COVID-19: A case for plasma derived natural anticoagulants?

Convalescent plasma was proposed for passive immunization against COVID-19; but so far there are conflicting results and still open questions. However, besides antibodies, other plasma proteins may be good candidates for further research and application. Thromboinflammation frequently complicates severe COVID-19, and classical anticoagulants like heparins seem to have limited effect. The natural protease inhibitors antithrombin III (ATIII), α1-antitrypsin (α1-AT) and α2-macroglobulin (α2-M), which are found decreased in severe COVD-19, play a crucial role in prothrombotic and inflammatory pathways. While ATIII and α1-AT are licensed as commercially prepared therapeutic concentrates, there is no preparation of α2-M available. The diagnostic, prognostic, and even therapeutic potential of plasma protease inhibitors should be further explored.

HIV transmission by human bite: a case report and review of the literature-implications for post-exposure prophylaxis.

We report a case of a probable HIV-1 transmission by human bite. The analyzed data from ten previously reported  suspected or allegedly confirmed HIV transmissions revealed a deep bleeding bite wound as the primary risk factor. A high HIV plasma viral load and bleeding oral lesions are present most of the time during HIV transmission by bite. HIV post-exposure prophylaxis (PEP) should be recommended in case of a bleeding wound resulting from a bite of an HIV-infected person. PEP was missed in this presented case.

Cytokines and chemokines involved in the defense reaction against HIV-1 and hepatitis B virus: isn't it time to use a standardized nomenclature of the involved mediators?

Discovery of new mediators of immune cell activation and interaction facilitated elucidation of the various ways of defense against infectious agents and happened some 40 years ago. Each involved group of researchers named the mediators according to their scope of investigation; often the same molecules were published at the same time with different names. To avoid confusion resulting from using different names for the same mediators and to prevent a Babylonian confusion, standardization was implemented-as in the field of metrics, music, or science including virology. For cytokines and chemokines a standard nomenclature was proposed some 10 years ago and in conclusion it should be used. In this paper the most relevant biomarkers in HIV-1 and HBV infection and their contribution during viral pathogenesis are listed.

Human immunodeficiency virus 1 dual-target nucleic acid technology improves blood safety: 5 years of experience of the German Red Cross blood donor service Baden-Württemberg-Hessen.

BACKGROUND: RNA viruses are associated with a high frequency of mutations because of the missing proofreading function of polymerases, such as reverse transcriptase. Between 2007 and 2010, six blood donations with false-negative nucleic acid technology (NAT) results were reported in Germany. Therefore, NAT screening in two viral genome regions was introduced by our blood donation service in 2010 on a voluntary basis and became mandatory in Germany since the beginning of 2015. STUDY DESIGN AND METHODS: Blood donor screening was done using, in parallel, the German Red Cross (GRC) HIV-1 CE long terminate repeats (LTR) PCR kit and the GRC HIV-1 gag CE PCR kit. In total, 7 million blood donations were screened during the study period from 2010 to 2014 with the GRC dual-target human immunodeficiency virus 1 (HIV-1) NAT system. Additionally, three suspicious specimens were analyzed by four monotargeted NAT assays and by five dual-target NAT assays. RESULTS: Three of 7 million donations tested negative using the 5'LTR-polymerase chain reaction, but they were positive if amplification was performed in the gag region. HIV antibodies were detected in all three donations. Nucleic acid sequence analysis identified a deletion of 22 bases within the 5'LTR probe binding region. Three different ltr-based monotargeted assays missed two donations, except for a low-reactive result obtained by one of the assays. In total, the detection rates for HIV-1-positive donations were 37.5% (3/8) for monotargeted assays and 100% (10/10) for dual-target assays. CONCLUSION: The current data demonstrate that dual-target NAT systems reduce the risk of false-negative HIV-1 NAT screening results.

Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients?

