The Effects of Curcuma longa L., Purple Sweet Potato, and Mixtures of the Two on Immunomodulation in C57BL/6J Mice Infected with LP-BM5 Murine Leukemia Retrovirus.

The immune response is stimulated to protect the body from external antigens and is controlled by several types of immune cells. In the present study, the immunomodulatory effects of Curcuma longa L., purple sweet potato, and mixtures of the two (CPM) were investigated in C57BL/6 mice infected with LP-BM5 murine leukemia virus (MuLV). Mice were divided into seven groups as follows: normal control, infected control (LP-BM5 MuLV infection), positive control (LP-BM5 MuLV infection+dietary supplement of red ginseng 300 mg/kg body weight), the original powder of C. longa L. (C; LP-BM5 MuLV infection+dietary supplement of C 189 mg/kg body weight), the original powder of purple sweet potato (P; LP-BM5 MuLV infection+dietary supplement of P 1811 mg/kg body weight), CPM Low (CPL; LP-BM5 MuLV infection+CPM 2 g/kg body weight), and CPM High (CPH; LP-BM5 MuLV infection+CPM 5 g/kg body weight). Dietary supplementation lasted for 12 weeks. Dietary supplementation of CPM inhibited LP-BM5 MuLV-induced lymphadenopathy and splenomegaly and inhibited reduction of messenger RNA (mRNA) expression of major histocompatibility complex (MHC) I and II. Moreover, CPM reduced the decrease in T- and B cell proliferation, reduced the population of CD4(+)/CD8(+) T cells, and remedied the unbalanced production of T helper-1 (Th1)/T helper-2 (Th2) cytokines in LP-BM5 MuLV-infected mice. In addition, CPM inhibited reduction of phagocytosis in peritoneal macrophages and decreased serum levels of immunoglobulin A (IgA), immunoglobulin E (IgE), and immunoglobulin G (IgG). These results suggest that CPM had a positive effect on immunomodulation in C57BL/6 mice induced by LP-BM5 leukemia retrovirus infection.

Murine cytomegalovirus downregulates interleukin-17 in mice with retrovirus-induced immunosuppression that are susceptible to experimental cytomegalovirus retinitis.

Interleukin-17 (IL-17), a pro-inflammatory cytokine produced by CD4+ Th17 cells, has been associated with the pathogenesis of several autoimmune diseases including uveitis. The fate of IL-17 during HIV/AIDS, however, remains unclear, and a possible role for IL-17 in the pathogenesis of AIDS-related diseases has not been investigated. Toward these ends, we performed studies using a well-established animal model of experimental murine cytomegalovirus (MCMV) retinitis that develops in C57/BL6 mice with retrovirus-induced immunosuppression (MAIDS). After establishing baseline levels for IL-17 production in whole splenic cells of healthy mice, we observed a significant increase in IL-17 mRNA levels in whole splenic cells of mice with MAIDS of 4-weeks (MAIDS-4), 8-weeks (MAIDS-8), and 10-weeks (MAIDS-10) duration. In contrast, enriched populations of splenic CD4+ T cells, splenic macrophages, and splenic neutrophils exhibited a reproducible decrease in levels of IL-17 mRNA during MAIDS progression. To explore a possible role for IL-17 during the pathogenesis of MAIDS-related MCMV retinitis, we first demonstrated constitutive IL-17 expression in retinal photoreceptor cells of uninfected eyes of healthy mice. Subsequent studies, however, revealed a significant decrease in intraocular levels of IL-17 mRNA and protein in MCMV-infected eyes of MAIDS-10 mice during retinitis development. That MCMV infection might cause a remarkable downregulation of IL-17 production was supported further by the finding that systemic MCMV infection of healthy, MAIDS-4, or MAIDS-10 mice also significantly decreased IL-17 mRNA production by splenic CD4+ T cells. Based on additional studies using IL-10 -/- mice infected systemically with MCMV and IL-10 -/- mice with MAIDS infected intraocularly with MCMV, we propose that MCMV infection downregulates IL-17 production via stimulation of suppressor of cytokine signaling (SOCS)-3 and interleukin-10.

Identification of putative endogenous retroviruses actively transcribed in the brain.

