The effects of Avemar treatment on feline immunodeficiency virus infected cell cultures.

INTRODUCTION: In addition to standard highly active antiretroviral therapy protocols, complementary therapies using natural compounds are widely used by human immunodeficiency virus (HIV)-infected human patients. One such compound is the fermented wheat germ extract (FWGE), named Avemar. MATERIALS AND METHODS: In this study, we investigate the effects of Avemar in a feline-acquired immunodeficiency syndrome model. MBM lymphoid cells were acutely infected by the American feline immunodeficiency virus (FIV)-Petaluma (FIV-Pet) and the European FIV Pisa-M2 strains. FL-4 lymphoid cells, continuously producing FIV-Pet, served as a model for chronic infection. Crandell Rees feline kidney (CRFK) cells were infected by either FIV-Pet or feline adenovirus (FeAdV) as a model for transactivation and opportunistic viral infection. Cell cultures were treated pre- and post-infection with serial dilutions of spray-dried FWGE (Avemar pulvis, AP), a standardized active ingredient in commercial Avemar products. Residual FIV and FeAdV infectivity was quantified. RESULTS: In a concentration-dependent manner, AP inhibited replication of FIV strains in MBM and CRFK cells by 3-5 log. Low AP concentration prevented FIV-Pet release from FL-4 cells. Higher concentrations destroyed virus-producing cells with cytopathic effects resembling apoptosis. AP strongly inhibited FeAdV production inside CRFK cells but not in HeLa cells. Adenovirus particles are then released via the disintegration of CRFK cells. DISCUSSION: This report is the first to describe the antiviral effects of Avemar. Further studies are required to confirm its in vitro and in vivo effects and to investigate the potential for its use as a nutraceutical in FIV-infected felines or HIV-infected humans. CONCLUSION: Avemar, as a single nutraceutical, inhibits FIV replication and destroys retrovirus carrier cells. An important conclusion is that prolonged Avemar treatment might reduce the number of retrovirus-producing cells in the host.

SARS-CoV-2 infection in HIV-infected patients: potential role in the high mutational load of the Omicron variant emerging in South Africa.

A new variant of SARS-CoV-2 named Omicron (B.1.1.529) was isolated from an HIV-infected patient in Botswana, South Africa, in November 2021. Whole genome sequencing revealed a multitude of mutations and its relationship to the mutation-rich Alpha variant that had been isolated from a cancer patient. It is conceivable that very high prevalence of HIV-infected individuals as susceptible hosts in South Africa and their immunocompromised state may predispose for accumulation of coronavirus mutations. Coronaviruses uniquely code for an N-terminal 3' to 5'exonuclease (ExoN, nsp14) that removes mismatched nucleotides paired by the RNA dependent RNA polymerase. Its activity depends preferably on Mg2+ and other divalent cations (manganese, cobalt and zinc). On the contrary, methyl transferase activity of non-structural protein (nsp) 14 and nsp16 both complexed with nsp10 requires Mn2+. Enzymes in successive stages of HIV infections require the same cations. In HIV-infected organisms, a subsequent coronavirus infection encounters with altered homeostasis of the body including relative starvation of divalent cations induced by interleukin production of HIV-infected cells. It is hypothesized that selective diminished efficacy of ExoN in the absence of sufficient amount of magnesium may result in the accumulation of mutations. Unusual mutations and recombinations of heterologous viruses detected in AIDS patients also suggest that long-lasting persistence of superinfecting viruses may also contribute to the selection of genetic variants. Non-nucleoside reverse transcriptase inhibitors partially restore divalent cations' equilibrium. As a practical approach, implementation of highly active antiretroviral therapy against HIV replication and vaccination against coronaviruses may be a successful strategy to reduce the risk of selection of similar mutants.

New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives.

