Effective Prophylactic Therapy for Exposure to Monkey B Virus (Macacine alphaherpesvirus 1).

Zoonotic monkey B virus (Macacine alphaherpesvirus 1; BV) infections are extremely serious and usually fatal. Drugs currently used for treatment were developed for the treatment of herpes simplex virus but are less effective against BV. Effective suppression of viral replication in the skin could prevent the virus from invading the nervous system. To test this hypothesis, the efficacy of topical administration of several drugs against lethal BV infection was evaluated in female BALB/c mice that were infected by scarification. Drugs were then applied to the site of inoculation. As 3% preparations, most drugs were only minimally effective or ineffective. In contrast, ganciclovir and cidofovir were very effective. The ED50 for cidofovir was 0.007%, compared with 1.1% for ganciclovir. At 0.5%, cidofovir protected against both death and neurologic signs, whereas 5% ganciclovir only protected against death but not neurologic involvement. All genotypes of BV were equally susceptible to cidofovir and ganciclovir. For maximal effectiveness, treatment with both cidofovir and ganciclovir had to be initiated within 8 h of infection. Cidofovir was completely protective when administered only on the day of infection, whereas a minimum of 5 d of treatment was required for maximal ganciclovir efficacy. These studies showed that topical cidofovir treatment started soon after BV exposure was very effective in preventing BV from invading the nervous system, whereas ganciclovir treatment was only partially effective. In addition, cidofovir was protective against a ganciclovir-resistant BV mutant, whereas ganciclovir was not. These studies showed that topical cidofovir treatment started soon after BV exposure is more effective than ganciclovir in preventing BV from invading the CNS.

Update in Herpes Zoster Prevention and the Role of Dermatologists

A recombinant vaccine (HZ/su) was approved in 2017 to prevent herpes zoster (HZ) infection and associated sequelae with greater efficacy and safety than its live precursor. Though dermatologists regularly encounter patients with HZ infection, recommendation of vaccination by dermatologists and other physicians has been minimal in past years. Overall patient awareness and utilization of the HZ vaccines has subsequently been low. While HZ/su touts several improvements over the live vaccine, dermatologists still face obstacles to vaccine recommendation and administration including concerns of efficacy, limited availability, and complex cost and reimbursement for administration. Additionally, dermatologists have not historically played a systematic role in the recommendation and administration of vaccines. A review of literature was completed to identify the current role of dermatologists in HZ prevention, the efficacy and safety of HZ/su, potential barriers to recommendation by dermatologists, and the feasibility of vaccine administration in dermatology offices. Pubmed/MEDLINE was used as the primary search database. Ultimately, widespread encouragement of dermatologists to recommend vaccination against HZ is crucial, and dermatologists are in a prime position to make the vaccine more accessible to their patient population. J Drugs Dermatol. 2019;18(1):18-22.

Herpes zoster vaccine: a protection for the elderly.

The Herpes Zoster vaccine is strongly recommended by the World Health Organization to promote healthy aging by preventing the corresponding age- related disease, also named shingles. The disease is due to the endogenous reactivation of Varicella Zoster Virus, the causal agent of chickenpox, that becomes latent at the peripheral nervous system level. Here, owing to the host's cell-mediated immunity, it may be confined for several decades. However, the immune senescence allows the possibility of virus reactivation, causing the onset of neuropathic pain and skin rash that characterize the acute disease. Sometimes, the neuralgia becomes chronic causing postherpetic neuralgia that has a significant impact on the quality of patient life, analogously to the ophthalmic HZ, a particularly feared form of disease. Due to the causal relationship between decreasing immune defenses and virus reactivation with disease onset, the incidence of Herpes Zoster, in Italy now equal to 6.42 (95%CI: 5.93-6.95) cases per 1,000 people per year will increase steadily in the future due to the longevity rise of the population. Considering epidemiological impact, complications and sequelae in the short- and long-term, costs of clinical-therapeutical management of patients, and, above all, the poor effectiveness of available therapy the only effective intervention is vaccination of the elderly. Currently in the European Union, there is only one vaccine for Herpes Zoster prevention, formed by live attenuated OKA-Merck virus strain that is also used for paediatric vaccine. According to the Health Technology Assessment surveys, the intervention cost (based on "Quality Adjusted Life Years") is clearly below the discriminating threshold value to judge the feasibility and, as predicted by the Italian National Plan of Vaccinal Prevention 2017-2019, the vaccine is offered free to all subjects >65 years.

