SARS-CoV-2 and Human Immunodeficiency Virus: Pathogen Pincer Attack

Abstract

Paramount efforts worldwide are seeking to increase understanding of the basic virology of SARS-CoV-2, characterize the spectrum of complications associated with COVID-19, and develop vaccines that can protect from new and recurrent infections with SARS-CoV-2. While we continue learning about this new virus, it is clear that 1) the virus is spread via the respiratory route, primarily by droplets and contact with contaminated surfaces and fomites, as well as by aerosol formation during invasive respiratory procedures; 2) the airborne route is still controversial; and 3) that those infected can spread the virus without necessarily developing COVID-19 (ie, asymptomatic). With the number of SARS-CoV-2 infections increasing globally, the possibility of co-infections and/or co-morbidities is becoming more concerning. Co-infection with Human Immunodeficiency Virus (HIV) is one such example of polyparasitism of interest. This military-themed comparative review of SARS-CoV-2 and HIV details their virology and describes them figuratively as separate enemy armies. HIV, an old enemy dug into trenches in individuals already infected, and SARS-CoV-2 the new army, attempting to attack and capture territories, tissues and organs, in order to provide resources for their expansion. This analogy serves to aid in discussion of three main areas of focus and draw attention to how these viruses may cooperate to gain the upper hand in securing a host. Here we compare their target, the key receptors found on those tissues, viral lifecycles and tactics for immune response surveillance. The last focus is on the immune response to infection, addressing similarities in cytokines released. While the majority of HIV cases can be successfully managed with antiretroviral therapy nowadays, treatments for SARS-CoV-2 are still undergoing research given the novelty of this army.

Keywords: ACE-2; AIDS; COVID-19; HIV; SARS-CoV-2; remdesivir.

Figure 1

Components of SARS-CoV-2 and HIV. A schematic representation of SARS-CoV-2 (left) and HIV (right) is shown, along with key structural components. For both viruses, the glycoproteins, embedded within the envelope proteins are required for the initial interaction of the virus with susceptible host cells. In SARS-CoV-2, the membrane protein is required for membrane fusion and interacts with other elements of the virus. The envelope protein aids in viral assembly within the host cell, and the single-stranded RNA enclosed in the nucleocapsid comprises the genetic material. In HIV, the capsid proteins are structural proteins arranged to house the viral genetic material. Viral enzymes, coded by the pol gene, include proteases, reverse transcriptase, and integrase. The HIV reverse transcriptase is an RNA-dependent DNA polymerase essential for synthesis of viral cDNA using RNA as template. The viral integrase creates a permanent copy of viral DNA in the infected cell by catalyzing viral DNA integration into host cell DNA. The protease cleaves the newly formed polypeptide into the components of mature virions. The matrix proteins are key in virion packaging. Illustration credit: Nicholas J. Evans.

Figure 2

Comparative overview of viral entry and receptor downregulation. Schematic representation of a host cell potentially co-infected with HIV (left side) and SARS-CoV-2 (right side). [1] Binding of HIV or SARS-CoV-2 to key receptors. Both SARS-CoV-2 require initial interaction with specific receptors at the cell membrane: HIV binds to CD4 and co-receptors CCR5 and CXCR4 (left) and SARS-CoV-2 binds to host cell receptors CD147 or ACE2 (right). Binding of SARS-CoV-2 to ACE2 receptor requires initial cleavage of the viral S1 glycoprotein assisted by human protease TMPRSS2 so that viral S2 protein can be internalized along with the rest of the virion (right). [2] Entry of virus into cell. HIV fusion with the cell membrane leads to disassembly of the virion in the cytoplasm, leading to the release of viral genetic material, reverse transcription and [4] eventual integration of viral DNA into the host cell DNA, whereas SARS-CoV-2 enters the cell through endocytosis after binding to ACE2 or CD147. [3] Downregulation of CD4 by NEF or ACE2 by ADAM17. Viral internalization (infection) leads to downregulation of the initial entry receptor for HIV (CD4, mediated by the viral Nef polypeptide) and ACE2 for SARS-CoV-2, which is cleaved by the host ADAM17. [5] Fusion of the endosome and the virus. The viral membrane and endosome membrane fuse, releasing SARS-CoV-2’s genome into the host cell. Illustration credit: Nicholas J. Evans.

Figure 3

Hypothetical differences in immune response in HIV/SARS CoV-2 co-infection and SARS-CoV-2 mono-infection and potential implications in the development of COVID-19. A milder immune response is observed in HIV/SARS CoV-2 co-infection, potentially due to a chronically lower immunocompetency in patients living with managed HIV. While the patients are not immunodeficient, they are immunosuppressed. This may reduce the severity of the inflammation that occurs with infection, and lead to a better prognosis for PLWH who become infected with SARS-CoV-2. In turn this would mean a weakened cytokine storm would occur when the virus has reached the lungs and entered the blood, spreading to other organs. The weakened cytokine storm would entail lower systemic inflammation and cause less damage to other organs.