In December 2019, the first case of COVID-19 surfaced in Wuhan, China. The relatively unknown SARS-CoV-2 virus led to the global 2020–2021 pandemic claiming thousands of lives. One of the major reasons for the prolonged duration of the pandemic consisting of multiple waves, due to sporadic surges in the number of cases, is the emerging variants. Such variants of the classic Wuhan strain hold multiple mutations that increase the viral fitness, improve transmissibility, aid in immune escape, and overall increase the virulence of the virus. Hence, studying and understanding the viral evolution and the interaction dynamics of the virus with the human immune system becomes vital. To that end, here, we review some of the immune aspects associated with SARS-CoV-2 and COVID-19 with a focus on immune responses to variants of concern. The article breaks down the normal immune response elicited against the virus and its variants along with various interesting concepts of antibody-dependent enhancement, immune escape, immune suppression, and immunophenomics while also highlighting the next frontiers in dealing with the virus. The unprecedented research into understanding the immunological underpinnings of the COVID-19 global pandemic will pave the way for evidence-based strategies for the management of this and any future widespread infectious diseases.

We have determined a 3.0 Å resolution X-ray crystal structure of HIV-1 reverse transcriptase (RT) complexed with DHBNH, an RNase H inhibitor (RNHI). HIV-1 RT uses two enzymatic activites, a polymerase and an RNase H, to convert the viral genomic singlestranded RNA into double-stranded DNA suitable for integration into the host genome [1]. RNase H is essential for virus replication; however, very few small molecule inhibitors targeting this function have been reported, and there are no crystal structures of HIV RT in a complex with an RNase H inhibitor. DHBNH is an N-acyl hydrazone derivative that inhibits RNase H with an IC 50 of 0.5 µM but does not inhibit the RT polymerase (IC 50 >20 µM). Despite this specificity, the inhibitor binds more than 40 Å away from the RNase H active site, at a novel binding site in the palm of the p66 subunit, between the primer grip and the polymerase active site. The inhibitor partially overlaps the non-nucleoside RT inhibitor (NNRTI) binding pocket. The inhibitor appears to interact with the conserved residues Asp186 and Trp229, as well as with Tyr188, Lys223, Asp224, Pro226, Phe227, and Leu228. Certain substitutions on DHBNH can enhance interactions in the NNRTI binding pocket, resulting in "dual inhibitors" that inhibit both the polymerase and RNase H activities of HIV-1 RT. Our results are consistent with the view that binding of DHBNH alters the trajectory of the nucleic acid substrate, affecting the RNase H activity. Knowledge gained from this study provides new opportunities for structure-based drug design.