Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity.

Unlabelled: Two alleles of segment 8 (NS) circulate in nonchiropteran influenza A viruses. The A allele is found in avian and mammalian viruses, but the B allele is viewed as being almost exclusively found in avian viruses. This might reflect the fact that one or both of its encoded proteins (NS1 and NEP) are maladapted for replication in mammalian hosts.

Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study.

Background: Healthy volunteer wild-type influenza challenge models offer a unique opportunity to evaluate multiple aspects of this important virus. Such studies have not been performed in the United States in more than a decade, limiting our capability to investigate this virus and develop countermeasures. We have completed the first ever wild-type influenza A challenge study under an Investigational New Drug application (IND).

Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice.

The 1918 influenza pandemic caused over 40 million deaths worldwide, with 675,000 deaths in the United States alone. Studies in several experimental animal models showed that 1918 influenza virus infection resulted in severe lung pathology associated with dysregulated immune and cell death responses. To determine if reactive oxygen species produced by host inflammatory responses play a central role in promoting severity of lung pathology, we treated 1918 influenza virus-infected mice with the catalytic catalase/superoxide dismutase mimetic, salen-manganese complex EUK-207 beginning 3 days postinfection.

Enhanced macrophage tropism of HIV in brain and lymphoid tissues is associated with sensitivity to the broadly neutralizing CD4 binding site antibody b12.

Macrophages in the central nervous system (CNS) and other tissues are an important cellular reservoir for human immunodeficiency virus type 1 (HIV) infection, particularly in the later stages of disease. Macrophage-tropic HIV strains have an enhanced capacity to enter cells expressing low levels of CD4 through mechanisms that are not well understood. Here, we use a panel of primary HIV envelopes from brain and lymphoid tissues to examine the relationship between neutralization sensitivity to reagents targeting the CD4 binding site and virus entry into macrophages.

Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS.

Background: CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively.

Results: Compared to PA-R5 Envs, A-R5 Envs had enhanced fusogenicity in quantitative cell-cell fusion assays, and reduced sensitivity to inhibition by the fusion inhibitor T-20.

Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia.

HIV infects macrophages and microglia in the central nervous system (CNS). Mechanisms that enhance HIV macrophage/microglial tropism are not well understood. Here, we identify an HIV Env variant in the V4 region of gp120, Asp 386 (D386), that eliminates an N-linked glycosylation site at position 386, enhances viral replication in macrophages, and is present at a higher frequency in AIDS patients with HIV-associated dementia (HAD) compared with non-HAD patients.

High frequency of defective vpu compared with tat and rev genes in brain from patients with HIV type 1-associated dementia.

Human immunodeficiency virus type 1 (HIV) infection of the central nervous system frequently causes HIV-associated dementia (HAD) and other neurological disorders. The role of HIV regulatory and accessory proteins in the pathogenesis of these disorders is unclear. Here we analyzed sequences of tat, rev, and vpu genes in 55 subgenomic clones previously shown to encode functional env genes from brain and lymphoid tissues of four AIDS patients with HAD.

Changes in the V3 region of gp120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Delta32 heterozygote.

Heterozygosity for the CCR5 Delta32 allele is associated with delayed progression to AIDS in human immunodeficiency virus type 1 (HIV-1) infection. Here we describe an unusual HIV-1 isolate from the blood of an asymptomatic individual who was heterozygous for the CCR5 Delta32 allele and had reduced levels of CCR5 expression. The primary virus used CCR5, CXCR4, and an unusually broad range of alternative coreceptors to enter transfected cells.

Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion.

HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue.

The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia.

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).

Mechanisms of HIV-1 neurotropism.

Human immunodeficiency virus type 1 (HIV) infects macrophages and microglia in the CNS and frequently causes neurocognitive impairment. Although antiviral therapy generally reduces the viral load in the CNS and improves HIV-associated neurological dysfunction, most current antiviral drugs have poor CNS penetrance and cannot completely suppress viral replication. Furthermore, drug-resistance mutations can evolve independently in the CNS.