Remnant proviral sequences in the genome resulting from the ancient germline infection of exogenous retroviruses are called endogenous retroviruses (ERVs). The transcriptional activation of human ERVs (HERVs) in the brain of patients with some neurologic diseases suggests that ERVs may participate in certain disease processes in the central nervous system. In this study, we identified putative murine ERVs (MuERVs) which are transcriptionally active in the brain and characterized their biological properties to better understand the ERVs' roles in the brain pathophysiology. The brain and selective non-nervous tissues (heart, muscle, adrenal gland, and salivary gland) of female C57BL/6J mice were subjected to RT-PCR analyses of MuERV expression by amplifying the 3'-end U3 regions and full-length/subgenomic transcripts. The expression patterns of the U3 regions and subgenomic transcripts in the brain were unique compared to the other tissues as well as the genomic MuERV profile. Two putative MuERVs (8,027 and 5,668 bp) were mapped on the mouse genome (chromosome 10, and chromosomes 4 and 8, respectively) using the MuERV U3 sequences, which were evidently expressed in the brain, as probes. Biological properties of these putative MuERVs, such as transcription potential, primer binding site, coding potential, integration age, recombination, and flanking host genes, were characterized. In particular, one of the two putative MuERV isolates had coding potentials for intact group specific antigen (gag), and truncated polymerase (pol) and envelope (env) polypeptides, while the other was defective for all three polypeptides. The findings from this study suggest that a specific group of MuERVs are constitutively expressed in the brain and they may participate in normal and pathogenic events pertaining to the brain through their replication gene products (e.g., gag and env polypeptides) as well as interactions with flanking host genes.

CD19 signaling pathways play a major role for murine AIDS induction and progression.

Infection of genetically susceptible mice with the LP-BM5 mixture of murine leukemia viruses including an etiologic defective virus (BM5def) causes an immunodeficiency syndrome called murine AIDS (MAIDS). The disease is characterized by interactions between B cells and CD4(+) T cells resulting in polyclonal activation of both cell types. It is known that BM5def is expressed at highest levels in B cells and that B cells serve as viral APC. The CD19-CD21 complex and CD22 on the surface of B cells play critical roles as regulators of B cell responses to a variety of stimuli, influencing cell activation, differentiation, and survival. CD19 integrates positive signals induced by B cell receptor ligation by interacting with the protooncogene Vav, which leads to subsequent tyrosine phosphorylation of this molecule. In contrast, CD22 negatively regulates Vav phosphorylation. To analyze the role of CD19, CD21, Vav, and CD22 in MAIDS, we infected mice deficient in CD19, CD21 (CR2), Vav-1, or CD22 with LP-BM5 murine leukemia viruses. Infected CR2(-/-) mice developed MAIDS with a time course and severity indistinguishable from that of wild-type mice. In contrast, CD19 as well as Vav-1 deficiency restricted viral replication and suppressed the development of typical signs of MAIDS including splenomegaly, lymphadenopathy, and hypergammaglobulinemia. Finally, CD22 deficiency was found to accelerate MAIDS development. These results provide novel insights into the B cell signaling pathways required for normal induction and progression of MAIDS.

Overexpression of interleukin-15 prevents the development of murine retrovirus-induced acquired immunodeficiency syndrome.

LP-BM5 murine leukemia virus (MuLV) infection causes murine acquired immunodeficiency syndrome (MAIDS), a disease characterized by varied functional abnormalities of immunocompetent cells. We found that MAIDS progression was severely retarded in IL-15 transgenic (Tg) mice constructed with cDNA encoding secretable IL-15 under the control of an MHC class I promoter. Several immune defects, including impaired natural killer activity, depressed IFN-gamma production by T cells stimulated with anti-T cell receptor cross-linking, and increased susceptibility to Mycobacterium bovis infection, were prevented in IL-15 Tg mice inoculated with LP-BM5 MuLV. Cytotoxic T lymphocyte response to a highly antigenic 10-mer peptide encoded by LP-BM5-defective virus gag p12 gene was detected in the spleen and peritoneal exudate cells from IL-15 Tg mice infected with LP-BM5 MuLV. Intramuscular injection of cDNA encoding secretable IL-15 also prevented the development of MAIDS. These results indicate that IL-15 prevents the progression of MAIDS and may provide insight into an immunotherapeutic approach using the IL-15 gene for controlling retrovirus-induced immunodeficiency.

Induction of CD4 T cell changes in murine AIDS is dependent on costimulation and involves a dysregulation of homeostasis.

