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Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration–approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections.

There is a clear need for novel, effective therapeutic approaches to hemorrhagic fever due to filoviruses. Ebola virus hemorrhagic fever is associated with robust interferon (IFN)–α production, with plasma concentrations of IFN-α that greatly (60- to 100-fold) exceed those seen in other viral infections, but little IFN-β production. While all of the type I IFNs signal through the same receptor complex, both quantitative and qualitative differences in biological activity are observed after stimulation of the receptor complex with different type I IFNs. Taken together, this suggested potential for IFN-β therapy in filovirus infection. Here we show that early postexposure treatment with IFN-β significantly increased survival time of rhesus macaques infected with a lethal dose of Ebola virus, although it failed to alter mortality. Early treatment with IFN-β also significantly increased survival time after Marburg virus infection. IFN-β may have promise as an adjunctive postexposure therapy in filovirus infection.

Kaposi's sarcoma (KS) and lymphoproliferative diseases induced by KS-associated herpesvirus (KSHV/human herpesvirus 8) cause substantial morbidity and mortality in human immunodeficiency virus-infected individuals. To understand KSHV biology it is useful to investigate closely related rhadinoviruses naturally occurring in nonhuman primates. Here we report evidence for a novel KSHV homolog in captive baboon species ( Papio anubis and other). Using degenerate PCR we identified a novel rhadinovirus, PapRV2, that has substantial sequence identity to two essential KSHV genes, the viral polymerase and thymidylate synthase. A subset of animals exhibited detectable PapRV2 viral load in peripheral blood mononuclear cells. Extensive serological analysis of nearly 200 animals in the colony demonstrated that the majority carried cross-reacting antibodies that recognize KSHV or macaque rhadinovirus antigens. Seroreactivity increased with age, similar to the age-specific prevalence of KSHV in the human population. This establishes baboons as a novel resource to investigate rhadinovirus biology, which can be developed into an animal model system for KSHV-associated human diseases, vaccine development, and therapy evaluation.

Serologic studies (1–5) indicate that an epidemic of human herpesvirus 8 (HHV8) or Kaposi’s sarcoma (KS)associated herpesvirus, the viral etiologic agent of KS, occurred among homosexual men in the United States and in Europe concurrently with the human immunodeficiency virus-1 (HIV) epidemic in the early 1980s. However, studies from the United States (1,6) suggest that HHV8 possibly had become prevalent in some gay communities before the HIV epidemic. Thus, in the first decade of the U.S. HIV epidemic, the risk of acquired immunodeficiency syndrome (AIDS)-related KS in homosexual men was higher in HIV epicenters, such as New York, than elsewhere (6). Accordingly, the risk among homosexual men of being or becoming HHV8 infected from 1982 through 1990 was higher in New York than in Washington, DC (1). Little is known about the epidemiology of HHV8 in Europe before the HIV epidemic. Although studies (4,7) indicate that HHV8 was disseminated to the European gay communities from the United States or from KS-endemic regions, such as Africa, in conjunction with the introduction of HIV, it is not known whether HHV8 was already prevalent in the gay communities before the HIV epidemic. To study the prevalence of HHV8 infection before the HIV epidemic, we examined sera for HHV8 antibodies in individuals attending an outpatient clinic for a sexually transmitted disease (STD) in Copenhagen, Denmark, from March 1976 through February 1977. This study was approved by the Scientific Ethics Committees for Copenhagen and Frederiksberg Municipalities and by the Danish Data Protection Agency. The study population has been described in detail elsewhere (8). Briefly, from March 1976–February 1977, individuals attending the largest STD outpatient clinic in Copenhagen were invited to participate in a serologic study of gonorrhea. For all participants, information was recorded on age, sex, place of birth, and history of gonorrhea, including the outcome of actual clinical and microbiologic examinations. All participants had blood drawn, and since the original study, the sera have been stored at –20 °C. For the present study, we analyzed the sera from 641 anonymous individuals. The sera were analyzed for antibodies against HHV8 as described previously (9). Specifically, antibodies against the lytic phase glycoprotein K8.1 were detected with the use of a recombinant protein enzyme-linked immunosorbent assay (ELISA) (9). The samples that had an optical density of greater than 0.5 were further analyzed for antibodies against the HHV8 latencyassociated nuclear antigen by an indirect immunofluorescence assay that used the latently HHV8-infected BCP-1 cell line (9). Sera were classified as HHV8 positive if the optical density reading in the ELISA was greater than 1.0 or for samples with optical density readings between 0.5 and 1.0 if they were also positive by the indirect immunofluorescence assay (9). This testing algorithm is estimated to detect antibodies for HHV8, with a sensitivity of approximately 85% and a specificity of approximately 97% (9). We assessed ageand sex-specific HHV8 antibody prevalence and also evaluated the relevance of a diagnosis of gonorrhea (ever versus never) and country of origin (participants from classic KS-endemic areas [defined here as African countries, Italy, Israel, and Greece] versus all other countries). The relative risk of having HHV8 antibodies was estimated as the odds ratio (OR) ascertained by logistic regression analyses (SAS version 6.12; SAS Institute Inc., Cary, NC), with likelihood ratio-based 95% confidence intervals (CIs). All statistical tests were twosided. Overall, 27 (4.2%) of 641 individuals had HHV8 antibodies. The distribution by age, sex, country of origin, and history of gonorrhea is provided in Table 1. The prevalence was 5.1% (20 of 391) in men (4.1% [13 of 314] among Danish men only) and 2.8% (seven of 250) in women (3.2% [seven of 216] among Danish women only), a statistically nonsignificant difference (P .14) (Table 1). Overall, the prevalence of HHV8 antibodies increased with age (Table 1). Originating from a classic KS-endemic area was associated with a 15.7-fold (95% CI 5.0 to 45.5) increased likelihood of having HHV8 antibodies (Table 1). Because of the small number of women from KS-endemic areas, however, the increased risk associated with origin could be demonstrated only in men (OR 15.5; 95% CI 4.7 to 48.2) (Table 1). Overall, history of gonorrhea was associated with a 3.4-fold (95% CI 1.4 to 10.4) increased likelihood of having HHV8 antibodies (Table 1). The increased risk of having HHV8 antibodies was associated more strongly with a history of gonorrhea in men (crude OR 4.5 [95% CI 1.3 to 15.8]; adjusting for country of origin, OR 3.8 [95% CI 1.2 to 16.6]) than in women (OR 1.9; 95% CI 0.4 to 13.2). However, after adjusting for country of origin, the difference in risk estimates between men and women was not statistically significant (P .24). The application of different serologic assays makes it difficult to compare directly the prevalence of HHV8 antibodies in different populations (10). Still, the prevalence of HHV8 antibodies in this study of STD clinic attendees from 1976 through 1977, ranging from 3.2% in women to 4.1% in men, is of a similar order of magnitude to that reported in recent blood donor surveys in other