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Infections
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Fusion inhibitors prevent HIV from entering target cells, by binding to the HIV envelope protein gp41, which is involved in viral entry. By blocking the interactions between regions of the gp41 molecule, fusion inhibitors interfere with the conformational change (folding) of the envelope molecule required for fusion with the target cell membrane.
Non-traumatic neurological conditions in medico-legal work
Published in Helen Whitwell, Christopher Milroy, Daniel du Plessis, Forensic Neuropathology, 2021
HIV infection is widespread throughout the world and remains a major clinical problem. In forensic practice, it is important to remember that a proportion of the intravenous drug abuser (IVDA) population are HIV positive. HIV infection results in the progressive depletion of CD4 T lymphocytes and subsequent immunosuppression causing acquired immune deficiency syndrome (AIDS). Neuropathology is seen in 70–90 per cent of AIDS cases, although much of this is caused by opportunistic infections (Morgello 2018). HIV itself can cause nervous system pathology, with neuropathology directly attributable to HIV being seen in 20–30 per cent of cases (Navia et al. 1986). HIV encephalopathy (HIVE) is a white matter disease characterised by multinucleated giant cells. HIVE has been shown to be more prevalent in IVDAs than in homosexuals. The HIV-related protein gp41 can be demonstrated immunohistochemically in relation to many multinucleated giant cells. Macroscopically, the HIVE brain often appears normal; microscopically, there are foci of perivascular lymphocytes and microglial nodules often lying adjacent to multinucleated giant cells. Vacuolar myelopathy is seen in AIDS patients and resembles subacute combined degeneration of the cord. The degeneration develops in the posterior and lateral columns of the spinal cord, and there is axonal degeneration. In AIDS patients, the disorder is not associated with vitamin B12 deficiency.
Antiviral Agents and Rational Drug Design
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
HIV is an RNA virus containing two identical (+)-ssRNA strands in the capsid, along with viral enzymes. The capsid is enclosed by a layer of matrix protein. This virus particle is enveloped by a membrane originating from that of the host cell and contains the viral glycoproteins gp120 and gp41, which are crucial for adsorption and penetration. The gp41 spans the membrane and is bound non-covalently to gp120, which projects from the surface. When the virus approaches the host T cell, the gp120 interacts and binds with a transmembrane protein called CD4 on the surface of the T cell. Conformational change of gp120 unveils gp41 which can now bind to the T cell, and anchors the virus to its host, then conformational change of gp41 pulls the virus towards the T cell so that their membranes can fuse and allow penetration of the HIV capsid.
Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2
Published in Expert Review of Anti-infective Therapy, 2021
Masoumeh Sadat Mousavi Maleki, Mosayeb Rostamian, Hamid Madanchi
The entry of HIV-1 virus is remarkably similar to the entry of SARS-CoV2 virus into their target cells [89,90]. HIV-1 virus enters the host cell with two glycoprotein subunits on its surface, namely the gp120 subunit (equivalent to S1 of SARS-CoV-2) which is responsible for binding to the receptor, and the gp41 subunit (equivalent to S2 of SARS-CoV-2) which is responsible for fusion to the host cell membrane. Refolding of the N-terminal heptad repeat (NHR) and the C-terminal heptad repeat (CHR) of the gp41 subunit in the form of a 6 helixes bundle (6-HB), brings the virus and the cell membranes closer together, leading to a fusion reaction. NHR and CHR sequence-derived antiviral peptides, such as the FDA-approved drug T20 or Enfuvirtide, can competitively inhibit the formation of viral 6-HB, thereby inhibiting the fusion of the virus to the host cell membranes and ultimately inhibiting the virus entry [22,91]. Because HIV-1 gp41 protein is structurally and functionally similar to SARS-CoV2 protein S2, the question is whether Enfuvirtide can inhibit SARS-CoV2 entry into the cell as well. In an in silico study using molecular docking and molecular dynamic (MD), Calligari et al. suggest Enfuvirtide as a SARS-Cov2 inhibitor [92]. More researches on this FDA-approved drug and conducting clinical trials in this area could help develop drug discovery and treatment for COVID-19.
Fostemsavir for the treatment of HIV
Published in Expert Review of Anti-infective Therapy, 2021
Nikhil Seval, Cynthia Frank, Michael Kozal
The entry inhibitors are a broad categorization of antiretroviral agents that are often used in drug regimens when the first-line drug classes are limited. Maraviroc, a CCR5 chemokine receptor antagonist, is limited in its indication to those with R5 tropic virus and can be complicated by both hepatotoxicity and drug–drug interactions. Enfuvirtide binds to the gp41 subunit of the HIV viral envelope protein thus preventing fusion and entry into CD4 cells – it is subcutaneous injection whose a twice-a-day administration is often found to be too cumbersome by patients. Ibalizumab is a recombinant monoclonal antibody that was FDA approved in 2018 and functions as a ‘post-attachment’ inhibitor by binding to domain 2 of CD4 cells. It requires an infusion every 2 weeks that may not be feasible for all patients. Fostemsavir represents the addition of a new drug class to the market in an oral formulation with a favorable tolerability profile.
Broad-Spectrum Antiviral Agents: A Crucial Pandemic Tool
Published in Expert Review of Anti-infective Therapy, 2019
Similarly, anti-HIV medications – of which there are now several classes – are primarily targeted at HIV-1 with antiretroviral drug classes such as non-nucleoside reverse transcriptase inhibitors (NNRTIs), certain protease inhibitors, and the gp41 fusion inhibitor enfuvirtide lacking efficacy even against HIV-2 [4]. It should be noted, however that nucleo(t)side reverse transcriptase inhibitors such as lamivudine, emtricitabine, and tenofovir do have activity outside of HIV as they are competitive substrate inhibitors for DNA synthesis and are also able to inhibit the reverse transcriptase enzyme encoded by the hepatitis B virus (HBV) [5], likely due to a shared evolutionary origin between HBV and retroviruses [6].