Interspecies transmission of macaque simian T-cell leukemia/lymphoma virus type 1 in baboons resulted in an outbreak of malignant lymphoma.

An outbreak of malignant lymphoma has been observed in one of the baboon (Papio hamadryas) stocks of Sukhumi Primate Center. More than 300 cases in this "high-lymphoma stock" have been registered since 1967. Human T-cell lymphotropic virus type 1 (HTLV-1)-related virus was implicated as the etiologic agent of Sukhumi baboon lymphoma. The origin of this virus remained unclear. Two possibilities were originally considered: the origin could be baboon simian T-cell leukemia/lymphoma virus type 1 (STLV-1) or HTLV-1 (before the outbreak started, some Sukhumi baboons were inoculated with human leukemic material). The third possibility entered recently: interspecies transmission of rhesus macaque STLV-1 to baboons. It was prompted by the finding of very close similarity between STLV-1 991-1cc (the strain isolated from a non-Sukhumi baboon inoculated with material from a Sukhumi lymphomatous baboon) and rhesus STLV-1. To test this hypothesis, we investigated 37 Sukhumi STLV-1 isolates from baboons of high-lymphoma stock by PCR discriminating rhesus type and baboon type STLV-1 isolates. All of them were proved to be rhesus type STLV-1. In contrast, all six STLV-1 isolates from baboons belonging to other stocks or populations were of baboon type. The PCR results were fully confirmed by DNA sequence data. The partial env gene gene sequences of all four STLV-1 isolates from Sukhumi lymphomatous baboons were 97 to 100% similar to the sequence of known rhesus STLV-1 and only 85% homologous with the sequence of conventional baboon STLV-1. Thus, interspecies transmission of STLV-1 from rhesus macaques (or closely related species) to baboons occurred at Sukhumi Primate Center. Most probably this event initiated the outbreak of lymphoma in Sukhumi baboons.     

Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques

Prolonged antiretroviral therapy (ART) is not likely to eradicate human immunodeficiency virus type I (HIV-I) infection. Here we explore the effect of therapeutic immunization in the context of ART during primary infection using the simian immunodeficiency virus (SIV251) macaque model. Vaccination of rhesus macaques with the highly attenuated poxvirus-based NYVAC-SIV vaccine expressing structural genes elicited vigorous virus-specific CD4 + and CD8+ T cell responses in macaques that responded effectively to ART. Following discontinuation of a six-month ART regimen, viral rebound occurred in most animals, but was transient in six of eight vaccinated animals. Viral rebound was also transient in four of seven mock-vaccinated control animals. These data establish the importance of antiretroviral treatment during primary infection and demonstrate that virus-specific immune responses in the infected host can be expanded by therapeutic immunization.     

A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration

Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl(4)-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl(4.) In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2'-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.     

Multiple origins of the western European house mouse in the Aeolian Archipelago: clues from mtDNA and chromosomes

The expansion of Mus musculus domesticus from its origin has been studied in detail. The colonization routes and times depended on its commensal habits which favoured a rapid and recent dispersal, making it difficult to unravel the expansion pattern. The situation is still obscure in the central Mediterranean area. Mitochondrial D-loop was sequenced for 65 mice from the Aeolian Archipelago and the sixteen haplotypes identified were compared with the 528 available mouse haplotypes. The central Mediterranean phylogeography, the demographic history of the Aeolian mice and the relationships between mtDNA and karyotypes was investigate. Five lineages are present, belonging to five of the haplogroups previously described for the Mediterranean basin, and most individuals fall within the European haplogroups. The Archipelago was subjected to multiple colonizations and chromosomal and molecular data agree in indicating Sicily and Italy as possible sources of colonization in recent times. Nevertheless, the signatures of earlier colonizations might have been lost through extinction and admixing of mice due to human movements. Drastic events during the entire colonization process have led to the present-day random distribution of haplotypes. Furthermore, Salina emerges as an ancestral condition and no relation between karyotype composition and haplotype variability was highlighted.     

Effect of reciprocal complementation of two defective human immunodeficiency virus type 1 (HIV-1) molecular clones on HIV-1 cell tropism and virulence.

