42 56 97 103.5t96 71.5q46 26 74 26q9 0 16 -2.5t14 -11.5t9.5 -24.5t-1 -44t-13.5 -68.5q-30 -117 -47 -200q-4 -19 -3.5 -25t6.5 -6q21 0 70 48z"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.863)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.863)"><path id="x37" d="M447 623l8 -12l-283 -613l-74 -10l-7 11q174 283 297 551h-216q-48 0 -62.5 -12t-33.5 -63h-29q10 60 18 148h382z"/></g><g transform="matrix(.017,0,0,-.017,36.168,10.863)"><path id="x38" d="M249 635q70 0 116 -43t46 -105q0 -46 -28 -80q-22 -25 -80 -64q62 -35 97 -75t35 -99q0 -81 -63 -131t-135 -50q-83 0 -137.5 45.5t-54.5 123.5q0 52 45 95q29 28 89 64q-109 62 -109 155q0 66 50.5 115t128.5 49zM238 603q-42 0 -67.5 -31t-25.5 -72q0 -50 32.5 -79.5&#xD;&#xA;t98.5 -62.5q61 48 61 124q0 59 -29.5 90t-69.5 31zM248 20q46 0 76.5 33.5t30.5 89.5q0 50 -39 85.5t-110 71.5q-81 -54 -81 -137q0 -67 35.5 -105t87.5 -38z"/></g>

		
	
</svg>) or HCV (<svg style="vertical-align:-0.1638pt;width:44.400002px;" id="M2" height="10.925" version="1.1" viewBox="0 0 44.400002 10.925" width="44.400002"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,10.65)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,0,0,-.017,13.305,10.65)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,0,0,-.017,28.008,10.65)"><path id="x35" d="M153 550l-26 -186q79 31 111 31q90 0 141.5 -51t51.5 -119q0 -93 -89 -166q-85 -69 -173 -71q-32 0 -61.5 11.5t-41.5 23.5q-18 17 -17 34q2 16 22 33q14 9 26 -1q61 -50 124 -50q60 0 93 43.5t33 104.5q0 69 -41.5 110t-121.5 41q-53 0 -102 -20l38 305h286l6 -8&#xD;&#xA;l-26 -65h-233z"/></g><g transform="matrix(.017,0,0,-.017,36.168,10.65)"><use xlink:href="#x37"/></g>

		
	
</svg>) were studied. Route of infection was vertical in 50&#x25;, parenteral in 11&#x25;, and unknown in 39&#x25;. ALT levels were above 1.5 times above normal in 30&#x25; while 70&#x25; had normal/near normal transaminases. 80&#x25; were Caucasian, 14&#x25; Asian, 1&#x25; black, and 4&#x25; unknown. Mean baseline height measured in SDS was significantly lower in the study population than in noninfected children (boys &#x2212;1.2, girls &#x2212;0.4, <svg style="vertical-align:-0.1638pt;width:58.712502px;" id="M3" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,11.113)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xD;&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z"/></g><g transform="matrix(.017,0,0,-.017,15.582,11.113)"><path id="x3C" d="M512 -3l-437 233v51l437 233v-58l-378 -200v-2l378 -199v-58z"/></g><g transform="matrix(.017,0,0,-.017,30.286,11.113)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xD;&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z"/></g><g transform="matrix(.017,0,0,-.017,38.446,11.113)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z"/></g><g transform="matrix(.017,0,0,-.017,42.321,11.113)"><use xlink:href="#x30"/></g><g transform="matrix(.017,0,0,-.017,50.481,11.113)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z"/></g>

		
	
</svg>). 28 children were below 2 standard deviations of the norm while 5 were above 2 standard deviations. SDS measures in relation to individual factors were as follows: elevated ALT: boys &#x2212;1.4, females &#x2212;0.5 (<svg style="vertical-align:-0.1638pt;width:58.712502px;" id="M4" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,11.113)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,0,0,-.017,15.582,11.113)"><use xlink:href="#x3C"/></g><g transform="matrix(.017,0,0,-.017,30.286,11.113)"><use xlink:href="#x30"/></g><g transform="matrix(.017,0,0,-.017,38.446,11.113)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,0,0,-.017,42.321,11.113)"><use xlink:href="#x30"/></g><g transform="matrix(.017,0,0,-.017,50.481,11.113)"><use xlink:href="#x31"/></g>

