Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virustransformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTV ATL, of an A‫-1020ء‬restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.

An increasing number of HIV-1-infected patients living in developing countries now have access to antiretroviral drugs. Information regarding the drug-resistant mutations of non-B subtype HIV-1 remains limited, however. The authors cross-sectionally compared patterns of the drug-resistant point mutations in patients infected with either subtype B or CRF01_AE (subtype E) among patients who acquired HIV by sexual transmission in Japan. Protease sequence data were available from 216 patients with a detectable level of RNA copies in plasma. Based on phylogenetic analysis of the protease and the C2V3 regions, 162 subtype B and 45 CRF01_AE cases were identified; 82 subtype B and 24 CRF01_AE patients had a treatment failure with nucleoside reverse transcriptase inhibitors; and 69 subtype B and 19 CRF01_AE patients had a treatment failure with a protease inhibitor. Antiretroviral drug history was similar in subtype B-infected and CRF01_AE-infected patients. The mutations T69N and V75M in reverse transcriptase and L10F, K20I, L33I, and N88S in protease were seen more frequently in patients infected with CRF01_AE than in patients with subtype B. The mutations, D30N, A71V, and N88D were found exclusively in patients with subtype B. Most of the characteristic mutation patterns were associated with a history of receiving nelfinavir. The pattern of drug resistance mutations differs between the subtypes. Data derived from subtype B drug-resistant genotypes may not always be applicable to non-B subtypes.

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses’ whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.