key: cord-259925-g28sx9qu
authors: Saleemi, Mansab Ali; Ahmad, Bilal; Benchoula, Khaled; Vohra, Muhammad Sufyan; Mea, Hing Jian; Chong, Pei Pei; Palanisamy, Navindra Kumari; Wong, Eng Hwa
title: Emergence and molecular mechanisms of SARS-CoV-2 and HIV to target host cells and potential therapeutics
date: 2020-10-06
journal: Infect Genet Evol
DOI: 10.1016/j.meegid.2020.104583
sha: 
doc_id: 259925
cord_uid: g28sx9qu

The emergence of a new coronavirus, in around late December 2019 which had first been reported in Wuhan, China has now developed into a massive threat to global public health. The World Health Organization (WHO) has named the disease caused by the virus as COVID-19 and the virus which is the culprit was renamed from the initial novel respiratory 2019 coronavirus to SARS-CoV-2. The person-to-person transmission of this virus is ongoing despite drastic public health mitigation measures such as social distancing and movement restrictions implemented in most countries. Understanding the source of such an infectious pathogen is crucial to develop a means of avoiding transmission and further to develop therapeutic drugs and vaccines. To identify the etiological source of a novel human pathogen is a dynamic process that needs comprehensive and extensive scientific validations, such as observed in the Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and human immunodeficiency virus (HIV) cases. In this context, this review is devoted to understanding the taxonomic characteristics of SARS-CoV-2 and HIV. Herein, we discuss the emergence and molecular mechanisms of both viral infections. Nevertheless, no vaccine or therapeutic drug is yet to be approved for the treatment of SARS-CoV-2, although it is highly likely that new effective medications that target the virus specifically will take years to establish. Therefore, this review reflects the latest repurpose of existing antiviral therapeutic drug choices available to combat SARS-CoV-2.

Coronaviruses (CoVs) are a group of enveloped and positive single-stranded RNA genome viruses that infect both animals and humans (Smith and Denison, 2013; Xu et al., 2020) . They contain the largest known RNA genomes ranging from 27-32 kilobases in length (Smith and Denison, 2013) .

Coronavirus-related infections are known to affect the liver, central nervous system (CNS), respiratory and gastrointestinal tract of various birds and mammals, including humans (Xu et al., 2020) . They are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus,

and Deltacoronavirus (Fung et al., 2020) . The novel 2019 coronavirus (2019-nCoV) also belongs to the same group of CoVs. It was named ‗severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV) (Fung et al., 2020) . The transmission pattern of SARS-CoV-2 primarily involves direct close contact with the infected person via nose and mouth secretions, however it can also be transmitted indirectly through contaminated objects or surfaces (World Health Organization). It was discovered in late December 2019 in Wuhan city of China in patients with acute respiratory distress syndrome (ARDS) symptoms, such as fever, cough, and dyspnea (Li et al., 2020; after isolated from the respiratory epithelium (Xu et al., 2020) . The genome sequence analysis of SARS-CoV-2 showed that it belongs to the Betacoronavirus genus (β-CoV) . The SARS-CoV-2-related disease was recently named as a novel respiratory 2019 coronavirus disease by the World Health Organization (WHO) (Xu et al., 2020) . Up to date, it is unclear how SARS-CoV-2 interacts with the host antiviral immunity, hence lessons can be learned from previous studies of other members of the coronavirus family and also human pathogenic viruses, such as human immunodeficiency viruses and severe acute respiratory syndrome (SARS) CoV known as human CoVs (HCoVs) due to their ability to cause human infections (Andersen et al., 2020) . Aside from NL63 and 229E; which belong to Alphacoronavirus and the remaining five viruses come under the Betacoronavirus genus.

