HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection

The magnitude of immunologic defects observed in HIV-1-infected individuals before the development of overt AIDS is disproportionately high in comparison to the levels of infectious virus in these patients--suggesting that factors other than direct virus-induced cytopathology may be involved. With this in mind, we investigated the immunologic consequences of the interaction between purified HIV-1 gp120 and the CD4 molecules expressed by uncommitted as well as Ag-specific lymphocytes. HIV-1 gp120 exhibited a dose-dependent immunosuppressive effect on: 1) Ag-driven proliferation of cloned CD4+ lymphocytes, 2) OKT3-driven proliferation of cloned CD4+ lymphocytes, and 3) cytolytic activity of CD4+, EBV-specific CTL. Thus, HIV-1 gp120 can, in a manner similar to OKT4A antibodies, suppress T cell activation and the expression of cytolytic activities through its interaction with CD4. Additionally, activated CD4+ lymphoblasts can be rendered susceptible to immune cytolysis by virtue of their binding of purified gp120. This "targeting" of activated lymphoblasts can occur with levels of gp120 far below that which is needed to saturate all OKT4A-defined CD4 epitopes. Adsorbed gp120 could be demonstrated on the surface of these cells for up to 12 h, a sufficient time for interaction with host cytolytic elements. The data from these in vitro modeling experiments highlight one of many potential mechanisms of HIV-1 induced immunosuppression and lymphocyte destruction that can occur in the absence of infectious virus and that is based on the unique interaction between HIV-1 gp120 and its cellular receptor, CD4.     

Oncogene alterations in in vitro transformed rat tracheal epithelial cells.

10 derivations of rat tracheal epithelial (RTE) cells, including normal cells, normal primary cultures, 7 tumorigenic cell lines and 1 nontumorigenic cell line transformed in vitro by treatment with 7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (BP) and/or 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for oncogene alterations. No abnormalities of Ha-ras or Ki-ras were seen that were suggestive of amplification, rearrangement or the presence of RFLPs. Analysis of specific-point mutations in Ha-ras using Pst I digestion (codon 12, GGA to GCA) or Ha-ras and Ki-ras using Xba I (codon 61, CAA to CTA) were negative. In one cell line derived by DMBA treatment, changes in the c-myc restriction digest pattern were seen after incubation with Bam HI and Hind III. Northern analysis revealed consistent differences between normal and transformed cells when probed with Ha-ras; c-myc expression was of low intensity, and the expression of Ki-ras could not be detected. Transfection of RTE cell DNAs into NIH/3T3 cells did not result in the appearance of morphologic transformants. The studies suggest that Ha-ras or Ki-ras codon 61 A to T transversions (CAA to CTA) are not associated with the immortal/tumorigenic phenotype in RTE cells transformed by DMBA or TPA, and are in contrast to results reported in some other biological systems.     

Lipoprotein(a) in women twins: heritability and relationship to apolipoprotein(a) phenotypes.

Lp(a) is a unique lipoprotein consisting of an LDL-like particle and a characteristic protein, apo(a). Increased levels of Lp(a) constitute a risk factor for coronary heart disease. Variation in the size of the apo(a) protein is a phenotype controlled by the apo(a) gene on chromosome 6 and is related to Lp(a) plasma levels. Based on 169 MZ and 125 DZ adult female twin pairs, this study's purpose was to estimate the proportion of the variation in Lp(a) levels that is due to genetic influences and to determine the extent to which the apo(a) locus explains this heritability. Lp(a) levels were significantly more similar in MZ twins than in DZ twins: mean co-twin differences were 3.9 +/- 5.7 mg/dl and 16.0 +/- 19.9 mg/dl (P less than .001), respectively. Intraclass correlations were .94 in MZ twins and .32 in DZ twins, resulting in a heritability estimate of .94 (P less than .001). Heritability was then calculated using only co-twins with the same apo(a) phenotype: the heritability estimate decreased to .45 but was still highly significant (P less than .001). Therefore, on the basis of heritability analysis of women twins, Lp(a) levels are almost entirely genetically controlled. Variation at the apo(a) locus contributes to this heritability, although other genetic factors could be involved.     

Specificity switching of the P1 plasmid centromere-like site.

The P1 plasmid partition site acts like a centromere, promoting accurate segregation of copies to daughter cells. A 34 bp segment is essential for partition and binds the plasmid ParB protein. Additional sequences act as specificity elements that direct the choice of copies for partition. They include a second ParB binding site and a site for the host integration host factor protein. Sites lacking one or more of these additional elements are switched to a different specificity. Defined mutants were scored for partition specificity and protein binding. The results suggest that the wild-type site is folded in a specific DNA-protein complex. Disruption of the complex leads to an open configuration which, while still active in partition, has altered recognition specificity.