Envelope sequences of two new United States HIV-1 isolates.

One of the striking molecular aspects of the human T-cell lymphotropic virus type III (HTLV-III) (now called HIV-1) is an unusually large variability in the env genes of different isolates. These differences are clustered primarily within the coding sequences for the large envelope protein and are interspersed among regions within the env gene of relative constancy. Differences among the envelopes of isolates from Africa are so far greater than those among U.S. isolates, but few U.S. isolates have been characterized to date. We report the sequence of the env gene of two U.S. isolates [HTLV-III(MN) and (SC)] and compare them with previously characterized isolates. These two isolates differ substantially from all previously described isolates, especially in the region coding for the large envelope proteins. The env genes of the two new HIV-1 isolates contain conserved and hypervariable regions similar to what has been reported for other isolates, helping to further define those regions. A comparison of the envelope sequences of all the U.S. isolates shows that the similarity between any two ranges from 81 to 85% [except for LAV(BRU) and HTLV-III(BH10) which are 97% similar]. Similar analyses of the African (Zairean) isolates give significantly lower values [71 to 78%, except for 88% between LAV(ELI) and Z6]. This suggests that the African isolates diverged earlier than the U.S. isolates or that transmission of the virus has been more rapid in Africa. Two previous presumptive Haitian isolates are similar to each other and to the U.S. isolates to the same degree as are other U.S. isolates, but differ more markedly from the African isolates suggesting a common lineage of Haitian and U.S. HIV-1 isolates.

Molecular epidemiology of HTLV-I-associated non-Hodgkin's lymphomas in Jamaica.

As part of epidemiologic studies of human T-lymphotropic virus (HTLV)-I-associated malignancies in Jamaica, the authors evaluated 26 patients with non-Hodgkin's lymphoma for the presence of integrated HTLV-I provirus in their malignant cells. Fifteen of 26 patients had integrated provirus. All 15 also were HTLV-I antibody positive. Eleven patients did not have integrated provirus, and all 11 were antibody negative. All of the antibody-positive cases had onset of their disease in adulthood (age range, 21-57 years) as opposed to the broad age range of negative cases (4-66 years). Clinical features which were more common in provirus positive than negative patients included leukemic phase, skin involvement, and hypercalcemia, which are all features frequently seen in HTLV-I-associated adult T-cell leukemia/lymphoma (ATLL). The presence of skin involvement, circulating malignant cells, abnormal liver function tests, or the presence of two or more of these four features were statistically significantly different between virus-positive and virus-negative cases. Although the survival of positive cases (6 months) was shorter than that of negative cases (9 months), this was not statistically significant. The only significant determinant of survival was hypercalcemia, with those who developed hypercalcemia at some point in their disease course, independent of their HTLV-I status, surviving a mean of 5 months as compared to a mean of 17.5 months in those who never became hypercalcemic. The six HTLV-I-positive lymphomas that underwent cell typing were all primarily OKT4 positive, whereas two HTLV-I antibody-negative cases that were typed were B-cell lymphomas.

Molecular epidemiology of HTLV-I-associated non-Hodgkin's lymphomas in Jamaica

As part of epidemiologic studies of human T-lymphotropic virus (HTLV)-I-associated malignancies in Jamaica, the authors evaluated 26 patients with non-Hodgkin's lymphoma for the presence of integrated HTLV-I provirus in their malignant cells. Fifteen of 26 patients had integrated provirus. All 15 also were HTLV-I antibody positive. Eleven patients did not have integrated provirus, and all 11 were antibody negative. All of the antibody-positive cases had onset of their disease in adulthood (age range, 21-57 years) as opposed to the broad age range of negative cases (4-66 years). Clinical features which were more common in provirus positive than negative patients included leukemic phase, skin involvement, and hypercalcemia, which are all features frequently seen in HTLV-I-associated adult T-cell leukemia/lymphoma (ATLL). The presence of skin involvement, circulating malignant cells, abnormal liver function tests, or the presence of two or more of these four features were statistically significantly different between virus-positive and virus-negative cases. Although the survival of positive cases (6 months) was shorter than that of negative cases (9 months), this was not statistically significant. The only significant determinant of survival was hypercalcemia, with those who developed hypercalcemia at some point in their disease course, independent of their HTLV-I status, surviving a mean of 5 months as compared to a mean of 17.5 months in those who never became hypercalcemic. The six HTLV-I-positive lymphomas that underwent cell typing were all primarily OKT4 positive, whereas two HTLV-I antibody-negative cases that were typed were B-cell lymphomas. (AU)

Sequence of simian immunodeficiency virus and its relationship to the human immunodeficiency viruses.

The characterization of HIV-1 (HTLV-III/LAV), the human retrovirus associated with AIDS (acquired immune deficiency syndrome) has led to the identification of a group of related human and simian retroviruses which also infect CD4-bearing T lymphocytes. Simian T-lymphotropic virus type III (simian immodeficiency virus) from macaques (STLV-IIIMAC) induces symptoms similar to those of AIDS in infected macaques, but isolates from African green monkeys (STLV-IIIAGM) and mangabeys (STLV-IIMM) appear to be non-pathogenic in these animals. A human virus immunologically related to STLV-IIIAGM (HTLV-IV), reported to have been isolated from healthy humans, has been shown to be almost identical to STLV-IIIAGM, which has called into question the independent origin of these viruses. Here we report the complete DNA sequence of STLV-IIIAGM and analyse its relationship with the genomes of the HTLV-IIIB strain of HIV-1, HIV-2ROD (previously called LAV-2) and several ungulate lentiretroviruses. STLV-IIIAGM and HIV-2 are closely related, and more distantly related to HIV-1.

Structure of the long terminal repeat of simian lymphotropic virus type III (African green monkey) and its relatedness to that of HIV.