However, SARS-CoV, MERS-CoV, and SARS-CoV-2 are known to cause severe disease leading to death, whereas 229E, OC43, NL63, and HKU1 have only been associated with mild symptoms in infected persons although they are recognized as a potentially zoonotic origins (Andersen et al., 2020; Corman et al., 2018) . All members of the Coronaviridae contain enveloped, positive-stranded spherical RNA virions with a length of 120-160 nm and are usually decorated with large visible petal-shaped surface projections known as ‗spikes' when viewed under an electron microscope (Singh et al., 2020) . In addition, members of the Coronaviridae share common characteristics, which are outlined in (Table 1) . Within the family, there is also another subfamily such as Torovirinae comprising two other genera Torovirus and Bafinivirus. They are different from Coronaviridae mainly due to their different tubular virion shape. The morphology of virion, such as Coronavirinae has been unraveled, as illustrated in (Fig. 1a) . Moreover, the classification of various genera within the subfamily is a little more complicated with high CoV recombination frequency, thus necessitating the development of precise criteria proposed over the years (Corman et al., 2018) . Currently, the primary means of establishing their phylogenetic relationship is through the genomic structure, as shown in (Fig. 2) . It is based on these differences that a particular host may be infected by specific genus of the virus, for instance, Alpha-and Beta-coronavirus infects only mammals and Gamma-and Delta-coronavirus infects primarily birds and some studies suggest the possibility of the latter genera infecting mammals as well (Cui et al., 2019; King et al., 2012; Woo et al., 2012) . The specific distinctions between four genera are closely associated with (1) the unique type of nsp1 known as a non-structural RNA-binding protein within their genome which may differ in size and sequence and

(2) the presence or absence of a commonly shared accessory gene (Sheikh et al., 2020) . Several examples of viruses within the genera with their unique accessory proteins and genome arrangements can be found in (Fig. 3) .

The complete SARS-CoV-2 genome sequencing data had begun to emerge as the real gravity of the situation started to loom over the medical personnels who first encountered this novel coronavirus back in December 2019. Their findings have since been published and provided us the information necessary to classify SARS-CoV-2 into its respective group under the Serbecovirus (β-B Group)

subgenus Chan et al., 2020) . The sequence is publicly available on GenBank with the accession number MN908947 possessing 30474 nucleotides with close relations to bat SARS-like J o u r n a l P r e -p r o o f Journal Pre-proof coronavirus (CoV) isolate bat SL-CoVZC45 (Genbank accession number MG772933) with 89.1% nucleotide identity similarities .

In contrast, the origins of HIV have been a subject of debate since its discovery back in 1980s with many theories floating about and evidences not sufficiently conclusive. What is known is that infected individuals were at risk of developing acquired immune deficiency syndrome (AIDS), which at that time resulted in opportunistic pathogens infecting the individual and due to a pronounced weakened immune system, the individual would succumb eventually to the infection. Current data suggest that over the past three decades, HIV has caused more than 35 million deaths worldwide with 35 million living with the virus (Pharr et al., 2017) . HIV is classified with other known immunodeficiency viruses, which belong to phylum Artveviricota, order Ortervirales, and family (Vemuri et al., 2020) . Besides, three other retroviruses, such as Human T-cell Lymphotropic Virus type 1, 2, 3 (HTLV 1, 2, 3) exist within the same subfamily but genus deltaretrovirus also affects the immune system in humans (Calattini et al., 2005) .

As mentioned earlier, HIV has been categorized into two types; HIV-1 and HIV-2, the former being known as a more pathogenic than the latter, making up the majority of AIDS cases around the globe, whereas HIV-2 mainly infects individuals in West Africa (Cloyd et al., 2000) . In general, the most plausible route of evolution can be established by genomic sequence of HIV, while its origin is yet to be understood. In 1986, the genomic analysis found that HIV-2 virus was morphologically similar but genetically different from type 1 and caused more serious AIDS disease in western Africa (Jaffar et al., 2004) . Another genomic study showed that HIV-2 is firmly associated with the simian immunodeficiency virus (SIV) isolated from macaque monkeys (Nakayama and Shioda, 2015) . Since then, the simian close relatives have been further expanded with more and more species of primates in Sub-Saharan Africa found to house similar viruses collectively named SIV with special suffixes denoting their species of origin. In general, SIV-derived host species have been found to be nonpathogenic, but can become pathogenic once they cross the species (Meyerson et al., 2018) ; resulting in the discovery of current pandemic HIV1 strain (group M or main) that is similar to SIV cpz in Chimpanzees (Pan troglodytes) after closer investigation. In addition, the natural host of viruses was identified in Cameroon (Hahn et al., 2000; Keele et al., 2006) .

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The morphological structure of HIV is usually spherical, enveloped with 80-100 nm in diameter, and 8 nm surface glycoprotein projections. The internal structure of the virus nucleocapsid, such as a rod or truncated cone-shaped has been shown in (Fig. 1b) . HIV viral genome follows the common pattern within the subfamily Orthoretrovirinae, which carries two copies with the arrangement order: 5'-gag-pro-pol-env-3', each at approximately 9.3 kb in size.