Strong CD4 T cell activation and proliferation are seen in susceptible mice infected with the murine retroviral inoculum, LP-BM5, which produces an immunodeficiency syndrome called murine AIDS (MAIDS). We developed a short term adoptive transfer model of MAIDS to examine the requirements for the CD4 T cell response. Naive CD4 T cells from uninfected donors responded quickly after adoptive transfer into MAIDS-infected hosts, becoming activated and proliferating within several days. Using blocking mAbs to costimulatory ligands and CD4 T cells deficient in expression of their receptors, we found that the CD4 T cell response requires CD28:B7.1/B7.2 interactions, but not CTLA4 or CD40-CD40 ligand interactions. Naive CD4 T cells did not respond in H-2M-deficient mice with MAIDS, suggesting that disease requires recognition of self peptide-MHC complexes. The self MHC-dependent division and accumulation of large numbers of CD4 T cells suggest that MAIDS involves a disruption of the balance of homeostatic signals. Supporting this hypothesis, CD4 T cells from mice with MAIDS failed to regulate the homeostatic division of naive CD4 T cells in a cotransfer model. Thus, a combination of up-regulation of costimulatory ligands and disruption of homeostatic control may be responsible for CD4 lymphoproliferation in MAIDS.

B cell immunodeficiency fails to develop in CD4-deficient mice infected with BM5: murine AIDS as a multistep disease.

The immunodeficiency syndrome murine AIDS (MAIDS), caused by the BM5 retrovirus preparation, involves the activation, division, and subsequent anergy of the entire CD4(+) T cell population as well as extensive B cell hyperproliferation and hypergammaglobulinemia, resulting in splenomegaly and lymphadenopathy, followed many weeks later by death. The development of MAIDS requires CD4(+) T cells and MHC class II expression by the infected host, supporting a role for T-B interaction in disease development or progression. To explore this possibility, we examined development of MAIDS in mice deficient in CD4 (CD4 knockout), in which T-B interactions are compromised. We find that in CD4 knockout hosts, BM5 causes T cell immunodeficiency in the remaining T cells but has only a limited ability to induce B cell phenotypic changes, hyperproliferation, hypergammaglobulinemia, or splenomegaly. There is also delayed death of infected mice. This implies that CD4 dependent T-B interaction is needed to induce the B cell aspects of disease and supports a multistep mechanism of disease in which B cell changes follow and are caused by CD4(+) T cell effects.

Anti-Gag cytolytic T lymphocytes specific for an alternative translational reading frame-derived epitope and resistance versus susceptibility to retrovirus-induced murine AIDS in F(1) mice.

Murine AIDS (MAIDS) develops in susceptible mouse strains after infection with the LP-BM5 murine leukemia virus complex that contains causative defective, and ecotropic helper, retroviruses. We previously demonstrated that the MAIDS-resistant H-2(d) strains BALB/cByJ and C57BL/KsJ generate MHC class I (K(d)) restricted virus-specific CD8(+) cytolytic T lymphocytes (CTLs) that lyse cells expressing either defective or ecotropic gag proteins. In contrast, the congenic BALB.B and closely related C57BL/6J MAIDS-susceptible H-2(b) strains were unable to serve as a source of gag-specific CTLs (Schwarz and Green, 1994), suggesting that anti-gag CTLs might provide a basis for resistance to MAIDS. Although its susceptibility to MAIDS was unknown, the (BALB/c x C57BL/6J) F(1) (CBY6F(1)) strain could also produce H-2(d)-, but not H-2(b)-, restricted, anti-gag CTLs (Schwarz and Green, 1994). Because of this correlation between anti-gag CTLs and resistance to MAIDS, it was important to provide more direct evidence in support of CTL-mediated protection and to determine both the fine specificity of CByB6F(1) anti-gag CTLs, in comparison with the resistant C57BL/Ks and BALB/c strains, and the susceptibility of this F(1) strain to LP-BM5-induced MAIDS. We report here that no symptoms of MAIDS were observed in CBY6F(1) (H-2(dxb)) mice. For F(2) mice, in contrast to the high susceptibility of H-2(b/b) mice, 77% of H-2(d/d) and 81% of H-2(b/d) F(2) mice did not exhibit MAIDS after LP-BM5 infection. These results are in contrast to other published studies that concluded that susceptibility, rather than resistance, is dominant in F(1) (resistant x susceptible or susceptible x resistant) mice. We also show that CBY6F(1) anti-gag CTLs exhibit a fine specificity shared by the MAIDS-resistant BALB/c and C57BL/Ks strains, that is, the immunodominant gag epitope, SYNTGRFPPL, encoded by an alternative open reading frame. Together with our direct demonstration here that in vivo monoclonal antibody (mAb) depletion of CD8(+) T cells converts genetically resistant mice to MAIDS susceptibility, these data on the ability to mount anti-ORF2/SYNTGRFPPL, gag-specific CTL responses strongly suggest that CTLs are a primary factor in determining MAIDS resistance. Accordingly, given the K(d)-restricted nature of the CTLs, the main genetic determinant of resistance appeared to be the codominant expression of the resistant H-2(d) haplotype. Interestingly, however, 19% of H-2(d/b) and 23% of the H-2(d/d) F(2) mice had at least one clinical aspect of MAIDS, suggesting that a non-MHC genetic determinant(s) can negatively influence T-cell protection and thus disease outcome

