Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV.

A central obstacle to the design of a global HIV-1 vaccine is virus diversity. Pathogen diversity is not unique to HIV-1, and has been successfully conquered in other fields by the creation of vaccine cocktails. Here we describe the testing of an HIV-1 envelope cocktail vaccine.

Recombinant Sendai virus as a novel vaccine candidate for respiratory syncytial virus.

Respiratory syncytial virus (RSV) is among the most important and serious pediatric respiratory diseases, and yet after more than four decades of research an effective vaccine is still unavailable. This review examines the role of the immune response in reducing disease severity; considers the history of RSV vaccine development; and advocates the potential utility of Sendai virus (a murine paramyxovirus) as a xenogenic vaccine vector for the delivery of RSV antigens. The immunogenicity and protective efficacy of RSV-recombinant Sendai virus vectors constructed using reverse genetics is examined.

HIV vaccines: brief review and discussion of future directions.

A major barrier to the design of a successful HIV vaccine is virus diversity,which is particularly apparent in the envelope glycoprotein, the target of neutralizing antibodies. An antibody generated to one envelope glycoprotein may not recognize an isolate bearing a different envelope glycoprotein. Thus, single-envelope glycoprotein vaccines have protected against homologous but not necessarily against heterologous challenge.

The HIV pandemic: a forgotten crisis?

The devastation caused by HIV and AIDS has touched virtually every world region. One concern is that the unrelenting nature of the HIV pandemic fosters a disposition, not of fear and determination, but of tolerance and complacency.

Application of the polyvalent approach to HIV-1 vaccine development.

One major obstacle to the design of a global HIV-1 vaccine is viral diversity. Presently, data suggest that a single antigen will not suffice to generate broadly reactive neutralizing antibodies to protect all individuals against all subtypes of HIV-1 infection. While some of the neutralizing epitopes are identified in the constant regions of the HIV-1 envelope (Env) glycoprotein, many are localized to variable regions and differ conformationally from one virus to the next.

CD8+ T-cells: are they sufficient to prevent, contain or eradicate HIV-1 infection?

The prevention of HIV-1 by vaccination has proven to be a formidable task. In an ongoing endeavor to end the HIV-1 pandemic, scientists seek vaccines that will elicit quantitatively and qualitatively robust B-cell and T-cell activities. Given that cytotoxic T-lymphocytes (CTL) play a substantial role in the immunological control of immunodeficiency virus infections, this review will focus on vaccines designed to elicit HIV-1-specific CTL.

Respiratory vaccination of mice against influenza virus: dissection of T- and B-cell priming functions.

We find that a single respiratory administration of replicationally inactivated influenza A viral particles most often elicits a waning serum antibody response, as the long-sustained bone marrow antiviral plasma cell populations characteristically induced by viral infection are lacking, though antiviral plasma cells at other sites may occasionally persist for a long time. To determine whether this alteration in the pattern of the B-cell response is a reflection of the nature of T-helper (Th) priming, we simultaneously primed B cells with inactivated influenza A/PR8(H1N1) and Th cells with infectious A/x31(H3N2). We show that Th cells cross-react extensively between these two viruses, although the antibody response to viral envelope glycoproteins is completely non-cross-reactive.

Clade, Country and Region-specific HIV-1 Vaccines: Are they necessary?

Today, scientists are often encouraged to custom-design vaccines based on a particular country or clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor to produce a unique vaccine for every world region or virus subtype may not be necessary.

HIV vaccine rationale, design and testing.

A central obstacle to the design of a global HIV vaccine is viral diversity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens.

Long lived multi-isotype anti-HIV antibody responses following a prime-double boost immunization strategy.

Despite decades of work, an effective HIV vaccine remains elusive. In an effort to elicit protective immunity, investigators have sought to define vaccines able to elicit durable HIV-specific B-cell and T-cell activities. Additionally, vaccines are sought which can induce antibodies of a variety of isotypes, as each isotype possesses unique attributes in terms of opsonization, Fc receptor binding capacity, complement fixation and location.

T cell epitope "hotspots" on the HIV Type 1 gp120 envelope protein overlap with tryptic fragments displayed by mass spectrometry.

Our previous work has shown that immunodominant T-helper cell epitopes cluster within distinct fragments on a single face of the HIV envelope gp120 protein. We show in this report that the general positions of immunodominant epitopes are shared by T cells derived from BALB/c, C57BL/6, and CB6F1 mice, yet the precise peptides recognized by the responding T cell populations may differ. In addition, we find that gp120 peptides displayed by tryptic digestion and mass spectrometry of a purified HIV envelope protein share location with peptides defined as immunodominant T cell targets.

A single domain in human DNA polymerase iota mediates interaction with PCNA: implications for translesion DNA synthesis.