A schematic illustration of the HIV genome is shown in ( into viral envelope precursors with other accessory proteins. In general, the unique sequences of viruses give each genus of a specific viral family its distinguishing characteristics allow its classification into the respective genus, which is Lentivirus in case of HIV. In addition to the primary structural genes reported, members of the Lentivirus genus also have additional genes, for instance, accessory protein genes vif, vpr, vpu, nef, and regulatory protein genes tat and rev. Several additional activities have been ascribed to the resulting proteins transcribed by these genes (secondary activities) which suggest the multifunctional role they play but generally their primary activities are highly conserved (Faust et al., 2017) . A summary of these accessory proteins and their role has been shown in (Table 2) .

atypical pneumonia cases emerged from the zoonotic transmission and showed >95% homology with bat coronaviruses and >70% similarity with the previous SARS-CoV McIntosh, 2020) . Thus, Chinese Health Authorities identified the outbreak as a novel coronavirus (COVID-19) . Although environmental samples taken from the market tested positive, researchers considered the possibility of human-to-human transmission in other geographical areas after people returned from Wuhan celebrating the Chinese New Year (CNY) with their families (Wang et al., 2020; Chen et al., 2020) . In this context, one study showed a significant correlation between domestic train transportation and the number of cases imported to other provinces in China. Besides, non-stop passenger flights were also linked to the number of cases reported abroad, subsequently the cause of this pandemic (Rodríguez-Morales et al., 2020) . Evidence suggests that virus is transmitted by respiratory droplets, direct contact, and airborne transmission. While analysis of confirmed and suspected cases of COVID-19 suggested that novel virus could go beyond the respiratory tract (Peng et al., 2020) . More interestingly, the study also found that virus can enter the body through eye exposure (Li et al., 2020) .

Notably, several asymptomatic cases have emerged across the globe, arguably the cause of such widespread transmission (Bai et al., 2020) . Earlier this year, Italy declared a state of emergency after registering two cases from Wuhan tourists with suspected symptoms of coronavirus after they arrived in Rome (Giovanetti et al., 2020) . Similarly, the USA confirmed the first positive case of SARS-CoV-2 identified in a woman in her 60's, who had returned from China with good health in mid-January. Later, her husband was also tested positive and admitted to the hospital. Although he did not travel but was considered to be in close contact with his wife (Ghinai et al., 2020) . Similarly, a 50-

year-old female entered the UK from Hubei province without previous medical history and no regular medications. After arrival, she developed symptoms of malaise and fever, accompanied by a sore throat and dry cough within three days (Lillie et al., 2020) .

As some cases show delayed symptoms, the possibility of human-to-human transmission could occur during the asymptomatic incubation period (Li et al., 2020; Backer et al., 2020) . Until an appropriate diagnostic cure is found, researchers have alerted countries to maintain a distance of one meter from infected persons to reduce the risk of transmission (Mehraeen et al., 2020) . Subsequently, many countries have now introduced movement control orders and lockdowns as preventative measures to curb the spread of the virus (Hamzelou, 1981) , urging their citizens to maintain social distance to minimize the spread of the virus.

In recent history, another deadly virus called the human immunodeficiency virus (HIV) had emerged, which is the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS). As a common disease in Asia, the concurrence of these diseases could present an alarming problem globally. Recently, Zhu and colleagues noted that -HIV infected patients need to be regarded as a vulnerable group,‖ after co-infection of COVID-19 and HIV was reported in a patient in Wuhan,

China . Previously, HIV-1 emerged in young homosexual men in 1981 (Brodie et al., 2004) . Five years later, HIV-2 virus was discovered with similar morphology to HIV-1, but antigenically distinct, which increased AIDS cases reported in patients from western Africa in 1986 (Clavel et al., 1986) . Nonetheless, HIV-2 viral strain was distantly related to HIV-1 and both strains were acquired by humans from non-human primates infected with simian immunodeficiency virus (SIV) (Heeney et al., 2006) .

Scientists believed that SIV was transmitted to humans after contact with the blood of infected chimpanzees during bushmeat handling. Notably, the virus mutated into HIV from its origins and gradually spread from Africa to other parts of the world (Sharp and Hahn, 2011; Ayouba et al., 2013; Sousa et al., 2017) . Thus, confirming the occurrence of both viruses (HIV-1 and HIV-2) as a result of zoonotic transmission from infected primates. In general, human-to-human spread is known to be transmitted from mother to child, and during unprotected sexual intercourse between couples (Kassa, 2018) . When HIV infected body fluids, including blood, breast milk, semen, vaginal, and rectal secretion come into contact with mucous membrane in the mouth, rectum, penis, and vagina, it destroys the tissue or injects directly into the bloodstream by a needle or syringe (Hladik and McElrath, 2008; Shaw and Hunter, 2012) .