		
	
</svg>), ALT normal/near normal: boys +0.4, females +0.6; parenteral transmission: boys &#x2212;3.3, girls &#x2212;0.9 (<svg style="vertical-align:-0.1638pt;width:58.712502px;" id="M5" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"      xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,0,0,-.017,.062,11.113)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,0,0,-.017,15.582,11.113)"><use xlink:href="#x3C"/></g><g transform="matrix(.017,0,0,-.017,30.286,11.113)"><use xlink:href="#x30"/></g><g transform="matrix(.017,0,0,-.017,38.446,11.113)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,0,0,-.017,42.321,11.113)"><use xlink:href="#x30"/></g><g transform="matrix(.017,0,0,-.017,50.481,11.113)"><use xlink:href="#x31"/></g>

		
	
</svg>), vertical transmission: boys &#x2212;0.2, females &#x2212;0.2. Antiviral treatment itself or HBV-DNA load did not reach statistically significant differences. <i  >Conclusions</i>.  Chronic HBV or HCV may lead to compromised growth which is mostly influenced by liver inflammation. Our data may argue for early antiviral treatment in children with significant ALT elevation.

P. Gerner

Andre Hörning

S. Kathemann

K. Willuweit

S. Wirth

Growth Abnormalities in Children with Chronic Hepatitis B or C

The genetic and symptom diversity of six virus isolates causing cassava brown streak disease (CBSD) in the endemic (Kenya, Mozambique, and Tanzania) and the recently affected epidemic areas (Uganda) of eastern Africa was studied. Five cassava varieties; Albert, Colombian, Ebwanateraka, TMS60444 (all susceptible) and Kiroba (tolerant) were graft inoculated with each isolate. Based on a number of parameters including the severity of leaf and root symptoms, and the extent of virus transmission by grafting, the viruses were classified as either severe or relatively mild. These results were further confirmed by the mechanical inoculation of 13 herbaceous hosts in which the virulent isolates caused plant death in <i>Nicotiana clevelandii</i> and <i>N. benthamiana</i> whereas the milder isolates did not. Phylogenetic analysis of complete coat protein gene sequences of these isolates together with sequences obtained from 14 other field-collected samples from Kenya and Zanzibar, and reference sequences grouped them into two distinct clusters, representing the two species of cassava brown streak viruses. Put together, these results did not suggest the association of a hypervirulent form of the virus with the current CBSD epidemic in Uganda. Identification of the severe and milder isolates, however, has further implications for disease management and quarantine requirements.

I. U. Mohammed

M. M. Abarshi

B. Muli

R. J. Hillocks

M. N. Maruthi

The Symptom and Genetic Diversity of Cassava Brown Streak Viruses Infecting Cassava in East Africa

Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high.  There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy.  A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses.

Mark S. Ferguson

Nicholas R. Lemoine

Yaohe Wang

Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles

Despite active research in virotherapy, this apparently safe modality has not achieved widespread success. The immune response to viral infection appears to be an essential factor that determines the efficacy of oncolytic viral therapy. The challenge is determining whether the viral-elicited immune response is a hindrance or a tool for viral treatment. NK cells are a key component of innate immunity that mediates antiviral immunity while also coordinating tumor clearance. Various reports have suggested that the NK response to oncolytic viral therapy is a critical factor in premature viral clearance while also mediating downstream antitumor immunity. As a result, particular attention should be given to the NK cell response to various oncolytic viral vectors and how their antiviral properties can be suppressed while maintaining tumor clearance. In this review we discuss the current literature on the NK response to oncolytic viral infection and how future studies clarify this intricate response.