The autoimmune accelerating yaa mutation does not accelerate murine AIDS.

Murine acquired immunodeficiency syndrome (MAIDS) is characterized by lymphoproliferation, polyclonal B cell activation resulting in the production of autoantibodies, and a progressive immunodeficiency. These are all hallmarks of some autoimmune diseases. Yaa is a Y-chromosome-linked gene that accelerates autoimmune diseases in some autoimmune-prone strains of mice. To further elucidate a possible relationship with autoimmunity, the effect of the Yaa gene on MAIDS was investigated. Analysis of phenotypic and functional disease parameters revealed that Yaa does not accelerate MAIDS disease. This is probably due to the generalized activation of most or all lymphoid cells in MAIDS, which cannot be enhanced by the Yaa gene. This result is in accordance with the selective enhancing effect of the Yaa gene on the immune response against self and foreign antigens in a specific genetic background. It suggests that the autoimmune response associated with MAIDS is a secondary phenomenon. Interestingly, even in wild-type C57BL/6 mice, autoantibody production may contribute overproportionally to the hypergammaglobulinemia associated with MAIDS.

Mice transgenic for a soluble form of murine cytotoxic T lymphocyte antigen 4 are refractory to murine acquired immune deficiency sydrome development.

Interactions between B and CD4+ T cells are central to the pathogenesis of retrovirus-induced murine acquired immune deficiency virus (MAIDS). Prompted by previous work showing that treatment with cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) partly inhibited the disease, we studied the course of infection in mice deficient for CD28-B7 interactions (mCTLA4-Hgamma1 transgenic mice). Despite a relative viral load identical to that of non-transgenic mice, the transgenic mice did not develop any of the major MAIDS symptoms (i.e. lymphoproliferation and immune anergy). The mCTLA4-Hgamma1 did not however, completely inhibit B-cell activation as indicated by a slight hypergammaglobulinaemia and microscopic blastic transformation. Absence of MAIDS in transgenic mice was associated with much lower levels of both interleukin-4 and interferon-gamma transcripts following viral infection. These results support the theory that the CD28/B7 costimulatory pathway is a critical determinant to MAIDS development.

Differential regulation of germinal center genes, BCL6 and SWAP-70, during the course of MAIDS.

Germinal centers (GC) are the sites of antigen-driven B cell switch recombination, V(D)J gene hypermutation, and selection to generate high-afinity CD38+ memory B cells. A marked expansion of GC associated with hypergammaglobulinemia followed by complete disruption of normal splenic architecture and a striking drop in immunoglobulin levels are prominent features of the murine retrovirus-induced immunodeficiency syndrome, MAIDS. B cell lymphomas are frequent in long-term infected mice. Normal GC formation is critically dependent on a number of genes including the transcription factor, Bcl6. Deregulated expression of BCL6 protein has been implicated in the development of human and mouse B cell lymphomas. Another nuclear protein, SWAP-70, has been identified as a subunit of the protein complex, SWAP, that recombines switch regions in vitro. To develop a fuller understanding of B cell biology in MAIDS, we examined the characteristics of BCL6, SWAP-70, CD38, and peanut agglutinin (PNA)-staining cells during the course of the disease. The levels of both nuclear proteins increased rapidly until 6-8 weeks after infection. During this time frame, BCL6 was expressed at highest levels in the usually rare CD4+ Thyl- T cell subset as well as in B cells. At later times. BCL6 levels dropped to undetectable levels while SWAP-70 levels continued to increase. Changes in the levels of either protein could not be ascribed to transcriptional regulation. PNA-reactive cells decreased in concert with BCL6 while CD38 staining increased with SWAP-70. These results demonstrate that progression of MAIDS results in the massive accumulation of B cells with the morphology of secretory cells that behave like post-GC cells for expression of BCL6 and CD38, and for PNA-staining but with abnormally high-level expression of SWAP-70.