In summary, it is still unknown whether any identified interrelationship presents between HIVs and SARS-CoV-2. Despite the remarkable number of patients infected with HIV and novel COVID-19 separately, which extends to cover a wide zone in Asia and worldwide. There are very few reports on the SARS-CoV-2 infection among patients infected with HIV (Joob and Wiwanitkit, 2020) .

It has been observed that HIV targets the specific CD4+ immune cells, including T cells, macrophages, and dendritic cells, resulting in a significant reduction in the number of these immune cells in HIV-infected patients (Lane, 2010) . These CD4+ T cells (known as helper cells) are the backbone of the immune system where they activate B cells, macrophage, and cytotoxic T cells to secrete antibodies, destroy ingested microbes and kill the infected cells, respectively (Laidlaw, 2016) .

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The HIV membrane contains a transmembrane glycoprotein called glycoprotein-41 (GP41) and

surface glycoprotein, namely glycoprotein-120 (GP120), which binds to CD4 receptors on the surface of CD4+ cells (Pancera et al., 2014) . There are two other chemokine co-receptors known as C-C chemokine receptor 5 (CCR5) and C-C chemokine receptor 4 (CXCR4), which facilitate HIV binding and infusion into CD4+ cells (Didigu et al., 2014) . CXCR4 co-receptor is expressed in many

peripheral T-cells lymphoma found in the lymphatic sides, including lymph nodes, bone marrow, and spleen (Machado et al., 2009) . However, CCR5 is highly expressed on the surface of T cells, macrophages, dendritic cells, eosinophils, and microglia (Moore et al., 2004) . The binding of GP120 to CD4 receptor leads to a change in the envelope structure of virus, which allows the co-receptor, either CCR5 or CXCR4 (CXCR4 for T-tropic HIV strains, and CCR5 for M-tropic HIV strains) bind to a specific domain in the gp120. After binding, the N-terminal fusion peptide (GP41) penetrates in the host cell membrane, followed by entry of viral capsid into the cytosol of T cell. After penetration, virus removes and exposes its capsid, which contains the RNA genome and its associated enzymes (reverse transcriptase and integrase) into the host cell (Naif, 2013) . The virus produces complementary DNA (cDNA) by transcribing its single-standard RNA based on reverse transcriptase activity for producing duplicate strands of viral DNA. However, complete viral DNA migrates to the nucleus and integrates with DNA inside the host cell and unfortunately affects the cellular activity.

The integrated DNA is used to generate mRNA, thus synthesizing the viral proteins and allowing the new virus copy to develop. It has been observed that virus sabotages the CD4+ immune T cells for replication, which leads to increase virus load in the blood and a significant decrease in CD4+ T cells (Goodsell, 2015) . Interestingly, some researchers found another mechanism of HIV destruction of CD4+ T cells (Bolton et al., 2002; Yue et al., 2005) . They observed that depletion of CD4+ T cells by apoptosis pathway because of direct HIV infection was only 5-10% of the total CD4+ T cell pool. It has been found that HIV enzyme (integrase) plays a crucial role in the activation of DNA-PK sensor of host cell, which activates the apoptotic cascade inside the cell. However, another HIV enzyme (protease) activates the caspase-8 that further triggers the apoptosis of infected cells. Besides, specific HIV proteins display on the surface of infected CD4+ T cells, which alarm CD8+ T cells to destroy the infected CD4+ T cells. The immune system reacts by producing antibodies, such as anti-HIV antibodies, which stick to the infected CD4+ T cells and mark their destruction by other immune cells (Selliah and Finkel, 2001) . However, it has been observed that indirect effect of HIV infection results in majority of CD4+ T cells death, which causes immune deficiency. The direct effect of HIV to CD4+ T cells triggers the expression of interferon-gamma induced protein-16 (IFI-16), followed by the activation of inflammatory cascade inside the infected cell, which ends up with cellular self-J o u r n a l P r e -p r o o f destruction called pyroptosis (Doitsh et al., 2014; Monroe et al., 2014) . The caspase-1 activated by high expression of IFI-16 triggers the production of cytokines, especially interleukin-1 beta inside the infected cells (Lupfer et al., 2015) . The high production of IL1-β leads to the creation of inflammatory environment inside the cell, resulting in the initiation of apoptosis (Feria et al., 2018) .

