The first bit of good news is that vaccines circumvent most viral defenses, inducing a much more robust and durable antiviral immune response than infection itself. Troubling though these strategies to circumvent innate immunity may be, they offer exciting opportunities for prevention and treatment. New variants of SARS-CoV-2 have proven strikingly more infectious than the original strain, both because of spike proteins that enhance binding affinity and evade antibody detection, and because some variants are more potent in repressing innate immunity. SARS-CoV-2 is protean, capable of changing its exterior to re-enter previously infected hosts. Last but not least is the capacity SARS-CoV-2 has for evolution. Perturbation of our initial immune defenses may be largely responsible for the violent reaction that seems to cause the most severe consequences of Covid-19. The peak of viral replication occurs before the onset of symptoms-meaning even mild symptoms occur only after the virus is on the wane. The second element of this tale is the puzzling pathogenesis of the virus. This early immune suppression may account for the generally weak antibody response in those infected, facilitating reinfection within months by variants that produce key neutralization epitopes. In addition, SARS-CoV-2 carries an impressive arsenal of proteins that actively suppress both the induction of interferon, the primary trigger of innate and adaptive immunity, and of interferon-induced genes and proteins. Upon entry into a susceptible cell, the virus conceals its presence by creating a privileged subcellular organelle in which it replicates unseen by intracellular alarms and by camouflaging its messenger RNAs to resemble those of cellular RNAs.
Early on, the virus acts at multiple levels to counteract innate immunity, the first line of defense against microbial invaders, allowing enough time for the virus to enter and exit before the full set of antiviral defenses can mobilize. SARS-CoV-2, as we shall see, has proved exceptional at this task. To establish infection all viruses must first defeat the body's well-honed defenses. The primary story, perhaps paradoxically, is one of immune suppression-not hyper-activation, which is seen so strikingly in those who fall seriously ill. Each revelation offers not just insight into our collective experience but new hope that we might prevail against this most dangerous pathogen.įirst and foremost, SARS-CoV-2 is a master at evading both the defenses of an infected cell and the entire immune system. How do we understand what has happened? How and why SARS-CoV-2 infects so many, why it causes severe disease in some yet affects most others only mildly, how it confounds natural immunity, and what is behind the variants? It is a tale of stealth and disguise worthy of any great mystery novel. I remain confident that a return to normal life can and will be the end result, but only if we remain dedicated to using the full power of our science, medicine, public health, and international organizations to understand and control SARS-CoV-2. I have seen too many premature announcements of victory over disease that I hesitate to declare our imminent success in controlling Covid-19. With some sadness, I see our dashed hopes for an early vaccine to end the pandemic and now, forty years and 35 million deaths later, see that HIV/AIDS lingers on with a million or more people dying each year. I remember the HIV epidemic, first for the sluggish reaction of our public health officials and leaders, then for the rapid science advances that led to a deep understanding of the virus and drugs to prevent and treat the disease. As a young Harvard researcher working on cancer and AIDS, I remember the War on Cancer and our hopes that we would vanquish the disease in a few short years or, conservatively, a decade or two at most. No doubt similar to what today's children will remember of the restrictions around Covid-19.
I remember polio and all the forbidden summer activities-swimming in public pools, playing with more than two other friends, or enjoying the latest serials in the cool, dark movie theaters I loved. This is the third major pandemic of my lifetime.