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SARS-Cov-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

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SARS-Cov-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise microorganisms Review SARS-CoV-2 Portrayed against HIV: Contrary Viral Strategies in Similar Disguise Ralf Duerr *, Keaton M. Crosse, Ana M. Valero-Jimenez and Meike Dittmann Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; [email protected] (K.M.C.); [email protected] (A.M.V.-J.); [email protected] (M.D.) * Correspondence: [email protected] Abstract: SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale, causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped viruses with positive-stranded RNA and envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses’ structural and functional characteristics, delineating their distinct strategies for efficient spread. Keywords: SARS-CoV-2; HIV; zoonotic viruses; COVID-19 and AIDS pandemics; viral entry Citation: Duerr, R.; Crosse, K.M.; Valero-Jimenez, A.M.; Dittmann, M. 1. Introduction SARS-CoV-2 Portrayed against HIV: SARS-CoV-2 and HIV each rapidly became and continue to be considerable global Contrary Viral Strategies in Similar health concerns. Unparalleled scientific efforts enabled characterization of these viruses Disguise. Microorganisms 2021, 9, 1389. and their resulting diseases in record time, which has led to rapid development of public https://doi.org/10.3390/ health measures and antiviral strategies. Both viruses have elementary similarities, being microorganisms9071389 enveloped viruses with a positive (+) single-stranded (ss) RNA genome. Consequently, preventive and therapeutic approaches that were studied or established for HIV have been Academic Editors: Ruth tested against SARS-CoV-2 including vaccination strategies, reverse vaccinology, mono- Serra-Moreno and Andrés Finzi clonal antibodies (mAbs), and investigational or approved anti-HIV drugs [1–3]. While more data keep unfolding, we know that despite overall similarities, both viruses have key Received: 6 April 2021 differences spanning structural and functional characteristics, cellular tropism, induced im- Accepted: 7 June 2021 mune responses, clinical outcome, and responsiveness to vaccines and treatments (Table1 ). Published: 27 June 2021 For SARS-CoV-2, emergency use authorizations of vaccines have been achieved to prevent severe coronavirus disease COVID-19; however, treatment options remain scarce. For Publisher’s Note: MDPI stays neutral HIV, more than 45 antiretroviral drugs are available to manage chronic disease and delay with regard to jurisdictional claims in published maps and institutional affil- AIDS; however, we still lack an efficient vaccine. This review illustrates the fundamen- iations. tal similarities and differences of SARS-CoV-2 and HIV to further our understanding of their biological and clinical characteristics and thus support the development of antiviral strategies against current and future viral outbreaks. Since HIV-1 is responsible for >95% of global HIV infections and HIV-2 has remained largely restricted to Western Africa [4], this review focuses on HIV-1. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Microorganisms 2021, 9, 1389. https://doi.org/10.3390/microorganisms9071389 https://www.mdpi.com/journal/microorganisms Microorganisms 2021, 9, 1389 2 of 61 Table 1. Comparison of key features between SARS-CoV-2 and HIV-1 and their associated diseases. HIV-1 SARS-CoV-2 Refs Demographic features West-Central Africa (Cameroon, DR geographic origin China (Wuhan) [5,6] Congo) first recorded case HIV-1: 1959 (DR Congo) SARS-CoV-2: Nov. 17, 2019 (China) [7–10] AIDS: 1981 (USA) COVID-19: Dec. 31, 2019 (China) est. time of origin/cross-species 1920s October/November 2019 [7,11–13] transmission primary host: bats, intermediate animal source non-human primates hosts: small mammals; yet [5,14–16] unconfirmed active cases 38 Mio a 12 Mio b [17,18] 76 Mio a (1.7 Mio new infections in cases since pandemic start 179 Mio b [17,18] 2019) deaths since pandemic start 33 Mio a (0.7 Mio in 2019) 3.9 Mio b [17–19] Viral features Baltimore virus classification Group VI Group IV [20,21] virus family Retroviridae Coronaviridae virus diameter 100–150 nm 60–140 nm [6,22,23] number of spikes per virus 7–14 15–40 [23–25] spike size (height × width) 12 × 15 nm 20 × 13 nm [26–29] spike amino acids 856 1273 [30,31] potential N-glyco sites per spike 31 (HxB2) 22 (Wuhan-Hu-1) [30,31] monomer spike proteolytic cleavage sites 1 2 [32,33] Conical (many hexagons and 12 capsid helical [34–36] pentagons of subunits) (+)ssRNA, diploid genome (+)ssRNA, haploid [37,38] dsDNA genome intermediate 9.7 kb (one of the smallest viral 29.7 kb (one of the largest viral genome size [30,31] genomes) genomes) proviral DNA: 4 × 10−3 per base per 1 × 10−3 per base per year (2 evolution rate