Patients with blood disorders (including leukaemia, platelet function disorders and coagulation factor deficiencies) or acute bleeding receive blood-derived products, such as red blood cells, platelet concentrates and plasma-derived products. Although the risk of pathogen contamination of blood products has fallen considerably over the past three decades, contamination is still a topic of concern. In order to counsel patients and obtain informed consent before transfusion, physicians are required to keep up to date with current knowledge on residual risk of pathogen transmission and methods of pathogen removal/inactivation. Here, we describe pathogens relevant to transfusion of blood products and discuss contemporary pathogen removal/inactivation procedures, as well as the potential risks associated with these products: the risk of contamination by infectious agents varies according to blood product/region, and there is a fine line between adequate inactivation and functional impairment of the product. The cost implications of implementing pathogen inactivation technology are also considered.

Aspects on the history of transmission and favor of distribution of viruses by iatrogenic action: perhaps an example of a paradigm of the worldwide spread of HIV.

Transmission of infectious agents might be associated with iatrogenic actions of charitable help in health care. An example is the vaccination against yellow fever in USA that transmitted hepatitis B virus. Another example is injections of praziquantel for treatment and cure of schistosomiasis in Central and Northern Africa, with a focus in Egypt that has spread hepatitis C virus. There is no indication that human T-lymphotropic virus type 1 was spread by injection treatment for African trypanosomiasis, syphilis and treponematosis, but these treatments might have contributed to the early spread of human immunodeficiency virus type 1 (HIV-1) in Central Africa. Slave trade contributed as well to the spread of viruses from Africa to the Americas; it was stopped in 1850. Until that date HIV-1 was not transported to the Americas. By analysis of nucleic acid sequence data it can be concluded that the continental spread of HCV and HIV-1 might have started around 1920 with an exponential phase from 1940 to 1970. Further iatrogenic actions that promoted the spread of HCV and HIV-1 might be vaccinations to prevent deadly diseases. The successful vaccination was followed by diminution of the infectious agent in the population such as small pox, yellow fever and measles. Measurements to reduce the spread of plague and cholera were further benefits increasing survival of diseased subjects in a population. Thus, the reduction of exposure to deadly infectious agents might have given a chance to HIV-1 infected subjects to survive and for HIV-1 to be distributed around the world starting from Central Africa in the 1950s.

Effect of antiretroviral HIV therapy on hepatitis B virus replication and pathogenicity.

Coinfections with hepatitis B virus (HBV) and HIV are very frequent. Although HBV is a DNA virus, it replicates via reverse transcription like HIV. Structural similarities between the enzymatic pocket of the HBV DNA polymerase and HIV-1 reverse transcriptase are the basis that certain drugs inhibit both enzymes and thus the replication of both viruses. HBV components increase the pathogenic action of HIV and vice versa directly by certain proteins like HBsAg in the case of HBV and HIV-encoded Tat and Vpr and by disturbing the cytokine balance in affected cells. Antiretroviral therapy is highly beneficial for HIV/HBV-coinfected patients, but carries the risk of drug-induced resistance development and hepatotoxicity. Even with restoration of the immune capacity, signs of hepatic inflammation may develop even after 10 years of treatment.

HIV-2EU: supporting standardized HIV-2 drug resistance interpretation in Europe.

Considering human immunodeficiency virus type 2 (HIV-2) phenotypic data and experience from HIV type 1 and from the follow-up of HIV-2-infected patients, a panel of European experts voted on a rule set for interpretation of mutations in HIV-2 protease, reverse transcriptase, and integrase and an automated tool for HIV-2 drug resistance analyses freely available on the Internet (http://www.hiv-grade.de).

Confirmation of putative HIV-1 group P in Cameroon.

We report the second human immunodeficiency virus (HIV) belonging to the new HIV type 1 (HIV-1) group P lineage that is closely related to the simian immunodeficiency virus found in gorillas. This virus was identified in an HIV-seropositive male hospital patient in Cameroon, confirming that the group P virus is circulating in humans. Results from screening 1,736 HIV-seropositive specimens collected in Cameroon indicate that HIV-1 group P infections are rare, accounting for only 0.06% of HIV infections. Despite its rarity, group P shows evidence of adaptation to humans.

