Antibodies predating infection: Immunological memory after infection with seasonal human coronaviruses (hCoVs) may potentially contribute to cross-protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ng et al. report that in a cohort of 350 SARS-CoV-2–uninfected individuals, a small proportion had circulating immunoglobulin G (IgG) antibodies that could cross-react with the S2 subunit of the SARS-CoV-2 spike protein (see the Perspective by Guthmiller and Wilson). By contrast, COVID-19 patients generated IgA, IgG, and IgM antibodies that recognized both the S1 and S2 subunits. The anti-S2 antibodies from SARS-CoV-2–uninfected patients showed specific neutralizing activity against both SARS-CoV-2 and SARS-CoV-2 S pseudotypes. A much higher percentage of SARS-CoV-2–uninfected children and adolescents were positive for these antibodies compared with adults. This pattern may be due to the fact that children and adolescents generally have higher hCoV infection rates and a more diverse antibody repertoire, which may explain the age distribution of COVID-19 susceptibility. Science , this issue p. 1339 ; see also p. 1272

HIV-1 replication relies on the proper functioning of specific viral proteins, three of which — protease, integrase, and reverse transcriptase with associated RNase H activity — are enzymes. Antiviral drugs that inhibit protease, integrase and reverse transcriptase (specifically, DNA polymerase) activities are approved for treating patients with AIDS. The highly active antiretroviral therapy (HAART) regimens use cocktails of three inhibitors to suppress HIV-1 replication and the outgrowth of drug-resistant virus strains. Replication of HIV-1 depends on a plethora of functional interactions between its proteins and those of the host. Certain other cellular proteins, referred to as restriction factors, counteract viral growth. TRIM5α, APOBEC3G, tetherin and SAMHD1 are examples of such restriction factors. In addition to enzyme active sites, critical viral protein–host protein interactions define targets for therapeutic intervention. Drugs can block interactions between the viral and host proteins that are needed for replication, as is the case for the approved entry inhibitor maraviroc, or they can enhance the effects of cellular restriction factors. Neutralization of the viral envelope glycoprotein gp120 by the adaptive immune system underscores the development strategies for AIDS vaccines. Structural biology studies yield three-dimensional glimpses of protein function at near atomic resolution. Such approaches form the cornerstone of modern efforts for the development of antiviral drugs and vaccines.

The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications.

Significance: Transportin 3 (Tnpo3) was shown to orchestrate nuclear import of splicing factors over a decade ago, but how it recognizes these cargoes remained unknown. Furthermore, the recently discovered role for Tnpo3 as a cofactor of HIV-1 replication requires mechanistic clarification. We show that Tnpo3 associates with a wide range of proteins involved in mRNA metabolism, the majority of which contain serine/arginine-rich domains. Using X-ray crystallography we determined the three-dimensional structures of Tnpo3 in its key functional states, explaining how this nuclear import factor binds and releases its cargoes. We also show that Tnpo3 mutants that are not able to interact with cleavage and polyadenylation specificity factor 6 do not facilitate HIV-1 infectivity, suggesting a potential route of pharmacological intervention in the treatment of AIDS.

Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.