The infected cells lead to release of interleukin-1 beta (IL-1β) to the outside cellular environment, which contributes to the activation of pyroptosis in the non-affected cells, causing a considerable loss of CD4+ T cells (Doitsh et al., 2014) .

Unlike HIV, the exact mechanism how COVID-19 induces immune defect is still unknown; however, it could be similar to the previous coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). These viruses induce low level of lymphocytes abnormality in blood, or it is known as lymphopenia related to HIV infection. The binding of coronavirus to the host cell required a specific class I viral glycol-transmembrane-protein, such as S protein on the surface of the virus envelope. It needs a specific receptor on the host cells called angiotensin-converting enzyme 2 (ACE2) receptor (Andersen et al., 2020; Dhama et al., 2020) . ACE2 is an enzyme spread in many cell membranes of different organs, including lungs, arteries, heart, kidney, and intestines; it plays a significant role in blood pressure regulation. The dramatic reduction in the peripheral CD4+ and CD8+ T cells is one of the symptoms in COVID-19 cases related to HIV infection Diao et al., 2020) .

Besides, over circulation of proinflammatory cytokines and chemokines, including interleukins (IL-1β, IL1RA, IL2, IL4, IL5, IL6, IL7, IL8, IL9, IL10, IL12p70, IL13, IL15, IL17A) , eotaxin, basic fibroblast growth factor (FGF2), granulocyte-colony stimulating factor (GCSF), granulocytemacrophage colony-stimulating factor (GMCSF), Interferon-gamma (IFNγ), IFN-γ-inducible protein-C-X-C Motif Chemokine Ligand 10 (CXCL10), interleukins (IL-1, IL-6, IL-8) with interferongamma (IFN-γ), and transforming growth factor-beta (TGF-β) occurred in the acute stage of SARS-CoV infection triggering the cytokine storm (Cameron et al., 2008; Huang et al., 2005) . Chloroquine is a primary therapeutic drug used to prevent and treat patients infected with malaria. However, the more extended use of chloroquine could produce severe side effects, such as cardiomyopathy (Bernstein, 1991; Ratliff et al., 1987) and the presence of some reports on macular retinopathy as a minor risk caused by this drug (Cubero et al., 1993) . A survey of the patients infected with SARS-CoV-2 for adverse side effects of chloroquine treatment is yet to be conducted.

Chloroquine was considered the best therapeutic drug choice available for treating SARS-CoV-2 infected patients in hospitals. Recently, the WHO has advocated a solidarity clinical trial for COVID-19 treatments. The solidarity clinical trial will compare four treatment choices, including chloroquine/hydroxychloroquine, remdesivir, lopinavir/ritonavir, and lopinavir/ritonavir plus interferon beta-1a against standard therapy and determine their relative efficacy against COVID-19

(World Health Organization, MEURI). (Cockrell et al., 2016) . They found that the enzyme carboxylesterase 1c (Ces1c) was deleted and receptor (dipeptidyl peptidase 4, hDPP4) of humanized MERS-CoV was expressed in order to increase the pharmacokinetics of nucleotide prodrugs. Another study conducted by Agostini et al. (2018) reported that two mutations were recognized, such as V553L and F276L in the RNAdependent RNA polymerase gene of the virus after 23 passages of remdesivir drug (Agostini et al., 2018) . They also observed that these changes in amino acid reduced the burden of virus and lessened the pathogenesis of SARS-CoV in mice. In recent months, the prophylactic efficacy of remdesivir was also tested in a rhesus macaque (non-human primate) MERS-CoV infection model (de Wit et al., 2020) . When the treatment with prophylactic remdesivir was started 24 hours before inoculation, MERS-CoV was found to be inhibited from replicating in the respiratory tissues and prevented from causing clinical disease, which inhibited the development of lung lesions. The same findings were obtained when treatment with remdesivir drug was initiated 12 hours after the virus inoculation (de Wit et al., 2020) . The remdesivir therapeutic drug safety data are readily available for humans (Mulangu et al., 2019) ; hence, human studies can be conducted to assess the effectiveness of this compound towards novel coronaviruses.

The Food and Drug Administration (FDA) approved the therapeutics against MERS-and SARS-CoV that have been assessed for antiviral activity. For instance, lopinavir (LPV), a protease inhibitor of

HIV-1, was tested to combine with ritonavir (RTV) in order to enhance the half-life of LPV. The combination of these two drugs (LPV/RTV) was found to be more effective in patients against SARS-CoV and in-vitro study. The calculated EC50 was 4 µg/ml for the fetal rhesus kidney-4 cells (Chu et al., 2004) . Meanwhile, Chan and coworkers reported that LPV/RTV also declined clinical sores, weight loss, and progression of disease in marmosets infected with MERS-CoV (Chan et al., 2015) . However, the antiviral activity of LPV towards MERS-CoV in the in-vitro study remains controversial. Another study conducted by Chan et al., (2013) found no optimal EC50 in the Vero cells, whereas EC50 was reported to be 8 µM in the Huh7 cells in a different study (de Wilde et al., 2014) .