cell (1 mutation every 250 base pairs) mutations per month) [12,39,40] virus in plasma: 2–17 × 10−3 per base per year within-host diversity (in the <5% (<10% for proviral env) <0.05% [41–43] absence of superinfection) replication cycle ~24 h (in vitro)–60 h (in vivo) ~7–36 h [44–48] Entry and host responses ACE2+ mucosal and endothelial primary target cells CD4+ T cells, Macrophages [49,50] cells primary entry receptors/proteins CD4, CCR5/CXCR4 ACE2, TMPRSS2 [51–53] Microorganisms 2021, 9, 1389 3 of 61 Table 1. Cont. HIV-1 SARS-CoV-2 Refs Ab binding and neutralization response Ab binding and neutralization develops in first month response develops in 1–2 weeks nAb development associated with nAb development associated with viremia and severity viremia and severity bnAb development usually requires 2–3 years of productive infection nAbs develop within weeks of antibody response (observed in ~10% of HIV-1-infected infection [54–57] individuals) Potent nAbs do not require high rates of somatic hypermutation bnAbs require high rates of somatic (SHM), but SHM fosters breadth, hypermutation potency, and resilience to viral escape impaired B cell, T cell and impaired B cell, T cell and cellular response [58–63] macrophage/monocyte responses macrophage/monocyte responses delayed and enhanced delayed and enhanced anti-inflammatory response, cytokine response anti-inflammatory response, impaired [64–70] impaired IFN response in severe IFN response in progressive cases cases Disease features, treatment, and vaccines AIDS COVID-19 (1) respiratory infection (fever, (1) initially mild, common cold-like cough, sore throat, fatigue, loss of symptoms clinical symptoms smell) (2) acquired immune deficiency and (2) systemic dissemination opportunistic infections and throughout the body (blood vessels, malignancies nervous system, inner organs) chronic (HIV-1 integrates as provirus [6,49,71–77] type of infection acute into host genome) 1–2 months (mild) duration of infection life-long 2–9 months (severe) and possible chronic complications lymphatic system of gut and primary site of infection respiratory system reproductive system primary mode of infection sexual transmission droplet infection of airways >45 FDA-approved drugs, strong (emergency use) authorization of a viral-suppressive effect but no cure few drugs, limited clinical benefit treatment [70,78–80] drugs mainly target the polymerase (dexamethasone, remdesivir, nAb region (reverse transcriptase, protease, cocktails) and integrase) (emergency use) authorization of a no vaccine few vaccines, up to 95% vaccine vaccine efficacy [81–85] 7 vaccine efficacy trials completed, best >200 vaccine trials ongoing or efficacy: 31% (RV144, 2009) completed animal models: neutralizing antibodies; human vaccine trial (RV144): ADCC, neutralizing antibodies, supported correlates of protection low plasma anti-Env IgA/IgG, [81,86,87] by cellular responses poly-functional B cell responses, non-neutralizing V2 antibodies a End of 2019; b June 2021. Microorganisms 2021, 9, 1389 4 of 61 2. Methods Structural analyses were performed using UCSF Chimera v.1.15rc [88] based on pdb files downloaded from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). Protein structures were generated using pdb files 3j5m or 6wpu (prefusion “closed” HIV-1 Env), S.pdb [89] (prefusion “closed” SARS-CoV-2 spike trimer), 4l1a (HIV-1 protease in complex with lopinavir), 6wnp (SARS-CoV-2 main protease in complex with Boceprevir), 3v4i/3v81 (HIV-1 reverse transcriptase [RT] in complex with DNA, azathioprine-triphosphate [3v4i; red], and nevirapine [3v81; purple], the latter superimposed after structural overlay of 3v4i and 3v81 RT structures), and 7bv2 (SARS- CoV-2 polymerase RdRp [NSP12] in complex with NSP7, NSP8, template-primer RNA, and Remdesivir triphosphate). Complex entry models were created using structural overlays using MatchMaker in Chimera of pdb structures 6vyb, 6m17, and S_ACE2 [89] (SARS- CoV-2), or 6met and 5vn3 (HIV-1). Models of fusion intermediates were created based on pdb files 6m3w (SARS-CoV-2) and 2zfc (HIV-1). In silico glycosylation of proteins was performed using GlyProt [90], and the composition of oligomannose, hybrid, and complex N-glycans matched with reference literature [91,92]. Viral life cycle schematics were created with BioRender including trimer structures of prefusion “closed” HIV-1 Env (pdb 3j5m) and SARS-CoV-2 spike (pdb 6vxx) as well as activated, “partially open” HIV-1 Env (pdb 5vn3) and SARS-CoV-2 spike (pdb 6vyb). Viral sequences were downloaded from the Global initiative on sharing all influenza data (GISAID)-EpiCoV and the Los Alamos National Laboratory (LANL) HIV Databases [30,93]. For better comparability, phylogenetics and genetic diversity analyses were performed using HIV-1 and SARS-CoV-2 sequences from one entire year, respectively.
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