Influenza's Cryptic Constraint Because of the well-known pandemic potential of influenza viruses, it is important to understand the range of molecular interactions between the virus and its host. Despite years of intensive research on the virus, Jagger et al. (p. 199 , published online 28 June; see the Perspective by Yewdell and Ince ) have found that the influenza A virus has been hiding a gene in its small negative-sense RNA genome. An overlapping open reading frame was found contained in the PA viral RNA polymerase gene, which is accessed by ribosomal frameshifting to produce a fusion protein containing the N-terminal messenger RNA (mRNA) endonuclease domain of PA and an alternative C-terminal X domain. The resulting polypeptide, PA-X, selectively degrades host mRNAs and, in a mouse model of infection, modulated cellular immune responses, thus limiting viral pathogenesis.

HIV infects tissue macrophages and brain microglia, which express lower levels of CD4 and CCR5 than CD4 ؉ T cells in peripheral blood. Mechanisms that enhance HIV tropism for macrophages in the CNS and other tissues are not well understood. Here, we identify an HIV envelope glycoprotein (Env) variant in the CD4-binding site of gp120, Asn 283 (N283), that is present at a high frequency in brain tissues from AIDS patients with HIV-associated dementia (HAD). N283 increases gp120 affinity for CD4 by decreasing the gp120-CD4 dissociation rate, enhancing the capacity of HIV Envs to use low levels of CD4 for virus entry and increasing viral replication in macrophages and microglia. Structural modeling suggests that the enhanced ability of Envs with N283 to use low levels of CD4 is due to a hydrogen bond formed with Gln 40 of CD4. N283 is significantly more frequent in brain-derived Envs from HAD patients (41%; n ‫؍‬ 330) compared with non-HAD patients (8%; n ‫؍‬ 151; P < 0.001). These findings suggest that the macrophage-tropic HIV Env variant N283 is associated with brain infection and dementia in vivo, representing an example of a HIV variant associated with a specific AIDS-related complication.CD4 ͉ envelope ͉ neurotropism ͉ microglia H IV type 1 (HIV) infects macrophages and microglia in the CNS and causes HIV-associated dementia (HAD) or mild neurocognitive impairment in 10-20% of patients with AIDS (1). Most antiretroviral therapies have poor CNS penetration, so the brain is a reservoir for viral persistence. HIV variants in brain are genetically distinct from those in lymphoid tissues and other organs, and specific sequences in the viral envelope glycoprotein (Env) have been associated with brain compartmentalization (2-9). Furthermore, brain-derived Envs from HAD and non-HAD AIDS patients are genetically and biologically distinct (7,8,(10)(11)(12). Rhesus macaque models of simian immunodeficiency virus (SIV) infection provide additional evidence that only a subset of strains are neurotropic (13-15). The capacity of HIV or SIV strains to replicate efficiently in macrophages has been correlated with increased neurotropism (9,14,(16)(17)(18)(19) and may also be linked to progression of HIV͞SIV disease (15,20,21). However, mechanisms that enhance HIV replication in macrophages in the CNS and other macrophage-rich tissues such as lung, colon, and bone marrow are not well understood.HIV Env, which is organized into trimers on virions, consists of the gp120 surface and gp41 transmembrane subunits. HIV entry into cells is initiated by a high-affinity interaction between gp120 and CD4, which induces a conformational change in gp120 that exposes the coreceptor-binding site (22). The interaction of CD4-bound gp120 with the coreceptor triggers a conformational change in gp120, which leads to a structural rearrangement in gp41 that enables fusion and virus entry. CCR5, the primary coreceptor used for infection of macrophages and microglia (17,19,23,24), is the coreceptor used by most viruses isolated from brain (11,17,18,23...

This study represents the first healthy volunteer influenza challenge model using a GMP-produced wild-type virus under an IND. This unique clinical research program will facilitate future studies of influenza pathogenesis, animal model validation, and the rapid, efficient, and cost-effective evaluation of efficacy of novel vaccines and therapeutics. Clinical Trials Registration.NCT01646138.