doi:10.1182/blood-2011-05-3503062011 117: 6973-6974

Patrick S. Moore and Yuan Chang KSHV: forgotten but not gone

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● ● ● CLINICAL TRIALS

Comment on Uldrick et al, page 6977

KSHV: forgotten but not gone----------------------------------------------------------------------------------------------------------------

Patrick S. Moore and Yuan Chang UNIVERSITY OF PITTSBURGH CANCER INSTITUTE

Thirty years ago, Kaposi sarcoma (KS) arose as a prominent manifestation of theAIDS epidemic. Seventeen years ago we discovered the virus that causes KS,1

Kaposi sarcoma–associated herpesvirus (KSHV), and within a year KSHV hadbeen also shown to be the likely cause of AIDS-associated primary effusion lym-phoma (PEL)2 and most cases of multicentric Castleman disease (MCD).3

S ince then, almost no progress has beenmade in treating the virus that causes

these tumors. In this issue of Blood, for thefirst time, Uldrick et al describe a long overdueapproach to MCD therapy based on directtargeting of KSHV.4

There are now 7 known human cancer vi-ruses but only scattered efforts to developed

drugs specifically targeting them. The suc-cesses of the human papillomavirus and hepa-titis B virus vaccines make clear that virus-oriented therapies have the potential to bemajor success stories in cancer management.If a virus causes a tumor, why are most phar-maceuticals targeting the host cancer cell in-stead of the causative virus? The most impor-

tant reason is economics: 1 in 5 cancersworldwide has an infectious origin, with mostcases concentrated in poor and developingcountries.

But to be fair to the pharmaceutical indus-try, drugs against viral cancers are also difficultto make. Almost all current antivirals targetviral replication machinery. The most well-known antiviral drug is acyclovir, a nucleosideanalog activated by the herpes simplex thymi-dine kinase enzyme. This viral protein is onlyexpressed during active viral replication toreplicate viral DNA and for this reason acyclo-vir is effective against cold sores but notagainst latent virus in trigeminal or sacral gan-glia. Acyclovir reduces symptoms but does notcure the underlying disease.

Similarly, viruses in most tumor cells arelatent as well. If viruses in cancer cells did ac-tively replicate, host innate and adaptive im-mune responses would kill the cell before itcould grow into a clinically apparent tumor,and for most viral cancers there is no targetthat can be hit with available drugs. Ganciclovir,for example, is remarkably effective in random-ized clinical trials to prevent KSHV replicationand KS5,6 but has no effect once KS tumorsemerge.7

The study by Uldrick et al looks at thisproblem in a different way—are there anyother KSHV-related tumors in which activelyreplicating virus can be targeted? Castlemandisease is a B-cell lymphoproliferative disor-der driven by IL-6 over-expression and inKSHV-related MCD, only a small percentageof tumor cells are actually KSHV-infected (seefigure). KSHV-infected MCD cells are sur-rounded by uninfected B cells forced to multi-ply by cytokine-induced mitogenesis, whichmake up the bulk of MCD tumors and are re-sponsible for most MCD symptoms and se-quelae. Viral replication machinery plays a keyrole in MCD because KSHV-encoded vIL-6is amplified as part of the virus’s replicationprogram (although the KSHV vIL-6 gene canbe activated in different ways and should notbe called a “lytic KSHV gene”).

KSHV-infected cells expressing vIL-6 within an adventitious germinal center in a multicentric Castlemandisease tumor. Illustration courtesy of C. Parravicini.

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Uldrick et al exploit this to develop a viralchemotherapy regimen against MCD. Thework extends previous studies suggesting thatantivirals can improve MCD patient survival.8

In their pilot study, Uldrick et al use the ganci-clovir prodrug, valganciclovir, together withzidovudine (AZT) to precisely target 2 viralenzymes involved in viral DNA synthesis, theviral phosphotransferase and thymidine ki-nase, respectively—a first in KSHV oncology.These drugs can potentially be paired withother standard chemotherapies to further im-prove outcome for this disease that otherwisehas a dismal prognosis.

Both drugs are approved for human usewith other viral infections having more favor-able pharmaco-economic indices than KSHV.In some African countries hard hit by AIDS,however, Kaposi sarcoma accounts for themajority of adult cancers reported to cancerregistries. In Southeast Asia, EBV-containingnasopharyngeal carcinoma is a major unmetpublic health problem. Despite the effective-nesss of papillomavirus vaccines, cervical can-cer remains a major killer throughout the de-veloping world, and 4000 women die from itannually in the US. For KSHV and mostother cancer viruses, the problem is not thatthere is no possible viral drug target. KSHVlatency-associated nuclear antigen 1 is neededby the virus to maintain its genome in everytumor cell. Finding drugs to target these latentviral proteins is more an economic than a sci-entific issue. In the words of the astronaut GusGrissom, “No bucks, no Buck Rogers.”

Rates of KS in developed countries havedramatically fallen with the development ofeffective antiretroviral therapy for HIV/AIDS, reducing the urgency to develop newcontrol approaches to KSHV tumors. Thecurrent respite in KSHV-related disease,however, may be only temporary. Antiretro-viral therapy does not affect latent, life-longKSHV infections and so resurgence ofKSHV-related tumors with aging of thecurrent HIV/AIDS population can be ex-pected. We have not used this quiet timewisely.