Christopher A. Alvarez-Breckenridge

Jianhua Yu

Balveen Kaur

Michael A. Caligiuri

E. Antonio Chiocca

Deciphering the Multifaceted Relationship between Oncolytic Viruses and Natural Killer Cells

Oncolytic virus therapy is based on the ability of viruses to effectively infect and kill tumor cells without destroying the normal tissues. While some viruses seem to have a natural preference for tumor cells, most viruses require the modification of their tropism to specifically enter and replicate in such cells. This review aims to describe the transductional targeting strategies currently employed to specifically redirect viruses towards surface receptors on tumor cells. Three major strategies can be distinguished; they involve (i) the incorporation of new targeting specificity into a viral surface protein, (ii) the incorporation of a scaffold into a viral surface protein to allow the attachment of targeting moieties, and (iii) the use of bispecific adapters to mediate targeting of a virus to a specified moiety on a tumor cell. Of each strategy key features, advantages and limitations are discussed and examples are given. Because of their potential to cause sustained, multiround infection&#8212;a desirable characteristic for eradicating tumors&#8212;particular attention is given to viruses engineered to become self-targeted by the genomic expression of a bispecific adapter protein.

M. H. Verheije

P. J. M. Rottier

Retargeting of Viruses to Generate Oncolytic Agents

Hematological malignancies such as leukemias, lymphomas, multiple myeloma (MM), and the myelodysplastic syndromes (MDSs) primarily affect adults and are difficult to treat. For high-risk disease, hematopoietic stem cell transplant (HCT) can be used. However, in the setting of autologous HCT, relapse due to contamination of the autograft with cancer cells remains a major challenge. <i>Ex vivo</i> manipulations of the autograft to purge cancer cells using chemotherapies and toxins have been attempted. Because these past strategies lack specificity for malignant cells and often impair the normal hematopoietic stem and progenitor cells, prior efforts to <i>ex vivo</i> purge autografts have resulted in prolonged cytopenias and graft failure. The ideal <i>ex vivo</i> purging agent would selectively target the contaminating cancer cells while spare normal stem and progenitor cells and would be applied quickly without toxicities to the recipient. One agent which meets these criteria is oncolytic viruses. This paper details experimental progress with reovirus, myxoma virus, measles virus, vesicular stomatitis virus, coxsackievirus, and vaccinia virus as well as requirements for translation of these results to the clinic.

Swarna Bais

Eric Bartee

Masmudur M. Rahman

Grant McFadden

Christopher R. Cogle

Oncolytic Virotherapy for Hematological Malignancies

Attempts at developing oncolytic viruses have been primarily based on rational design. However, this approach has been met with limited success. An alternative approach employs directed evolution as a means of producing highly selective and potent anticancer viruses. In this method, diverse viruses are grown under conditions that maximize diversity and then passaged under conditions meant to mimic those encountered in the human cancer microenvironment. Viruses which evolve to thrive under this selective pressure are isolated and tested to identify those with increased potency (i.e., ability to replicate and spread) and/or an increased therapeutic window (i.e., differentiated replication and spread on tumor versus normal cells), both of which have potential value but the latter of which defines an oncolytic virus. Using ColoAd1, an oncolytic virus derived by this approach as a prototype, we highlight the benefits of directed evolution, discuss methods to &#8220;arm&#8221; these novel viruses, and introduce techniques for their genetic modulation and control.

Maxine Bauzon

Terry W. Hermiston

Oncolytic Viruses: The Power of Directed Evolution

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<p><em>Advances in Virology</em> publishes articles in all aspect of viruses and viral diseases. Topics covered include viral structure, function, and genetics, as well as virus-host interactions, viral disease outbreaks, and antiviral therapeutics.</p>


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Advances in Virology - Table of contents 2012

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Advances in Virology publishes articles in all aspect of viruses and viral diseases. Topics covered include viral structure, function, and genetics, as well as virus-host interactions, viral disease outbreaks, and antiviral therapeutics.

Advances in Virology