Human immunodeficiency virus type 1 (HIV-1) displays both interstrain and intrastrain genetic variability. Virus populations with extensive microheterogeneity have been defined as swarms or quasispecies. Many of the genomes within HIV-1 swarms appear to be defective in one or more genes required for viral replication. It is unclear to what extent defective viruses play a role in the process of HIV-1 infection or in the pathogenesis of AIDS. We have isolated two biologically active HIV-1 clones: LW 12.3, which contains defects in the vif and vpr genes, and MN ST.1, which has a defect in the vpu gene. LW 12.3 is unable to replicate in peripheral blood mononuclear cells (PBMC). The growth of MN-ST.1 in SupT1 cells is marked by a 3-week lag in extracellular virus production and by the presence of unusually abundant viral buds. We demonstrate here that coinfection of PBMC with these two partially defective HIV-1 clones extends the cellular host range of LW 12.3, significantly increases the replication rate of both viral genomes, and eliminates the delay in production observed with the vpu-defective MN ST.1. When the lesions in vpr and vif of LW 12.3 are repaired, the resultant virus grows normally in PBMC. This is also the case when only vif is repaired, indicating that complementation of LW 12.3 in PBMC by MN ST.1 is mediated by vif in trans. The reciprocal complementation results in a dramatic increase of HIV-1 virulence. This two-component model represents a simplified version of the in vivo situation and illustrates one way in which interaction of defective viruses could increase the spread of infection and progression of disease.     

Interplay between alpha/beta and gamma interferons with B, T, and natural killer cells in the defense against herpes simplex virus type 1

The essential components of the immune system that control primary and chronic infection with herpes simplex virus type 1 (HSV-1) in mice were investigated. Infection within the first few days can be controlled by alpha/beta interferon (IFN-alpha/beta) alone without significant contribution of B, T, or NK cells. IFN-alpha/beta and IFN-gamma cooperate in the elimination of virus in the absence of these lymphocytes. In contrast, B, T, or NK cells appear to be required to control persistent infection with HSV-1. These results suggest that distinct and essential immune elements are recruited in a time-dependent fashion to control acute and persistent HSV-1 infection.     

Differentiation of C2C12 myoblasts is critically regulated by FAK signaling

This study examined whether focal adhesion kinase (FAK) plays a role in the differentiation of C(2)C(12) myoblasts into myotubes. Differentiation of C(2)C(12) myoblasts induced by switch to differentiation culture medium was accompanied by a transient reduction of FAK phosphorylation at Tyr-397 (to approximately 50%, at 1 and 2 h), followed by an increase thereafter (to 240% up to 5 days), although FAK protein expression remained unchanged. FAK and phosphorylated FAK were found at the edge of lamellipodia in proliferating cells, whereas the later increase in FAK phosphorylation in differentiating cells was accompanied by its preferential location at the tip of well-organized actin stress fibers. Hyperexpression of FAK autophosphorylation site (Tyr-397) mutant (MT-FAK) reduced FAK phosphorylation at Tyr-397 in proliferating cells and was accompanied by reduction of cyclin D1 and increase of myogenin expression. These cells failed to progress to myotubes in differentiation medium. In contrast, hyperexpression of a wild-type FAK construction (WT-FAK) increased baseline and abolished the transient reduction of FAK phosphorylation at Tyr-397 in serum-starved C(2)C(12) cells. Cells transfected with WT-FAK failed to reduce cyclin D1 and to increase myogenin expression, as well as to progress to terminal differentiation in differentiation medium. These data indicate that FAK signaling plays a critical role in the control of cell cycle as well as in the progression of C(2)C(12) cells to terminal differentiation. Transient inhibition of FAK phosphorylation at Tyr-397 contributes to trigger the myogenic genetic program, but its later activation is also central to terminal differentiation into myotubes.     

Vaccine-induced CD8+ central memory T cells in protection from simian AIDS

Critical to the development of an effective HIV vaccine is the identification of adaptive immune responses that prevent infection or disease. In this study we demonstrate in a relevant nonhuman primate model of AIDS that the magnitude of vaccine-induced virus-specific CD8(+) central memory T cells (T(CM)), but not that of CD8(+) effector memory T cells, inversely correlates with the level of SIVmac251 replication, suggesting their pivotal role in the control of viral replication. We propose that effective preventive or therapeutic T cell vaccines for HIV-1 should induce long-term protective central memory T cells.