It was found that infections with MERS-CoV were mediated by replication of the virus and host inflammatory responses after clinical observations in both humans and animals. Those studies had suggested the use of combination therapies including interferons I and II. However, interferon-beta (IFNb) reduced the replication of MERS-CoV in the tissue culture and showed the best efficacy with 1.37-17 IU/ml EC50s (Chan et al., 2013; Hart et al., 2014) . From the study on marmosets infected J o u r n a l P r e -p r o o f with MERS-CoV, Chan et al., (2015) reported the clinical improvement with the use of LPV/RTV with IFNb. Also, the clinical randomized control trials were started in Saudi Arabia in order to determine the efficacy of combinations of therapies, such as IFNb and LPV/RTV in improving the clinical outcomes against MERS-CoV (Arabi et al., 2018) . Notably, China has launched another controlled trial to test the effectiveness of IFNα-2b and LPV/RTV in hospitalized SARS-CoV-2 patients (ChiCTR2000029308).

In addition, the therapeutic and prophylactic activities of LPV/RTV-IFNb and remdesivir were compared in a transgenic mouse model infected with MERS-CoV (Sheahan et al., 2020) . It was found that remdesivir reduced lung viral titers, virus replication, and improved the pulmonary function. At the same time, prophylactic combined therapeutics, such as LPV/RTV-IFNb, only resulted in a moderate decline in viral titers and did not produce any effects on other parameters of disease. The combined therapy boosted pulmonary function but did not influence viral replication (Sheahan et al., 2020) . Thus, it was observed that remdesivir has shown to be effective for treating

Another antiviral prodrug, Ribavirin is a guanosine analogue used to treat many infections caused by viruses, such as hepatitis C respiratory syncytial virus, and patients coinfected with HIV and hepatitis B. In 1980, it was launched to the marketplace for treating the respiratory syncytial virus, especially in children. In most cases, it is used in combination with interferon (IFN). Falzarano and co-authors found promising results when ribavirin was combined with IFNα-2b against the rhesus macaque model infected with MERS-CoV (Falzarano et al., 2013) , but there have been some contradictory data on the MERS-CoV infected patients treated with IFNα2a or IFNβ1 and ribavirin (Arabi et al., 2017) . Besides, ribavirin also produces adverse side effect such as decreasing haemoglobin concentrations in patient with respiratory disorder that could not be appropriate for use against SAR-CoV-2. In addition, various other antiviral therapeutic drugs/cocktails, including favipiravir, nitazoxanide, ganciclovir, acyclovir/penciclovir, and the latest FDA-approved ivermectin are listed in Table 3 .

In summary, the repurposing of preexisting antiviral therapeutic drugs is finite, so it is almost inevitable that both new and repurposed drugs will be required to treat COVID-19. Therapeutic drug choices in response to COVID-19 are urgently required and fortunately, some of the preexisting antiviral therapeutics are already progressing into human clinical trials. it is important for PWH to regularly attend their healthcare providers and adhere to therapy (National Institute of Allergy and Infectious Disease, 2020). The treatment of PWH can be affected due to stay at home orders enforced by countries worldwide. For instance, several medical practitioners canceled their appointments with HIV suspected people in the USA and switched to telehealth appointments to follow the WHO guidelines (Ives, 2020) . However, telehealth programs are restricted in the wide range of resources that can be given to the customers (Siwicki, 2020) , therefore, PWH may not be able to completely access the services needed for HIV therapy. In addition, many PWH patients may not be able to get access to telehealth services for many reasons, such as limited access to technology and lack of knowledge about telehealth that could hinder their therapy progression.

PWH are more vulnerable group to contract opportunistic infections, such as tuberculosis, toxoplasmosis, pneumonia, etc. (Department of veteran affairs, 2020), than those without immunocompromised systems. HIV-infected people who have suffered from any other disorders may undergo delayed treatment because of COVID-19. This can happen in already taxed healthcare system due to hospital overcrowding. Moreover, PWH who seek out emergency treatment can face a high risk of experiencing COVID-19 among other disorders in the healthcare systems (Collins, 2008) .