Upregulation of Gfi-1, a gene involved in IL-2-independent growth of T cells, in a murine retrovirus-induced immunodeficiency syndrome.

BACKGROUND: A prominent feature of retrovirus-induced immunodeficiency in mice (MAIDS) is early polyclonal activation of CD4+ T cells followed by the appearance of monoclonal lymphomas marked by clonal proviral integrations. These events appear to occur independent of interleukin-2 (IL-2), suggesting the activity of an alternative growth-promoting pathway. We studied the possible contributions to T cell expansion of a gene, Gfi-1, previously shown to confer IL-2 independence to rat T cell lymphomas. MATERIALS, RESULTS, CONCLUSIONS: We studied 17 mice with MAIDS that had clonal populations of T cells. Proviral integrations at Gfi-1 were detected in two animals. These integrations were associated with enhanced transcription of Gfi-1. Unexpectedly, elevated levels of Gfi-1 transcripts were also observed in four T cell lymphomas without detectable integrations at this locus. This suggests that IL-2-independent T cell growth in MAIDS may be driven by transcriptional activation of Gfi-1 by proviral insertion or transactivation.

The xid mutation plays an important role in delayed development of murine acquired immunodeficiency syndrome.

Infection of C57BL/6 mice with LP-BM5 murine leukemia virus (MuLV) leads to the development of murine acquired immunodeficiency syndrome (MAIDS) characterized by abnormal lymphoproliferation, hypergammaglobulinemia and severe immunodeficiency. Progression of MAIDS is delayed in X chromosome-linked immunodeficient (XID) mice, which have an abnormality of Bruton's tyrosine kinase (Btk) and lack functionally mature B cells including CD5+ B cells. In this study, we report the following four major findings. (i) Susceptibility to disease induction is not reconstituted by transfer of CD5+ B cells to XID mice. (ii) Spleen cells from asymptomatic XID mice are able to transmit MAIDS to wild-type mice. (iii) MAIDS can be transmitted to XID mice with the transfer of B cells, but not T cells, from C57BL/6 mice with MAIDS. (iv) Cells which undergo massive lymphoproliferation in XID mice with MAIDS by cell transfer are of host origin, but are not from the donor. We suggest from these results that a B cell subpopulation that is impaired in XID mice plays an important role in the initiation of MAIDS.

Recovery from retrovirus-induced immune suppression in BDP/J mice: dominance of the "regressor' phenotype.

Murine acquired immune deficiency syndrome (MAIDS) is an immunosuppressive disease of mice induced by infection with the LP-BM5 murine leukemia virus (MuLV) retrovirus isolate. Certain inbred strains of mice are resistant to disease, but F1 crosses between sensitive and resistant strains are predominantly sensitive to MAIDS. One inbred strain, BDP, demonstrates a novel disease phenotype, recovery of immune function after a period of profound immune suppression. This trait is genetically dominant in crosses between BDP and either sensitive or resistant strains. The 'regressor' phenotype reveals the existence of a mechanism for recovery from immunosuppressive retrovirus infections, which may be of import in developing therapies for AIDS patients.

MHC class I presentation of an exogenous polypeptide antigen encoded by the murine AIDS defective virus.

Peptides derived from endogenous proteins are presented by MHC class I molecules, whereas those derived from exogenous proteins are presented by MHC class II molecules. This strict segregation has been reconsidered in recent reports in which exogenous antigens are shown to be presented by MHC class I molecules in the phagocytic pathway. In this report, the presentation pathway of an exogenously added highly antigenic polypeptide encoded by the murine AIDS (MAIDS) defective virus gag p12 gene is investigated. A 25-mer polypeptide (P12-25) encoded within the gag p12 region of the MAIDS defective virus was found to be effective in stimulating unprimed B6 (H-2b) CD8+ T cells in vitro. The presentation of P12-25 is sensitive to cytochalasin B and D, brefeldin A and gelonin, a ribosome-inactivating protein synthesis inhibitor, but less sensitive or resistant to lactacystin, a highly specific inhibitor of the proteasome. Interestingly, CA-074, a selective inhibitor of cathepsin B, inhibited presentation of the polypeptide, indicating its involvement in the degradation of the P12-25 polypeptide. In fact, when P12-25 was digested with purified cathepsin B in vitro, a highly antigenic 11-mer peptide containing the class I (H-2Db)-binding motif was obtained. Our results favor the phagosome/macropinosome-to-cytosol-to-endoplasmic reticulum (ER)-to-cell surface pathway for exogenous antigens presented by MHC class I molecules. These findings may be relevant to exploiting peptide vaccines that specifically elicit CD8+ T cell immunity in vivo.