Thiolated pyrimidine derivatives have been synthetized and their antiretroviral effect against human immunodeficiency virus type 1 (HIV-1IIIB) and HIV-1 chimeric pseudovirions have been quantitatively determined in cell-based viral infectivity assays including syncytium inhibition assay as well as a single-cycle viral infection assay on HeLaCD4-LTR/ß-gal cells. Pseudotype virions prepared bearing HIV-1 envelope preference for CCR5 coreceptor, CXCR4 coreceptor or for both, respectively, with a HIV-1 core containing luciferase reporter gene were able to infect susceptible cells but are replication defective so unable to replicate in the cells . Data indicate that thiolated pyrimidine derivatives inhibited effectively virally induced cell fusion in vitro as well as infectivity of primary HIV-1IIIB strain and HIV-1 pseudovirions using chemokine receptors CCR5 or CXCR4 or both for virus entry a dose dependent manner. Inhibition was selective, depended on the pseudovirus coreceptor preference. Our results suggest that some of these sulfur containing pyrimidines interact with redoxactive -SH groups required for successful HIV entry, including a redox active disulfide in the CD4 molecule as well as -SH groups in HIV viral envelope gp120. This mode of action is unique representing a new class of potential HIV entry inhibitors.

Immunochemistry of adenoviruses: limitations and new horizons of gene therapy.

Adenoviruses have increasingly been recognized as significant viral pathogens causing high morbidity and mortality especially among immunocompromised individuals such as transplant recipients and AIDS patients. Through the infection process, after the adenovirus fiber and penton are bonded to cell surface receptors through special amino acid moieties, secondary messengers activate protein kinases, pro-inflammatory cytokines and chemokines. Serotype and species specific antibodies also are induced. Recombinant human adenoviruses have been pivotal in the development of gene therapy strategies and have shown a great promise for the treatment of genetic disorders and malignancies. Recent studies have enlightened their harmful immunological effects dependent on fiber and hexon polypeptide structure and receptor binding. Pre-existing antibodies or those elicited by vectors neutralize input recombinant adenovirus particles rendering them ineffective. Mediators induce serious even lethal side effects and cytotoxic reactions which extinguish transgene expression. To overcome these difficulties new strategies are required in the application of recombinant adenoviruses to redirect vector entry from the natural receptors to alternative binding sites or using rare human or animal adenovirus fiber molecules to modify the native fiber structure by altering amino acid structure and creating chimeric fibers. This requires searching for, isolating and characterizing new serotypes, mutants or variants for new generation vectors. Human adenovirus 1 feline isolate (feline adenovirus) might fulfil these criteria.

[Adenovirus infections in immunocompromised patients]. / Adenovírus-fertozések immunszuppresszált betegekben.

Human adenoviruses function as genetic models and vectors for gene therapy. Upper respiratory, gastrointestinal or ocular infections usually have mild course without any major complication in immunocompetent individuals. However, reactivation from latency in immunocompromised patients may lead to death. Depending on the underlying diseases, different adenovirus serotypes damage different organs. In children with severe combined immunodeficiency syndrome, serotypes of species A and C induce lung, liver or bladder inflammation. Paediatric hematopoietic stem cell transplantation is frequently followed by serotype 31-induced pneumonia, enteritis, cystitis. B serotypes can destroy transplanted organs. In AIDS patients, D and novel F serotypes cause enteritis. Recombinants of B serotypes induce urinary tract infections. Progression of lymphomas, tumours, and systemic lupus erythematosus might be facilitated by immunosuppressive effects of adenoviruses. As far as the diagnostic work-up of adenoviruses, detection of viral DNA and virus copy number is predictive, while serology testing is quite unreliable. For treatment, cidofovir derivates, ribavirin, ganciclovir, vidarabine and microRNA have been used.

[Human herpesvirus 7]. / Az emberi 7-es herpeszvírus.

Human herpesvirus 7 known since 1990 is closely related to herpesvirus 6B. It replicates in human cells only after binding CD4 receptor. It establishes lifelong latency in infected cells, and its frequent reactivations result in asymptomatic virus shedding through saliva. Most children acquire infection by age 3 and 4, but in any later age group seronegative individuals are at risk of infection. Rarely, exanthema subitum or convulsions with fever in children, pityriasis rosea in young adults, lethal complications in immunocompromised persons with concomitant herpesvirus 6B and cytomegalovirus reactivation occur. The most important pathogenic changes are due to the altered cytokine and growth factor secretion from infected lymphocytes with subsequent chain reaction on immune and other cells. Antiviral antibodies are detected by commercial kits (immunofluorescence, ELISA, immunoblot), nucleic acid by nested polymerase chain reaction. The majority of conditions due to infection do not require antiviral medication, but the severe complications are treated with ganciclovir and its derivates or foscarnet and cidofovir.

[Human herpesvirus 6]. / Az emberi 6-os herpeszvírus.