DNA polymerases (Pols) of the Y family rescue stalled replication forks by promoting replication through DNA lesions. Humans have four Y family Pols, eta, iota, kappa, and Rev1, of which Pols eta, iota, and kappa have been shown to physically interact with proliferating cell nuclear antigen (PCNA) and be functionally stimulated by it. However, in sharp contrast to the large increase in processivity that PCNA binding imparts to the replicative Pol, Poldelta, the processivity of Y family Pols is not enhanced upon PCNA binding.

Studies of the properties of human origin recognition complex and its Walker A motif mutants.

The eukaryotic six-subunit origin recognition complex (ORC) governs the initiation site of DNA replication and formation of the prereplication complex. In this report we describe the isolation of the wild-type Homo sapiens (Hs)ORC and variants containing a Walker A motif mutation in the Orc1, Orc4, or Orc5 subunit using the baculovirus-expression system. Coexpression of all six HsORC subunits yielded a stable complex containing HsOrc subunits 1-5 (HsORC1-5) with virtually no Orc6 protein (Orc6p).

Atomic force microscopic analysis of the binding of the Schizosaccharomyces pombe origin recognition complex and the spOrc4 protein with origin DNA.

In eukaryotes, the initiation of DNA replication requires the interaction between origin sequences and the origin recognition complex (ORC), which is highly conserved. In this report, atomic force microscopy (AFM) was used to examine the binding of Schizosaccharomyces pombe (sp) ORC and the spOrc4 protein with the sp autonomously replicating sequence 1 (ars1). AFM imaging revealed that spORC binding to ars1 occurred solely through spOrc4p and depended on the N-terminal AT-hook domains present in spOrc4p.

Accumulation of hRad9 protein in the nuclei of nonsmall cell lung carcinoma cells.

Background: DNA damage sensor proteins have received much attention as upstream components of the DNA damage checkpoint signaling pathway that are required for cell cycle control and the induction of apoptosis. Deficiencies in these proteins are directly linked to the accumulation of gene mutations, which can induce cellular transformation and result in malignant disease.

Methods: Using 48 sets of tumor tissue specimens and peripheral normal lung tissue specimens from 48 patients with nonsmall cell lung carcinoma (NSCLC) who underwent surgery, the authors investigated the expression of hRad9 protein, a member of the human DNA damage sensor family, using immunohistochemical and Western blot analyses.

A conserved interaction between the replicative clamp loader and DNA ligase in eukaryotes: implications for Okazaki fragment joining.

The recruitment of DNA ligase I to replication foci and the efficient joining of Okazaki fragments is dependent on the interaction between DNA ligase I and proliferating cell nuclear antigen (PCNA). Although the PCNA sliding clamp tethers DNA ligase I to nicked duplex DNA circles, the interaction does not enhance DNA joining. This suggests that other factors may be involved in the joining of Okazaki fragments.

Identification of retained intracanalicular plugs with ultrasound biomicroscopy.

Background: Punctal plugs may be associated with complications, the most common being secondary epiphora due to canalicular obstruction. Simple lacrimal irrigation will diagnose an obstruction within the canaliculus but will not determine whether the plug is still present at the site of the obstruction. We performed a study to determine the feasibility of imaging retained intracanalicular plugs with ultrasound biomicroscopy (UBM).

Inhibins, activins, and follistatin in the aging female and male.

Dimeric inhibins, activins, and follistatin (FS) were all initially characterized as reproductive endocrine hormones that regulate follicle-stimulating hormone (FSH) secretion. This model, however, has expanded under the weight of current medical evidence. Activin appears to play a central auto/paracrine role in reproductive and nonreproductive tissues.

Safety and immunogenicity of intranasal murine parainfluenza virus type 1 (Sendai virus) in healthy human adults.

Human parainfluenza virus-type 1 (hPIV-1) is the most common cause of pediatric laryngotracheobronchitis (croup) and results in close to 30,000 US hospitalizations each year. No effective vaccine is available. We examined murine PIV-1 (Sendai virus, SeV) as a live, xenotropic vaccine for the closely related human PIV-1 in a phase I, dose escalation study in healthy adults.

Recombinant Sendai virus expressing the G glycoprotein of respiratory syncytial virus (RSV) elicits immune protection against RSV.

Although RSV causes serious pediatric respiratory disease, an effective vaccine does not exist. To capture the strengths of a live virus vaccine, we have used the murine parainfluenza virus type 1 (Sendai virus [SV]) as a xenogeneic vector to deliver the G glycoprotein of RSV. It was previously shown (J.

Minor components of a multi-envelope HIV vaccine are recognized by type-specific T-helper cells.

HIV has thus far evaded control by vaccines, in part due to the high diversity among viral isolates. To effectively target HIV diversity, we propose that multi-envelope HIV vaccines should be designed. We hypothesize that minor components of complex envelope cocktail vaccines can be immunogenic and can thus elicit unique T-cell responses.