The simian T-lymphotropic virus type III (STLV-III[AGM]) is a retrovirus in wild African green monkeys which is serologically related to the human T-lymphotropic virus type III (HTLV-III/LAV-1/HIV) and other related human retroviruses. The long terminal repeats (LTR) contained in clones of viral DNA of (STLV-III[AGM]) were subcloned in M13 and their DNA sequence was determined and compared with that of HIV (HTLV-III[BH10]). The STLV-III(AGM) LTR is considerably larger than that of HTLV-III(BH10) (800 bp vs 634 bp) and contains a 498 bp U3 region, a 176 bp R region, and a 126 bp U5 region. These two LTR sequences share regions of significant homology. Regions of greatest homology include the 5' portion of U3, a core enhancer sequence in U3, sequences including and surrounding the TATAA promoter box in U3 and the AATAAA polyadenylation/termination signal in R, and the 3'-most region of U5. The relatively larger size of the STLV-III LTR is due to the presence in all three parts of the LTR of sequences which have no apparent homolog in the HIV LTR. Overall, the two LTRs are 47% homologous. Even greater homology (75%) is evident with a 300 bp segment including R and some of U3 from the LTR of another human retrovirus, HIV-2/LAV-2. The STLV-III LTR contains an imperfect 28 bp direct repeat in the R region which is not present in HIV. There are no obvious direct repeats in U3 homologous to the 10 bp repeat in the U3 of HTLV-III.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of in vivo growth of murine plasmacytoma MOPC-460 by monoclonal anti-idiotypic antibodies directed at distinct idiotypes of the immunoglobulin on the surface of MOPC-460.

The effect of several well-characterized monoclonal anti-idiotypic antibodies on the in vivo growth of idiotype-bearing murine plasmacytoma cells was examined. They were chosen from a group of immunoglobulin G1 antibodies which react with the binding site determinants of M460, the immunoglobulin A dinitrophenyl-binding myeloma protein secreted by and present on the surface of MOPC-460, and included representatives of two families which recognize different determinants in the M460 variable region. The antibodies were administered daily, beginning 2 hr before i.v. tumor cell inoculation, and the effect on the appearance of tumor colony formation in the spleen was judged after 14 days. All four antibodies tested were inhibitory. At the highest doses used, the number of splenic tumor foci was reduced by up to 97%. The effect was highly specific since the growth of MOPC-315, which also produces an immunoglobulin A dinitrophenyl-binding myeloma protein, was unaffected by the antibodies, and a similarly prepared immunoglobulin G1 monoclonal antibody against an unrelated idiotype did not affect the growth of MOPC-460. The inhibition of tumor growth appears to be independent of complement and antibody-dependent cellular cytotoxicity mechanisms. A small fraction of clones escaping the antitumor effect of anti-idiotypic antibodies has stopped expressing the idiotype.

Serum pseudouridine as a biochemical marker in the development of AKR mouse lymphoma.

Pseudouridine is a modified nucleoside derived from the degradation of some species of RNA, primarily transfer RNA, the level of which is elevated in biological fluids of tumor-bearing subjects. In order to study the relationship between pseudouridine levels and the development and progression of neoplasia, we have measured pseudouridine levels in the serum of inbred mice with high (AKR) and low (BALB/c) incidence of spontaneous lymphoma and in mice carrying transplantable lymphoid tumors. Our results show that the serum level of pseudouridine: (a) in healthy mice, is higher in females than in males; (b) increases significantly in female AKR mice in the period preceding the development of lymphoma (preneoplastic period occurring at about 6 months of age); and (c) is highest in AKR mice with lymphoma, the most elevated levels being found in mice with widely disseminated disease. The latter observation was confirmed by experiments with a transplantable AKR lymphoma (T2), where a positive correlation between tumor burden and serum pseudouridine levels was found. On the contrary, in BALB/c mice carrying a transplantable myeloma tumor (MOPC-460), no increase was seen despite the presence of a considerable tumor burden. The increase of pseudouridine in the preneoplastic period, in the absence of overt disease is viewed as an early sign of the development of the disease.

Synthesis, no synthesis, or synthesis and degradation of ribosomal ribonucleic acid in various Escherichia coli strains starved for an amino acid.

A standard stringent strain of Escherichia coli makes little or no ribosomal ribonucleic acid (RNA) during starvation for an essential amino acid, whereas the isogenic relaxed strain makes both ribosomal and messenger RNA. A third class of strains was found which continues to make ribosomal RNA during starvation, but the RNA made is apparently unstable. There is little accumulation of RNA in the third class of strains, and few complete newly formed chains of (3)H-ribosomal RNA are observed in sedimentation analyses, even after long labeling times.

Mechanism of carcinogenesis by RNA tumor viruses. I. An RNA-dependent DNA polymerase in murine sarcoma viruses.

A highly active and stable DNA polymerase was found in purified preparations of two murine sarcoma viruses. Enzyme activity is not detected in most virus preparations unless they are treated with low concentrations of a nonionic detergent such as Nonidet P-40. The incorporation of labeled thymidine triphosphate requires all four deoxyribonucleoside triphosphates and either Mg(2+) or Mn(2+). Enzyme activity is proportional to virus concentration and is linear with time up to 90 min. That the template is RNA is suggested by the reduction in polymerase activity upon treatment of murine sarcoma virus with RNase, and by the absence of detectable amounts of DNA in the virus. That the product is DNA is shown by the incorporation of all four deoxyribo-nucleoside triphosphates into an acid-insoluble product which is stable in alkali, is destroyed by DNase, sediments in alkaline sucrose gradients with a sedimentation coefficient of 7 S, and bands in isopycnic CsCl gradients with a mean buoyant density of 1.700.