The occurrence of person-to-person transmission for COVID-19 is increasing, which means that . They propositioned that persons infected with HIV need to be considered as a vulnerable group for COVID-19. Nonetheless, no robust evidence of any interrelationship between these two viral infections is yet to be identified.

Despite the high number of patients infected with HIV as well as the remarkable number of patients with the novel COVID-19 disease, which extends to cover a wide zone in Asia and worldwide. There are very few reports on the co-infection of HIV and SARS-CoV. In addition, antiviral therapeutic drugs are broadly used for treating HIV-infected patients, and these drugs have potential to be used against SARS-CoV-2 (Felber et al., 1990; Savarino et al., 2003) . Thus, the patients infected with HIV who are receiving anti-HIV therapeutic drugs might be at a lower risk for COVID-19 compared to the general population. Some antiviral therapeutic drugs, including chloroquine, remdesivir, ribavirin, lopinavir/ritonavir, and now FDA-approved ivermectin and others (summarized Table 3) have the potential to treat patients infected with SARS-CoV-2. At the same time, more clinical trials are required in order to obtain robust data. Also, further studies are urgently required to explore the pathogenicity, mechanisms, and transmission of novel coronavirus.

To obtain a better insight of the novel virus, countries should strive to provide more reliable and accurate data by transparency and sharing of data, and more research studies need to be conducted on the reported cases. Therefore, countries should continue to work towards developing preventive measures to minimize both the transmission and number of infected patients. In addition to unravelling the uncertainty of the mechanisms of viral replication and host cell entry, which will provide the fundamental knowledge for future research into the development of targeted vaccines and antiviral therapeutic drugs. With continuing efforts to curb the widespread transmission of COVID-19 globally, we hope that the novel coronavirus pandemic may alleviate after a few months. In summary, there is an urgent need to develop a new broad-spectrum antiviral therapeutic agent that will be effective to fight against not only the novel respiratory 2019 coronavirus, but also to prepare for a possibly similar virus outbreak in the future. For -If there is any message coming out from the latest outbreaks, it is almost certain that it will happen again.‖

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Origins of HIV and the evolution of resistance to AIDS

Setting the stage: host invasion by HIV

Strategies of development of antiviral agents directed against influenza virus replication

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

An interferon-γ-related cytokine storm in SARS patients

Telemedicine Surges, Fueled by Coronavirus Fears and Shift in Payment Rules

HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages

The natural history of HIV-1 and HIV-2 infections in adults in Africa: a literature review

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Complement receptor C5aR1 inhibition reduces pyroptosis in hDPP4-transgenic mice infected with MERS-CoV

SARS-CoV-2 and HIV

Mother-to-child transmission of HIV infection and its associated factors in Ethiopia: a systematic review and meta-analysis

Chimpanzee reservoirs of pandemic and nonpandemic HIV-1

CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression

Virus taxonomy. Ninth Rep Int Comm Taxon Viruses

Pathogenesis of HIV infection: total CD4+ T-cell pool, immune activation, and inflammation

The multifaceted role of CD4+ T cells in CD8+ T cell memory

Lentiviral Vif degrades the APOBEC3Z3/APOBEC3H protein of its mammalian host and is capable of cross-species activity

Activation of the ATR pathway by human immunodeficiency virus type 1 Vpr involves its direct binding to chromatin in vivo

Novel coronavirus disease (Covid-19): the first two patients in the UK with person to person transmission

Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia

GS-5734) protects African green monkeys from Nipah virus challenge

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Outbreak of Pneumonia of Unknown Etiology in Wuhan China: the Mystery and the Miracle

Inflammasome control of viral infection

Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)?

Decreased T cell populations contribute to the increased severity of COVID-19

Expression and function of T cell homing molecules in Hodgkin's lymphoma

Influenza treatment with oseltamivir outside of labeled recommendations

Coronavirus genomic RNA packaging

Coronavirus disease 2019

Self-Care Instructions for People Not Requiring Hospitalization for Coronavirus Disease 2019 (COVID-19)

Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes

A randomized, controlled trial of Ebola virus disease therapeutics

Pathogenesis of HIV infection

Impact of TRIM5α in vivo

Seeing Your Healthcare Provider. HIV Gov

A structural analysis of M protein in coronavirus assembly and morphology

A synthetic serine protease inhibitor, Nafamostat Mesilate, is a drug potentially applicable to the treatment of Ebola virus disease