This study by Uldrick et al provides a keylesson that antiviral chemotherapy in KSHVtumors can work— but only because ofMCD’s unusual pathoetiology. MCD actsmore like a smoldering virus infection than aneoplasm. If new classes of antivirals were tobe developed targeting latent cancer virus on-coproteins, there is promise that remarkable

clinical outcomes could emerge. These drugscould lead to cures instead of palliation forsome viral infections. They might also be farless toxic than current cancer chemotherapiesbecause they target foreign proteins—muchlike the miraculous antibiotics of the 1940s.The study reported in this issue Blood is animportant first step in this direction.

Conflict-of-interest disclosure: The authorshold patents related to KSHV that have beenassigned to Columbia University. ■

REFERENCES1. Chang Y, Cesarman E, Pessin MS, et al. Identificationof herpesvirus-like DNA sequences in AIDS-associatedKaposi’s sarcoma. Science. 1994;265(5192):1865-1869.

2. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM.Kaposi’s sarcoma-associated herpesvirus-like DNA sequencesin AIDS-related body-cavity-based lymphomas.N EnglJ Med. 1995;332(18):1186-1191.

3. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’ssarcoma-associated herpesvirus-like DNA sequences inmulticentric Castleman’s disease.Blood. 1995;86(4):1276-1280.

4. Uldrick TS, Polizzotto MN, Aleman K, et al. High-dosezidovudine plus valganciclovir for Kaposi sarcoma herpes-virus-associated multicentric Castleman disease: a pilotstudy of virus-activated cytotoxic therapy.Blood. 2011;117(26):6977-6986.

5. Martin DF, Kuppermann BD, Wolitz RA, Palestine AG,Li H, Robinson CA. Oral ganciclovir for patients with cyto-megalovirus retinitis treated with a ganciclovir implant.N EnglJ Med. 1999;340(14):1063-1070.

6. Casper C, Krantz EM, Corey L, et al. Valganciclovir forsuppression of human herpesvirus-8 replication: a random-ized, double-blind, placebo-controlled, crossover trial. J In-fect Dis. 2008;198(1):23-30.

7. Krown SE, Dittmer DP, Cesarman E. Pilot study of oralvalganciclovir therapy in patients with classic kaposi sar-coma. J Infect Dis. 2011;203(8):1082-1086.

8. Casper C, Nichols WG, Huang ML, Corey L, Wald A.Remission of HHV-8 and HIV-associated multicentricCastleman disease with ganciclovir treatment. Blood.2004;103(5):1632-1634.

● ● ● IMMUNOBIOLOGY

Comment on Barao et al, page 7032

Unlicensed natural born killers----------------------------------------------------------------------------------------------------------------

Andreas Lundqvist and Richard Childs KAROLINSKA INSTITUTET; NATIONAL INSTITUTES OF HEALTH

In this issue of Blood, Barao and colleagues describe repopulation of Ly49G2single-positive NK cells after congenic hematopoietic stem cell transplantation(HSCT) that appear fully functional, having tumor cytolytic capacity despite re-cipients lacking MHC molecules thought necessary to license them.

Natural killer (NK) cells are innate lym-phocytes capable of killing tumors and

virus-infected cells. Their function is regu-lated through a variety of different receptors.In humans, the largest group of receptors be-longs to the killer Immunoglobulin-like fam-ily, or KIRs. Although structurally differentfrom KIRs, mice possess Ly49 receptors thatshare similar functional characteristics; bothKIRs and Ly49 receptors are composed ofmembers possessing inhibitory or activatingproperties that regulate the function of theNK cell on binding its cognate MHC class Iligand. Although cell subsets lacking inhibi-tory receptors for self-MHC have been ob-served in both man and mouse, in vitro studieshave shown that these potentially auto-reactive NK-cell populations are in most caseshyporesponsive. In contrast, NK cells whoseinhibitory receptors interact with self-MHCclass I acquire functional competence, a pro-cess referred to as licensing.1 Such licensedNK cells are immunologically competent and

are capable of responding to stimuli in vitroand in vivo.

In this issue of Blood, Barao et al investi-gated whether licensing plays a role in the re-constitution of NK cells bearing differentLy49 receptors in mice undergoing HSCT.2

Initial experiments focused on transfer of bonemarrow cells in congenic C57BL/6 mice(H-2b-positive). In these mice, Ly49G2single-positive NK cells are considered unli-censed because of their inability to bind H2b.Contrary to expectations, early NK-cell re-population after HSCT was dominated byLy49G2 single-positive NK cells. Remark-ably, these unlicensed NK cells were pheno-typically mature and were not hyporesponsive,lysing tumor targets to a similar degree aslicensed NK-cell controls. When experimentswere repeated in mice on an H-2d background,a selective expansion of Ly49G2 single-positive NK cells was again observed. Thus, itappears that NK-cell repopulation early afterHSCT is dominated by Ly49G2 single-

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