Neonatal herpes simplex virus infections.

Neonatal herpes simplex virus (HSV) is an uncommon but devastating infection in the newborn, associated with significant morbidity and mortality. The use of PCR for identification of infected infants and acyclovir for treatment has significantly improved the prognosis for affected infants. The subsequent use of suppressive therapy with oral acyclovir following completion of parenteral treatment of acute disease has further enhanced the long-term prognosis for these infants. This review article will discuss the epidemiology, risk factors and routes of acquisition, clinical presentation, and evaluation of an infant suspected to have the infection, and treatment of proven neonatal HSV disease.

Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease.

Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation.

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (T(RM)) cells are identified by their expression of the α-chain from the integrin α(E)(CD103)ß(7), and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103(+)CD8(+) T(RM) cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T(RM) phenotype. The CD8(+) T(RM) cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T(RM) cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.

Dermatological diseases of compulsory notification in Brazil.

The development of a Brazilian National Surveillance System in 1975 led to a compulsory reporting of selected infectious diseases aiming to reduce the burden of these events in the country. However, shifts in the epidemiology of these diseases associated with modern life style, demand constant revision of surveillance activities. In this manuscript we present the epidemiology, trends and differential diagnosis of the following compulsory notifiable diseases in Brazil: Aids, dengue fever, hanseniasis, American tegumentary leishmaniasis, measles, rubella and congenital rubella syndrome and syphilis. Additionally, the current challenges for control and prevention of each disease are presented.

Doenças dermatológicas de notificação compulsória no Brasil / Dermatological diseases of compulsory notification in Brazil

A estruturação do Sistema Nacional de Vigilância Epidemiológica do Brasil, em 1975, tornou obrigatória a notificação de algumas doenças transmissíveis com o objetivo de reduzir a carga destes eventos no país. Entretanto, as alterações no perfil epidemiológico destas doenças, associadas a características da sociedade contemporânea, determinam a constante adequação das atividades de vigilância a este cenário. Neste manuscrito, são descritos epidemiologia, tendências e diagnóstico diferencial das seguintes doenças dermatológicas de notificação compulsória no Brasil: aids, dengue, hanseníase, leishmaniose tegumentar americana, sarampo, rubéola e síndrome da rubéola congênita e sífilis. Também são apresentados os principais desafios atuais para o controle e prevenção para cada uma dessas doenças no Brasil.

The development of a Brazilian National Surveillance System in 1975 led to a compulsory reporting of selected infectious diseases aiming to reduce the burden of these events in the country. However, shifts in the epidemiology of these diseases associated with modern life style, demand constant revision of surveillance activities. In this manuscript we present the epidemiology, trends and differential diagnosis of the following compulsory notifiable diseases in Brazil: Aids, dengue fever, hanseniasis, American tegumentary leishmaniasis, measles, rubella and congenital rubella syndrome and syphilis. Additionally, the current challenges for control and prevention of each disease are presented.

Vaccines in dermatological diseases.

Vaccines have been a cornerstone in medicine and public health since their inception in the 18th century by Edward Jenner. Today, greater than 20 vaccines are used worldwide for the prevention of both viral and bacterial diseases. This article will review the vaccines used for the following dermatological diseases: smallpox, measles, mumps, rubella, chickenpox, shingles, and human papillomavirus.

Dermatologic manifestations of HIV in Africa.

