SARS-CoV-2 spike N-terminal domain harbors a potent epitope that can be modulated by binding of natural linear tetrapyrroles.

The replication and pathogenicity of lentiviruses is crucially modulated by ”auxiliary proteins” which are expressed in addition to the canonical retroviral ORFs gag, pol and env. Strategies to inhibit the activity of such proteins are often sought and proposed as possible additions to increase efficacy of the traditional antiretroviral therapy. This requires the acquisition of an in-depth knowledge of the molecular mechanisms underlying their function.The Nef auxiliary protein is expressed uniquely by primate lentiviruses and plays an important role in virus replication in vivo and the onset of AIDS. Among its several activities Nef enhances the intrinsic infectivity of progeny virions through a mechanism which remains today enigmatic. Here we review the current knowledge surrounding such activity and we discuss its possible role in HIV and SIV biology.

Significance: Serine incorporators (SERINC) 5 and 3 are recently discovered cellular inhibitors of retroviruses, which are incorporated into virus particles and impair their ability to propagate the infection to target cells. Only two groups of viruses (represented by HIV-1 and murine leukemia virus) had been identified as having evolved the ability to counteract SERINC inhibition. We found that equine infectious anemia virus, which causes a debilitating disease in horses, also has acquired the capacity to protect the virus particle from inhibition by SERINC5 and SERINC3 by using its small protein S2. That three different retroviruses have independently evolved the ability to elude inhibition by SERINC5 and SERINC3 indicates that these cellular factors play a fundamental role against various retrovirus pathogens.

The ability of a virus to spread between individuals, its replication capacity and the clinical course of the infection are macroscopic consequences of a multifaceted molecular interaction of viral components with the host cell. The heavy impact of COVID-19 on the world population, economics and sanitary systems calls for therapeutic and prophylactic solutions that require a deep characterization of the interactions occurring between virus and host cells. Unveiling how SARS-CoV-2 engages with host factors throughout its life cycle is therefore fundamental to understand the pathogenic mechanisms underlying the viral infection and to design antiviral therapies and prophylactic strategies. Two years into the SARS-CoV-2 pandemic, this review provides an overview of the interplay between SARS-CoV-2 and the host cell, with focus on the machinery and compartments pivotal for virus replication and the antiviral cellular response. Starting with the interaction with the cell surface, following the virus replicative cycle through the characterization of the entry pathways, the survival and replication in the cytoplasm, to the mechanisms of egress from the infected cell, this review unravels the complex network of interactions between SARS-CoV-2 and the host cell, highlighting the knowledge that has the potential to set the basis for the development of innovative antiviral strategies.