Competitive reverse transcription-polymerase chain reaction for quantifying murine AIDS virus.

The causative agent of murine AIDS (MAIDS) is the defective murine leukemia virus BM5d, that requires the replication-competent ecotropic MuLV (BM5e) helper virus. We developed a competitive quantitative PCR method including specific internal standards to quantify the expression of BM5d in the spleen of infected mice and to characterize BM5d expression kinetics following experimental infection. Specimen RNA was reverse-transcribed and co-amplified with a competitive template containing a gag sequence specific for BM5d that can be discriminated from that corresponding to wild-type cDNA by the presence of a unique restriction site, Bg/II. PCR products were quantified by means of densitometric analysis after ethidium bromide staining of gels. To standardise the RNA extraction and reverse transcription steps, the amount of defective-virus mRNA was compared to a constant copy number of murine beta actin mRNA. LP-BM5 production was measured in the spleen of infected mice. Defective gag mRNA production was compared to that of the ecotropic virus. The mRNA level of the defective virus and the titre of replicative virus increased with the duration of infection, and the amount of defective virus mRNA correlated with the titre of replicating virus.

Contribution of B cell subsets to delayed development of MAIDS in xid mice.

C57BL/6 (B6) mice develop a syndrome of progressive lymphoproliferation and immunodeficiency, murine AIDS (MAIDS), when infected with an etiologic replication-defective virus termed BM5def. Induction of MAIDS requires the presence of CD4+ T cells and B cells. B6 mice with altered conventional B cell function and a deficit in CD5+ B cells due to the xid mutation develop disease with a greatly prolonged latency. The association of this mutation with resistance to MAIDS was confirmed in studies of P.xid mice. To test the hypothesis that conventional B cells are required for rapid induction of disease, B6.xid mice were injected with spleen cells from nude mice or were given bone marrow from aged donors. Both sets of recipients developed advanced disease by 10 weeks post infection, suggesting that resistance to MAIDS in xid mutants may be due to effects of B cells other than the CD5+ subset.

Impact of MHC class I gene on resistance to murine AIDS.

Development of murine AIDS in mice following infection with LP-BM5 murine leukaemia virus (MuLV) is highly strain dependent, with strain differences determined by genes within and outside H-2. Among H-2 genes, the Dd gene is the most closely associated with resistance to LP-BM5 MuLV infection. However, the Dd-mediated resistance is highly influenced by outside H-2 genes, i.e. A lineage strains are more resistant than mice strains of B6/B10 lineage. In this study, the mice having BALB background were analysed and, similarly to A lineage mice, only Dd gene products were found to be required to provide resistance to LP-BM5 MuLV infection. Furthermore, BALB/c Kh mice bearing both Dd and Ld genes clearly showed obviously higher resistance than BALB/c-H-2dm2 mice solely having the Dd gene. In addition, in the long-term observation of the effect of the Dd gene on B6/B10 background mice, D8 mice having the Dd gene as a transgene and expressing a high level Dd gene product showed higher resistance than naturally recombinant B10.A(18R) mice. These results suggest that the MAIDS resistance associated with the D end loci is dependent on the level of expression of an MHC class I gene.

Sequence heterogeneity of murine acquired immunodeficiency syndrome virus: the role of endogenous virus.

A defective murine leukemia virus is the causative agent of murine acquired immunodeficiency syndrome (MAIDS). We have cloned cDNAs from both virus infected and non-infected cells using the PCR methods with primers corresponding to the franking sequence of the unique p12 gag gene. Sequence analysis of these cDNA clones revealed: (i) the presence of endogenous virus related to MAIDS virus in C57BL/6 mice, (ii) B cell lineage specific expression of endogenous virus and (iii) extensive heterogeneity of MAIDS virus recovered from virus infected cells due to the recombination of the related viruses (defective pathogenic virus, ecotropic virus and endogenous virus). These findings suggest that the creation of virus variants in infected cells may play an important role in virus pathogenesis and escape from immune attack during the development of MAIDS.