HIV types, groups, subtypes and recombinant forms: errors in replication, selection pressure and quasispecies.

HIV-1 is a chimpanzee virus which was transmitted to humans by several zoonotic events resulting in infection with HIV-1 groups M-P, and in parallel transmission events from sooty mangabey monkey viruses leading to infections with HIV-2 groups A-H. Both viruses have circulated in the human population for about 80 years. In the infected patient, HIV mutates, and by elimination of some of the viruses by the action of the immune system individual quasispecies are formed. Along with the selection of the fittest viruses, mutation and recombination after superinfection with HIV from different groups or subtypes have resulted in the diversity of their patterns of geographic distribution. Despite the high variability observed, some essential parts of the HIV genome are highly conserved. Viral diversity is further facilitated in some parts of the HIV genome by drug selection pressure and may also be enhanced by different genetic factors, including HLA in patients from different regions of the world. Viral and human genetic factors influence pathogenesis. Viral genetic factors are proteins such as Tat, Vif and Rev. Human genetic factors associated with a better clinical outcome are proteins such as APOBEC, langerin, tetherin and chemokine receptor 5 (CCR5) and HLA B27, B57, DRB1*1303, KIR and PARD3B.

The evolution of drug resistance interpretation algorithms: ANRS, REGA and extension of resistance analysis to HIV-1 group O and HIV-2.

Antiretroviral drug resistance is mostly linked to a complex interaction of several amino acids with variable importance or a single amino acid. To facilitate the interpretation of observed mutation patterns, hospital university centers have developed several interpretation systems. All the currently available interpretation algorithms evolved, are being continuously updated and have been improved during the last decade. Some discrepancies are still evident that are partially smoothened by link of the individual programs with other systems. After the interpretation of HIV-1 group M subtype B mutations, a refined algorithm for the other group M subtypes was developed followed by the interpretation of HIV-1 group O and HIV-2 mutations. The process of improvement is ongoing, due to the better understanding and interpretation of single and cluster mutations and the availability of new antiretroviral substances. The knowledge gained from the experience of HIV drug resistance testing has been used to establish the interpretation of HBV polymerase mutations and will be extended for the treatment of HCV infected with protease inhibitors.

Comparison of drug resistance scores for tipranavir in protease inhibitor-naive patients infected with HIV-1 B and non-B subtypes.

Genotypes of samples from protease inhibitor-naïve patients in Frankfurt's HIV Cohort were analyzed with five tipranavir resistance prediction algorithms. Mean scores were higher in non-B than in B subtypes. The proportion of non-B subtypes increased with increasing scores, except in weighted algorithms. Virtual and in vitro phenotype analyses of samples with increased scores showed no reduced tipranavir susceptibility. Current algorithms appear suboptimal for interpretation of resistance to tipranavir in non-B subtypes; increased scores might reflect algorithm bias rather than "natural resistance."

[SARS-CoV-2 vaccines and reaction of the immune system. Can the epidemic spread of the virus be prevented by vaccination?] / SARS-CoV-2-Impfstoffe und Reaktion des Immunsystems. Kann die epidemische Ausbreitung des Virus durch Impfung verhindert werden?

Since the end of 2019 a new coronavirus, SARS-CoV-2, first identified in Wuhan, China, is spreading around the world partially associated with a high death toll. Besides hygienic measurements to reduce the spread of the virus vaccines have been confected, partially based on the experiences with Ebola virus vaccine, based on recombinant human or chimpanzee adenovirus carrying the spike protein and its ACE2 receptor binding domain (RBD). Further vaccines are constructed by spike protein coding mRNA incorporated in lipid nano vesicles that after entry in human cells produce spike protein. Both vaccine types induce a strong immune response that lasts for months possibly for T-cell immunity a few years. Due to mutations in the coronavirus genome in several parts of the world variants selected, that were partially more pathogenic and partially easier transmissible - variants of concern (VOC). Until now vaccinees are protected against the VOC, even when protection might be reduced compared to the Wuhan wild virus.An open field is still how long the vaccine induced immunity will be sufficient to prevent infection and/or disease; and how long the time period will last until revaccination will be required for life saving protection, whether a third vaccination is needed, and whether revaccination with an adenovirus-based vaccine will be tolerated.