Human herpesvirus 6 discovered in 1986 is the most ancient human herpesvirus shown by molecular characteristics. Variant B infects children under the age of 2 years by droplets from asymptomatic virus shedding adults occasionally causing exanthema subitum. The virus infects CD4+ macrophages and lymphocytes; subsequently establishes lifelong latency and persistence with occasional shedding through the saliva. This variant frequently reactivates in bone marrow and organ transplant recipients with concomitant immunosuppression causing even fatal complications. It is a cofactor in the pathogenesis of multiple sclerosis, chronic fatigue syndrome, Hodgkin and non-Hodgkin lymphomas. The direct consequences of variant A infection and latency in CD4+ cells are not known. It transactivates HIV infection in vitro and in humans, and facilitates tumor progression induced by human papilloma viruses. Pathogenic effects of both variants are mediated by altered cytokine and chemokine profiles. Serological differentiation of the two variants is unreliable; however, it is possible by using PCR. Ganciclovir, foscarnet and cidofovir can be used for treatment and chemoprophylaxis of severe complications.

[Studies on the novel association of human herpesvirus-7 with skin diseases]. / Az emberi 7-es herpesvírus újabb szerepének vizsgálata bórbetegségekben.

INTRODUCTION AND AIM: Human herpesvirus 7 in pityriasis rosea, this and other viruses in papular-purpuric gloves-and-socks syndrome have been implicated, but their primary or recurrent infections are still in question. PATIENT AND METHODS: In one available blood sample, therefore, IgM, IgG and its high avidity fraction characteristic for recurrent infections were quantitated by indirect immunofluorescence. Peripheral lymphocytes were subjected to nested polymerase chain reaction to detect viral DNA, or cocultivated with several cell cultures. RESULTS: One third of 33 pityriasis rosea patients had elevated IgM, another third had elevated IgG without high avidity molecules to human herpesvirus 7 suggesting primary infection. Thirty percent of controls, more than half of the patients had virtual DNA in their lymphocytes, but only one in 5 skin biopsy specimens were PCR positive. All three co-cultivation attempts yielded viruses extremely rapidly, verified by electron microscopy, polymerase chain reaction and monoclonal antibodies as human herpesvirus 7. These are the first isolates in the geographical regions of Hungary. These data suggest that pityriasis rosea is the consequence of a primary human herpesvirus 7 infection in seronegative adults, and only occasionally is due to virus reactivation. One patient with gloves-and-socks syndrome had an acute, another patient had a persistent coinfection with human herpesvirus 7 and parvovirus B19, two others had a primary herpesvirus 7 infection. Interestingly, this disease might be elicited by both viruses individually or in synergism. CONCLUSION: Neither human herpesvirus 7 nor parvovirus B19 infect skin cells, but both can be detected in the infiltrating lymphocytes of skin eruptions, in which they induce an altered mediator production, that might be responsible for the general and local symptoms.

[Microbial warfare and bioterrorism]. / Mikrobiológiai hadviselés és terrorizmus.

Infectious diseases have been used as warfares since ancient times. Since the 1920s military organizations have studied bacteria of anthrax, plague, tularemia, botulism, brucelloses, glander, Q-fever, and smallpox virus, Filo-, Arena-, Bunyaviruses causing hemorrhagic fever or Alphaviruses eliciting encephalitis. These can be dispersed by aerosol. Salmonellae, Shigellae, Vibrio cholerae, distinguished Escherichia coli strains are suitable to contaminate food, water, pharmaceutical products. Fanatical groups or terrorist individuals deploy microbe weapons. In the future, genetically engineered recombinant microbes could be used with genomes containing multiple resistance elements to antimicrobial compounds and additional virulence factors. These become resistant to all known treatment regimens, vaccination and the host immune response. Microbial terrorist attacks result in an outbrake on a restricted area with large number of casualties. The disease course is severe and unusual followed by high mortality. Identification of microbes is complicated and delayed. Most countries have neither laboratories at high biosafety level nor specially trained personnel. Physicians might misdiagnose these diseases. Health care systems with minimal elasticity face difficulties in maintaining mass quarantine. A considerable part of health care workers leave hospitals. No plan is available to stockpile medicines. Robust surveillance and laboratory systems coordinated at international level must be established. All health care personnel should be trained periodically to gain practical skills. Additional standards governing working conditions with selected microbes will be enforced by law. Related scientific data might be published with restricted access only.