Dermatologic disease is common in HIV-infected individuals, and clinicians caring for patients with HIV infection or AIDS in Africa are routinely confronted with skin problems in their patients. Scarce access to dermatologic specialty care and limited educational resources describing the unique clinical characteristics of HIV-related skin disease can make diagnosing and treating skin diseases a challenge in Africa. This article describes common HIV-related dermatologic conditions in Africa and their differential diagnoses and includes treatment strategies that are likely to be available locally. It is not meant to be comprehensive but rather to serve as a practical resource to aid practitioners by providing images of common conditions and describing distinctive clinical presentations of common conditions.

Virus-like particles and capsomeres are potent vaccines against cutaneous alpha HPVs.

The potential as prophylactic vaccines of L1-based particles from cutaneous genus alpha human papillomavirus (HPV) types has not been assessed so far. However, there is a high medical need for such vaccines since HPV-induced skin warts represent a major burden for children and for immunocompromised adults, such as organ transplant recipients. In this study, we have examined the immunogenicity of capsomeres and virus-like particles (VLPs) from HPV types 2, 27, and 57, the most frequent causative agents of skin warts. Immunization of mice induced immune responses resembling those observed upon vaccination with HPV 16 L1-based antigens. The antibody responses were cross-reactive but type-restricted in their neutralizing capacities. Application of adjuvant led to an enhanced potential to neutralize the respective immunogen type but did not improve cross-neutralization. Vaccination with capsomeres and VLPs from all four analyzed HPV types induced robust IFNgamma-associated T-cell activation. Immunization with mixed VLPs from HPV types 2, 27, and 57 triggered an antibody response similar to that after single-type immunization and capable of efficiently neutralizing all three types. Our results imply that vaccination with combinations of VLPs from cutaneous HPV types constitutes a promising strategy to prevent HPV-induced skin lesions.

Skin diseases and sexually transmitted diseases in HIV-infected patients on HAART compared to a non-infected population - results of a retrospective study.

BACKGROUND: The prevalence of skin diseases and sexually transmitted diseases has always played a special role in studying HIV infections, both because of immunosuppression and simultaneous transmission. In the early years of the HIV epidemic, skin diseases were often a pathognomonic sign in heavily immunosuppressed patients. With highly active antiretroviral therapy (HAART), HIV infection has become a treatable chronic disease. For this reason the spectrum as well as the prevalence of skin diseases has changed. Pathognomonic skin diseases have become rare and the wide spectrum today ranges from infectious to iatrogenic skin diseases. PATIENTS AND METHODS: From April to October 2007 166 HIV-infected patients and 173 patients of a comparison group were surveyed in retrospect by means of a questionnaire about skin diseases and sexually transmitted diseases that appeared over the entire year 2006. RESULTS AND CONCLUSIONS: The study confirmed the shift to a wide variety of mostly trivial skin diseases and away from severe opportunistic skin diseases. HIV-infected patients today have more numerous skin problems than the non-infected population and thus need regular dermatologic control examinations.

Impact of prophylactic human papillomavirus vaccines on dermatology and venereology.

Prophylactic HPV L1 VLP quadrivalent and bivalent vaccines have a great importance for patients seen by dermatologists and venereologists. Both vaccines protect against HPV16- and HPV 18-associated anogenital cancers, as well as cancers of the mouth, the upper respiratory tract and skin, especially of the fingers and periungual region. The quadrivalent HPV6, 11, 16, 18 vaccine also prevents anogenital warts (condylomata acuminata) which are the most common benign tumors of this body region. HPV-vaccination (Gardasil) has been approved in Germany and other European Countries since October 2006 for young girls between 9-16 and young women between 16-26 years of age. Many experts feel that boys and young men should also be vaccinated. Men would profit from a vaccine that protects against HPV infections, especially anogenital warts, as well as penile and anal carcinomas. In immunosuppressed organ transplant recipients and HIV-positive patients. HPV disease can be widespread, chronic and often may rapidly progress to malignant tumors. Thus, these individuals would greatly benefit from prophylactic HPV immunization.