Enfuvirtide: a review of its use in the management of HIV infection

Structure and immune recognition of trimeric pre-fusion HIV-1 Env

Transmission routes of 2019-nCoV and controls in dental practice

The latest evidence for possible HIV-1 curative strategies

A cross-sectional study of the role of HIV/AIDS knowledge in risky sexual behaviors of adolescents in Nigeria

Diagnosis of chloroquine cardiomyopathy by endomyocardial biopsy

Going global-Travel and the 2019 novel coronavirus

Nitazoxanide: a first-in-class broad-spectrum antiviral agent

Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus

Differential regulation of NF-κB-mediated proviral and antiviral host gene expression by primate lentiviral Nef and Vpu proteins

Effects of chloroquine on viral infections: an old drug against today's diseases

Coronavirus envelope protein: current knowledge

The extended impact of human immunodeficiency virus/AIDS research

Biochemical mechanisms of HIV induced T cell apoptosis

Cold Spring Harb Perspect Med

Origins of HIV and the AIDS pandemic

Antiviral drugs against alphaherpesvirus

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

A review of coronavirus disease-2019 (COVID-19)

Telemedicine during COVID-19: Benefits, Limitations, Burdens, Adaptation. Health Care News

Coronaviruses as DNA wannabes: a new model for the regulation of RNA virus replication fidelity

Synthesis and characterization of a native, oligomeric form of recombinant severe acute respiratory syndrome coronavirus spike glycoprotein

The epidemic emergence of HIV: what novel enabling factors were involved?

Cytokine storm in COVID-19: the current evidence and treatment strategies

Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir

Evolution, Distribution, and Diversity of Immunodeficiency Viruses. Dyn Immune Act Viral Dis

A novel coronavirus outbreak of global health concern

Monitored emergency use of unregistered and experimental interventions (MEURI

Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavi

Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV

Preferential apoptosis of HIV-1-specific CD4+ T cells

HIV-1 Vpr induces interferon-stimulated genes in human monocyte-derived macrophages

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Reply to Comments on'Co-infection of SARS-CoV-2 and HIV in a patient in Wuhan city

A novel coronavirus from patients with pneumonia in China

The coronavirus replicase

Human immunodeficiency virus type 1 Vpr induces DNA replication stress in vitro and in vivo

Emerging genetic diversity among clinical isolates of SARS-CoV-2: Lessons for today

The proximal origin of SARS-CoV-2

Mapping the genomic landscape & diversity of COVID-19 based on > 3950 clinical isolates of SARS-CoV-2: Likely origin & transmission dynamics of isolates sequenced in India

The authors declare no conflicts of interest

Coronaviruses CNSCentral nervous system SARS-CoV-2 MERS-CoV Severe acute respiratory syndrome coronavirus 2 Middle East respiratory syndrome coronavirus ARDS Acute respiratory distress syndrome WHO World Health Organization HIVsHuman immunodeficiency viruses SIV Immunodeficiency virus GP41Glycoprotein-41 CCR5 C-C chemokine receptor-5 CXCR4 C-C chemokine receptor-4 (IFI)-16Interferon-gamma induced protein-16 IL-1βInterleukin-1β ACE2Angiotensin-converting enzyme-2 FGF2Basic fibroblast growth factor 2 GCSF Granulocyte-colony stimulating factor IFNγ Interferon-gamma IP10IFN-γ-inducible protein-10 MCP1Monocyte chemoattractant protein 1 MIP1AMacrophage inflammatory proteins TNF-α Tumor necrosis factor-alpha J o u r n a l P r e -p r o o f 

Generally, 5'-UTR-replicase-S-M-N-UTR-3' (Fung et al., 2020; Replicase gene Overlapped with ORFs 1a and 1b that codes two huge polyproteins, pp1a and pp1ab that are processed autoproteolytically into 16 non-structural proteins involved in genome transcription and replication. (Sheikh et al., 2020; Singh et al., 2020; Chan et al., 2020; Clavel et al., 1986; Zahoor et al., 2014) Morphogenesis Assembly of virion takes place at the smooth intracellular membranes of the endoplasmic reticulum/early Golgi compartments. (Masters, 2019) J o u r n a l P r e -p r o o f (Geyer et al., 2001; Sauter et al., 2015) tat  An HIV transcription factor that supports the generation of full-length viral mRNAs. Induces transcription and secretion of chemokines which attracts T cells and monocytes increasing infectivity.  (Feinberg et al., 1991; Izmailova et al., 2003) rev  Directs exports of viral messages that are translated into viral proteins, providing genomic RNA for packaging and budding virion J o u r n a l P r e -p r o o f