Thromboinflammation in COVID-19: Can α2 -macroglobulin help to control the fire?

The complex COVID-19-associated coagulopathy appears to impair prognosis. Recently, we presented the hypothesis that children are to some extent protected by higher α2 -macroglobulin (α2 -M) levels from severe COVID-19. In addition to endothelial cells, thrombin, and platelets, neutrophil granulocytes also appear to play an important role. Neutrophils extrude extracellular nets, which are histone- and protease-coated web-like DNA structures; activate coagulation and platelets; and release radicals and proteases such as elastase. The unique phylogenetically ancient and "versatile" inhibitor α2 -M contributes particularly during childhood to the antithrombin activity of plasma, binds a broad spectrum of proteases, and interacts with other mediators of inflammation such as cytokines. It is suggested that the scope of basic research and clinical studies would include the potential role of α2 -M in COVID-19.

Prevalence- and gender-specific immune response to opportunistic infections in HIV-infected patients in Lesotho.

BACKGROUND: The objective of this study was to assess the seroprevalence of coinfecting viruses and Treponema pallidum (T. pallidum) in a cohort of 205 antiretrovirally treated HIV-infected individuals (152 females and 53 males, aged: 19-71 years) in rural Lesotho. Furthermore agent-specific immune responses were investigated by analyzing antibody titers against herpes simplex virus type 2 (HSV-2) and against T. pallidum. METHODS: Serum samples were tested by enzyme-linked immunosorbent assay for antibodies against HSV-2, cytomegalovirus, hepatitis A, B, and C viruses, and T. pallidum. RESULTS: Seroprevalences (95% confidence intervals) were found to be 100% (98.5%-100%) for anti-cytomegalovirus, 98.5% (95.7%-99.7%) for anti-hepatitis A virus, 35.5% (28.9%-42.6%) for anti-HBc, 5.5% (2.8%-9.6%) for hepatitis B surface antigen, and 0.5% (0.0%-2.8%) for anti-hepatitis C virus. Only 78.5% (72.2%-84.0%) were anti-HSV-2 positive and 29.0% (22.8%-35.8%) had antibodies against T. pallidum. Only anti-HSV-2 titers showed gender- and CD4 cell-count dependent differences: females with >500 CD4 cells/microL had an average anti-HSV-2 titer of 446 compared with males of 398 AU/mL (not significant), but in those with 250 to 500 CD4 cells/microL, there was a significant difference with a mean titer of 467 compared to 302 AU/mL in males (P = 0.001). CONCLUSIONS: A high seroprevalence of CMV, HAV, and HBV was found in both genders. One-third of the patients had been exposed to HBV and T. pallidum. The generally high HSV-2 prevalence showed gender- and CD4 cell count-dependent differences in HSV-2 antibody titer.

Regional spread of HIV-1 M subtype B in middle-aged patients by random env-C2V4 region sequencing.

A transmission cluster of HIV-1 M:B was identified in 11 patients with a median age of 52 (range 26-65) in North-East Germany by C2V4 region sequencing of the env gene of HIV-1, who-except of one-were not aware of any risky behaviour. The 10 male and 1 female patients deteriorated immunologically, according to their information made available, within 4 years after a putative HIV acquisition. Nucleic acid sequence analysis showed a R5 virus in all patients and in 7 of 11 a crown motif of the V3 loop, GPGSALFTT, which is found rarely. Analysis of formation of this cluster showed that there is still a huge discrepancy between awareness and behaviour regarding HIV transmission in middle-aged patients, and that a local outbreak can be detected by nucleic acid analysis of the hypervariable env region.