[Impact of prophylactic HPV vaccines on dermatology and venereology]. / Bedeutung der prophylaktischen HPV-Vakzine für die Dermatologie und Venerologie.

Prophylactic HPV L1 VLP quadrivalent and bivalent vaccines are of great importance for patients seen by dermatologists and venereologists. Both vaccines protect against HPV16- and HPV18-associated anogenital cancers, as well as cancers of the mouth, the upper respiratory tract and skin, especially of the fingers and periungual region. The quadrivalent HPV6, 11, 16, 18 vaccine also prevents anogenital warts (condylomata acuminata) which are the most common benign tumors of this body region. HPV-vaccination (Gardasil) has been approved in Germany since October 2006 for young girls between 9-16 and young women between 16-26 years of age. Many experts feel that boys and young men should also be vaccinated. Men would profit from a vaccine that protects against HPV infections, especially anogenital warts, as well as penile and anal carcinomas. In immunosuppressed organ transplant recipients and HIV-positive individuals, HPV can be widespread, chronic and often rapidly progressive to malignant tumors; thus these groups would greatly benefit from HPV immunization.

Conversion to sirolimus: a useful strategy for recalcitrant cutaneous viral warts in liver transplant recipient.

Dermatological complications following transplantation are very common and the majority of immunosuppressed transplant recipients develop some to many warts due to human papillomavirus (HPV) infection. In the setting of immunosuppression, therapeutic management may be disappointing because of the extent of the lesions in patients unable to develop a sufficient immune response directed against HPV. We report here a case of a young liver transplant recipient who developed diffuse recalcitrant HPV-induced warts leading to an impairment of her quality of life. Taking into account the antiproliferative and cytostatic properties of the target-of-rapamycin (TOR) inhibitors, a new class of immunosuppressive drug, we significantly modified the immunosuppressive regimen. Conversion to sirolimus was followed by a rapid improvement of cutaneous state suggesting that this strategy may be useful for recalcitrant cutaneous viral warts in transplant recipient.

An antivector vaccine protects against a lethal vector-borne pathogen.

Vaccines that target blood-feeding disease vectors, such as mosquitoes and ticks, have the potential to protect against the many diseases caused by vector-borne pathogens. We tested the ability of an anti-tick vaccine derived from a tick cement protein (64TRP) of Rhipicephalus appendiculatus to protect mice against tick-borne encephalitis virus (TBEV) transmitted by infected Ixodes ricinus ticks. The vaccine has a "dual action" in immunized animals: when infested with ticks, the inflammatory and immune responses first disrupt the skin feeding site, resulting in impaired blood feeding, and then specific anti-64TRP antibodies cross-react with midgut antigenic epitopes, causing rupture of the tick midgut and death of engorged ticks. Three parameters were measured: "transmission," number of uninfected nymphal ticks that became infected when cofeeding with an infected adult female tick; "support," number of mice supporting virus transmission from the infected tick to cofeeding uninfected nymphs; and "survival," number of mice that survived infection by tick bite and subsequent challenge by intraperitoneal inoculation of a lethal dose of TBEV. We show that one dose of the 64TRP vaccine protects mice against lethal challenge by infected ticks; control animals developed a fatal viral encephalitis. The protective effect of the 64TRP vaccine was comparable to that of a single dose of a commercial TBEV vaccine, while the transmission-blocking effect of 64TRP was better than that of the antiviral vaccine in reducing the number of animals supporting virus transmission. By contrast, the commercial antitick vaccine (TickGARD) that targets only the tick's midgut showed transmission-blocking activity but was not protective. The 64TRP vaccine demonstrates the potential to control vector-borne disease by interfering with pathogen transmission, apparently by mediating a local cutaneous inflammatory immune response at the tick-feeding site.

Role of antiretroviral therapies in mucocutaneous manifestations in HIV-infected children over a period of two decades.

