Organ-specific autoimmune diseases such as oophoritis, gastritis, thyroiditis, and orchitis were induced in female or male nude (nu/nu) mice by the transfer of nu/+spleen cells from which particular Lyt T cell subset(s) had been removed: nu/+spleen cells treated with anti-Lyt-1 plus complement (C) caused disease in recipient nude mice; anti-Lyt-2 plus C-treated spleen cells, in contrast, did not. The cells responsible for disease induction are believed to be Thy-1+, Lyt-1-, 2,3- (Thy-1, Lyt-1, 2,3), since spleen cells treated with mixed antisera, including anti-Lyt-1 and anti-Lyt-2, plus C, could induce the disease with almost the same incidence as anti-Lyt-1 plus C-treated cells (oophoritis 50%, gastritis 25%, thyroiditis 10-20%, and orchitis 40%). Cells treated with mixed antisera of anti-Thy-1, anti-Lyt-1, and anti-Lyt-2, plus C, could not induce autoimmune disease. Each induced autoimmune disease could be adoptively transferred to other nude mice via spleen cells, with resulting histological lesion of corresponding organs and development of specific circulating autoantibodies. Since anti-Thy-1 plus C treatment of donor spleen cells abrogated the capacity to transfer the disease, we conclude that T cells are required as effector cells, and that these may develop from Lyt-1-, 2,3- cells. Lyt-1+, 2,3- cells were demonstrated to have suppressive activity upon the development of the diseases; induction of autoimmunity was completely inhibited by the cotransfer of Lyt-1+, 2,3- cells with Lyt-1-, 2,3- cells. When anti-Lyt-2 plus C-treated cells (i.e., Lyt-1+, 2,3- and Lyt-1-, 2,3- cells) were mixed with anti-Lyt-1 and anti-Lyt-2 plus C-treated cells (i.e., Lyt-1-, 2,3- cells) in various ratios, then transferred to nude mice, the development of each autoimmune disease was clearly inhibited, even by small doses of Lyt-1+, 2,3- cells. The autoimmune disease we were able to induce was quite similar to human organ-specific autoimmune disease in terms of the spectrum of organs involved, histopathological features, and the development of autoantibodies to corresponding organ components (oocytes, parietal cells, thyroid colloid, including thyroglobulin, and sperm).(ABSTRACT TRUNCATED AT 400 WORDS)

Sixteen isolates of simian retrovirus closely related to human immunodeficiency virus (HIV) were obtained from healthy African green monkeys (AGM) (Cercopithecus aethiops). The first isolate was obtained from a monkey seropositive for HIV, and the others were isolated from monkeys harboring antibodies to the first isolate. These simian retroviruses were referred to as simian immunodeficiency virus from AGM, SIV[AGM], due to their cross-reactivities with HIV structural proteins. These SIV[AGM] isolates were found by Western blotting analysis to have virus-specific proteins of 120, 66, 55, 32-40, 24 and 17 kDa, which were all similar in size to the analogous proteins of HIV. Putative gag proteins of p55, p24 and p17 were recognized by sera of human AIDS patients, but the corresponding env proteins of 32-40 and 120 kDa showed only weak cross-reactivity with those of HIV. The transmembrane glycoproteins of these 3 SIV[AGM] isolates showed size heterogeneity, being 32, 35 and 40 kDa. This virus had particles that were morphologically similar to those of HIV, and had Mg2+-dependent reverse transcriptase. Furthermore, the SIV[AGM] showed tropism and cytopathic effects on CD4-positive human cell lines. In a sero-epidemiological survey of SIV[AGM] in various non-human primates, 2 other African monkey species, the mandrill and de Brazza's monkey, were also found to have antibodies to SIV[AGM]. These HIV-related simian retroviruses will be important in determining the origin and transmission of HIV group viruses, and may provide useful animal models for studies on the infection and pathogenesis of HIV and AIDS.

Human immunodeficiency virus type 1 integrase (HIV-1 IN) is thought to have several putative roles at steps prior to integration, such as reverse transcription and nuclear transport of the preintegration complex (PIC).Here, we investigated new functional aspects of HIV-1 IN in the context of the viral replication cycle through point mutagenesis of Ser, Thr, Tyr, Lys, and Arg residues conserved in IN, some of which are located at possible phosphorylation sites. Our results showed that mutations of these Ser or Thr residues had no effect on reverse transcription and nuclear transport of PIC but had a slight effect on integration. Of note, mutations in the conserved KRK motif (amino acids 186 to 189), proposed previously as a putative nuclear localization signal Retroviruses establish a proviral state in which a doublestranded DNA copy of the viral genomic RNA is integrated into the host genome in a stable manner, through several steps following binding and entry into the target cell. These early events include uncoating, reverse transcription, nuclear transport of the viral genome, and integration. The viral enzyme integrase (IN) is encoded by the pol gene and the attachment (att) site located at the U3 and U5 termini of the viral DNA and is required for integration, which is the last event (6,14,43,47,53,56,57,61,66,74). The detailed mechanism of retroviral integration has been elucidated from in vitro studies using recombinant IN protein and a synthetic DNA substrate mimicking the viral att sites. These studies, using in vitro assays, have contributed much information toward the currently accepted mechanism of retroviral integration (reviewed in references 34, 42, and 75). Mutational and structural studies of human immunodeficiency virus type 1 (HIV-1) IN have identified three functional domains: a central catalytic core domain, an N-terminal zinc binding domain, and a C-terminal nonspecific DNA binding domain. The core domain contains the highly conserved D,D35E motif, which is directly involved in the catalytic activities of IN (7,23,46,48). The N-terminal domain contains a highly conserved HHCC motif, which binds to zinc. Through a tetrahedral attachment to the HHCC motif, zinc enhances both multimerization and enzymatic activities of 8,21,79). The C terminus, consisting of a structure that closely resembles Src homology 3 domains, possesses sequence-and metal ion-independent DNA binding activity (20,51). Each domain has been demonstrated to form a dimer or higher multimerization state of IN (8,19,20), which might be required for its full activity (13,21,22,66,70,73).Genetic analysis of HIV-1 IN has demonstrated multiple effects of mutations at steps distinct from integration. These steps include correct viral particle formation (24, 59), uncoating (54, 59), and reverse transcription (49,54). During the early events of the infection cycle, prior to integration, around 50-100 protomers of IN exist as one of the major components of the preintegration complex (PIC). This is composed of the viral genome, the matr...

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