Retroviruses must gain access to the host cell nucleus for subsequent replication and viral propagation. Human immunodeficiency virus type 1 (HIV-1) and other primate lentiviruses are distinguished from the gammaretroviruses by their ability to infect nondividing cells such as macrophages, an important viral reservoir in vivo. Rather than requiring nuclear membrane breakdown during cell division, the HIV-1 preintegration complex (PIC) enters the nucleus by traversing the central aqueous channel of the limiting nuclear pore complex. The HIV-1 PIC contains three nucleophilic proteins, matrix, integrase, and Vpr, all of which have been implicated in nuclear targeting. The mechanism by which Vpr can display such nucleophilic properties and yet also be available for incorporation into virions assembling at the plasma membrane is unresolved. We recently characterized Vpr as a nucleocytoplasmic shuttling protein that contains two novel nuclear import signals and an exportin-1-dependent nuclear export signal (NES). We now demonstrate that mutation of this NES impairs the incorporation of Vpr into newly formed virions. Furthermore, we find that the Vpr NES is required for efficient HIV replication in tissue macrophages present in human spleens and tonsils. These findings underscore how the nucleocytoplasmic shuttling of Vpr not only contributes to nuclear import of the HIV-1 PIC but also enables Vpr to be present in the cytoplasm for incorporation into virions, leading to enhancement of viral spread within nondividing tissue macrophages.Human immunodeficiency virus type 1 (HIV-1) and other primate lentiviruses are able to infect nondividing cells, notably terminally differentiated macrophages (41), an important viral reservoir within the infected host (31,34,53). This biological feature distinguishes the lentiviruses from the oncoretroviruses (or gammaretroviruses), in which cell division associated with nuclear membrane dissolution is required for infection (33,42,62). HIV-1 is also able to infect resting, nondividing T cells in lymphoid tissues (13). These nondividing T cells may contribute to the establishment of protected reservoirs in the host, undermining attempts to eradicate virusproducing cells in the long term (5,6,15,56,77).After entry by fusion and uncoating, the viral reverse transcriptase complex traverses the cytoplasm while reverse transcribing the two strands of RNA into DNA (20), forming the viral preintegration complex (PIC). The nuclear envelope forms a barrier that the PIC must negotiate. The nuclear envelope is studded with nuclear pore complexes (NPCs) that form a conduit with a central aqueous channel mediating bidirectional transport of many macromolecules. The NPC corresponds to a 125-MDa structure comprising 50 to 100 polypeptides. Many of these proteins are members of the nucleoporin family characterized by FG repeats (46). During active transport, the central aqueous channel accommodates protein complexes as large as 25 nm in diameter. However, the HIV-1 PIC exhibits a Stokes diameter of 56 n...

These results demonstrate functional integrity of the CN/NFAT signaling cascade in RB cells and suggest that CSA is cytotoxic to RB cells through inhibition of this pathway and consequent apoptosis induction.

To enter human cells, HIV-1 usually uses CD4 and 1 of 2 coreceptors: CCR5 and CXCR4. Interestingly, even though CCR5 is expressed on far fewer T cells than is CXCR4, many patients in early- and late-stage HIV disease maintain high levels of CCR5-tropic (R5) viruses. We hypothesized that such high R5 viral loads may be sustained because, relative to CXCR4-tropic (X4) HIV-1 infection, R5 HIV-1 infection of permissive CD4(+)CCR5(+)CXCR4(+) T cells results in the production of significantly more infectious virus particles per target cell. To investigate this possibility, we compared the levels of virus production per target cell after isogenic R5 and X4 HIV-1 infection of 2 in vitro primary human lymphocyte culture systems: T-cell receptor-stimulated blood-derived CD4(+) T cells and tonsil histoculture (which requires no exogenous stimulation for ex vivo infection). We provide evidence that R5 HIV-1 does indeed compensate for a small target cell population by producing, on average, 5 to 10 times more infectious virus per CCR5(+) target cell than X4 HIV-1. This replicative advantage may contribute to the predominance of R5 HIV-1 in vivo.

Es werden Wellenl~ngenmessungen des Spektrums einer kondensierten Entladung dureh Schwefeldampf ausgefiihrt. Es treten neben den Schwefelfunkenlinien auch stark die Bogenlinien auf. Es gelingt, das bisher bekannte Termsystem yon S I zu vervollst~indigen und viele, schon yon Frerichs gemessene Linien einzuordnen. Dutch eine Serienrechnung werden die Terme neu normiert.

Bei der Aufnahme yon Lithiumexplosionsspektren wurden die verbotenen I4ombinationen 1 s --md (m = 3, 4, 5) in Absorption gefunden. ~ Die yon Anderson** und anderen eingehend behandelte und zur Untersuchung der Spektren verschiedener Elemente benutzte Methode der elel/triseh zerst~ubten Dr~hte wurde in vorliegender Arbeit auf Lithium angewandt. In diesem Falle hat man es mit einem verh~ltnismal~ig einfaehen Spektrum zu tun und hofft deshalb auf besonders durehsiehtige Verh~tnisse; au~erdem hat Lithium gegeniiber den anderen Alkalien den Vorzug, dal3 es sieh leichter in Drahtform verarbeiten l~Bt.Apparatur.