BACKGROUND: Human immunodeficiency virus (HIV) infection causes a severe cellular immunodeficiency, which results in a greater susceptibility to infectious, inflammatory and malignant conditions. Among these, pathologies of the skin seem to be those most frequently observed in HIV+ patients. However, there are few reports on how antiretroviral therapy affects skin disorders in HIV-infected children. OBJECTIVE: To study the incidence and prevalence of skin disorders in a cohort of HIV-infected children, in relation to the antiviral therapy [nontreated, monotherapy, combined therapy and highly active antiretroviral therapy (HAART)] received, and their impact on immunological and virological markers. The treatments were those available in different calendar periods in the history of antiviral treatment. MATERIALS AND METHODS: A retrospective, observational study in a cohort of 210 HIV-infected children was carried out. These children were followed up every 3 months throughout 22 years. The viral load (HIV RNA copies mL(-1)) was quantified using reverse transcriptase-polymerase chain reaction and the viral phenotype of HIV-1 isolates was determined by in vitro culture. T-lymphocyte subsets in peripheral blood were quantified by flow cytometry. RESULTS: Mucocutaneous manifestations were diagnosed in 17% of the untreated infected children. Of the treated children in different treatment periods, 22% in the monotherapy period, 25% in the combined therapy period but only 10% on HAART had some type of mucocutaneous manifestation, concordant with a higher number of CD4+ T cells, a lower viral load and less cytopathic virus in the last group. Mucocutaneous manifestations of infectious aetiology were most frequently observed; they were detected in 13% of the children during the first calendar period (untreated children), 16% during the second and third periods (monotherapy and combined therapy) and only 5% in the last period (HAART). Interestingly, syncytium-inducing virus was present in 69% of all children with mucocutaneous manifestations of infectious aetiology. CONCLUSION: Only in the last calendar period (HAART) was a significant decrease observed in the prevalence of mucocutaneous manifestations with HIV infection associated with an increase in CD4+ T cells. In addition, we found a strong association between children who had mucocutaneous manifestations with an infectious aetiology and a more cytopathic (X4/SI) viral phenotype.

Therapy of other viral infections: herpes to hepatitis.

Over the past several years, there has been an increase in knowledge pertaining to the diagnosis and management strategies for the herpes family (Types 1-8), the pox viruses, mumps, measles, rubella, and parvovirus B19 as well as the viral etiologies of hepatitis. Various antiviral treatments, such as nucleoside analogs and interferon therapy, have been available to reduce the signs and symptoms of these common viral infections. This article summarizes the preferred treatment strategies to be employed for each of the viruses for reducing severity, duration, recurrences (notably in the herpes family), transmission rates, as well as preventive alternatives. The majority of the therapeutic options attenuate the course of disease. Treatment decisions are driven by knowledge of the natural history and often are tailored to incorporate clinical circumstances for individual patients. Promotion of community awareness and the development of vaccines should be emphasized in the battle against these common viruses, particularly the herpes simplex viruses, the pox viruses, and hepatitis B.

Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation.

HSV infects skin or mucosal epithelium as well as entering the sensory nerves and ganglia. We have used TCR-transgenic T cells specific for the immunodominant class I-restricted determinant from HSV glycoprotein B (gB) combined with a flank zosteriform model of infection to examine the ability of CD8+ T cells to deal with infection. During the course of zosteriform disease, virus rapidly spreads from the primary inoculation site in the skin to sensory dorsal root ganglia and subsequently reappears in the distal flank. Virus begins to be cleared from all sites about 5 days after infection when gB-specific CD8+ T cells first appear within infected tissues. Although activated gB-specific effectors can partially limit virus egress from the skin, they do so only at the earliest times after infection and are ineffective at halting the progression of zosteriform disease once virus has left the inoculation site. In contrast, these same T cells can completely clear ongoing lytic replication if transferred into infected immunocompromised RAG-1-/- mice. Therefore, we propose that the role of CD8+ T cells during the normal course of disease is to clear replicating virus after infection is well established rather than limit the initial spread of HSV from the primary site of inoculation.