Susceptibility of inbred strains of mice to murine AIDS (MAIDS) correlates with target cell expansion and high expression of defective MAIDS virus.

Murine AIDS (MAIDS) is readily induced by the Duplan strain of defective murine leukemia virus in susceptible C57BL/6 mice. To identify mouse strains resistant to MAIDS, and to understand the genetic factors controlling susceptibility to the disease, we screened more than 20 inbred strains of mice for their susceptibility to MAIDS. For this study, mice of the Fv-1n/n, Fv-1b/b, or Fv-1n/b genotype were inoculated with stocks of defective MAIDS virus pseudotyped with N-tropic, B-tropic, or NB-tropic helper murine leukemia virus, respectively. Strains could be classified as susceptible, resistant, or moderately resistant. None of the individual H-2 haplotypes examined appears to explain resistance to MAIDS by itself. However, a very good correlation between the susceptibility or resistance phenotype and the presence or absence of defective proviral DNA and RNA in the spleen of these animals was found. Since the presence of defective proviral DNA and RNA reflects the oligoclonal proliferation of the cells infected by the defective MAIDS virus, our results strongly suggest that this target cell expansion is genetically controlled and is necessary and perhaps even sufficient for the development of the disease.     

The p15gag and p12gag regions are both necessary for the pathogenicity of the murine AIDS virus.

The defective murine AIDS (MAIDS) virus has unique sequences in its p15gag and p12gag regions. To clarify whether these sequences are responsible for the development of MAIDS, we constructed recombinant viruses by replacing various regions of the gag gene of the nonpathogenic replication-competent LP-BM5 ecotropic virus with those of the MAIDS virus. Recombinants containing both unique sequences of the MAIDS virus were replication defective and induced MAIDS. However, a recombinant containing either the p15gag or p12gag region of the MAIDS virus was also replication defective but nonpathogenic in mice. A recombinant virus containing only the p30gag region of the MAIDS virus was replication competent and nonpathogenic. These results indicate that the p15gag and p12gag regions of the MAIDS virus do not function like those of replication-competent viruses and that both of the unique sequences in the p15gag and p12gag regions are required to develop MAIDS.     

The majority of cells infected with the defective murine AIDS virus belong to the B-cell lineage.

Murine AIDS (MAIDS) is caused by a defective retrovirus which encodes a gag fusion protein (Pr60gag). We previously reported that this virus induced an oligoclonal proliferation of infected cells and suggested that this cell expansion was an important event in the pathogenesis of MAIDS. To identify these target cells, we constructed novel defective viruses whose genomes could be detected with specific probes. Helper-free stocks of these viruses induced MAIDS. Using in situ hybridization and immunocytochemistry and Southern analysis, we found that most infected cells belong to the B-cell lineage. Transformation of these B cells appears to be the primary event responsible for the development of immunodeficiency. This animal model may be relevant to our understanding of AIDS, of the immunodeficiencies associated with B-cell lymphoproliferative disorders, and of the role of B-cell proliferation and transformation in the effects of superantigens, since Pr60gag appears to be a superantigen.     

Analysis of role of CD8+ T cells in resistance to murine AIDS in A/J mice.

The mixture of retroviruses termed LP-BM5 murine leukemia virus (MuLV) contains a replication-defective genome (BM5def), the crucial element for induction of murine AIDS (MAIDS), as well as helper B-tropic ecotropic and mink cell focus-forming MuLV. Among Fv-1b mouse strains, C57BL mice are sensitive to infection by these viruses and to development of MAIDS, but A/J mice are highly resistant to all viral components and to induction of disease. Inasmuch as previous genetic studies indicated a major role in susceptibility for the H-2D locus within the MHC, the effect of CD8+ T cells in A/J resistance to MAIDS was analyzed by depletion of this subset using mAb. A/J mice treated with anti-CD8 mAb beginning soon after inoculation with LP-BM5 MuLV developed disease within 5 wk after virus inoculation. Histopathologic and flow cytometry alteration of tissues and cells from the mAb-treated mice were identical to those seen in virus-infected MAIDS-sensitive strains, and assays for MuLV demonstrated high-level expression of ecotropic MuLV and integration of BM5def. Parallel studies of A/J mice treated with anti-CD4 mAb after infection revealed enhanced expression of ecotropic MuLV but no integration of BM5def, and no signs of MAIDS were detected. These observations indicate that CD8+ T cells are critical in the resistance of A/J mice to LP-BM5 MuLV replication and development of disease and suggest that CD4+ T cells play a role in regulation of ecotropic virus replication.     

Myristylation of Pr60gag of the murine AIDS-defective virus is required to induce disease and notably for the expansion of its target cells.

Murine AIDS (MAIDS) is characterized by severe lymphadenopathy and splenomegaly. The proliferation of the infected target B cells is also an important manifestation of the disease (M. Huang, C. Simard, D. G. Kay, and P. Jolicoeur, J. Virol. 65:6562-6571, 1991). The etiologic agent of MAIDS is a defective murine leukemia virus that is deleted of most of its pol and env genes and appears to encode a single protein, the Gag precursor Pr60gag protein. Pr60gag is myristylated and attached to the plasma membrane. To study the role myristylation on the function of Pr60gag, we have generated a myristylation-negative (Myr-) mutant of the MAIDS defective virus. We found that Myr- Pr60gag interacted less tightly with the plasma membrane. In addition, the Myr- MAIDS defective virus mutant was unable to induce expansion of infected cells and was nonpathogenic. These results emphasize the essential role of Pr60gag in the disease process. Our data also suggest that Pr60gag, once recruited to the cell membrane through its myristylation, interacts with other membrane-bound effectors to send signals to induce proliferation of the infected cells and to initiate immune dysfunctions.     

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.     

Studies of the susceptibility of nude, CD4 knockout, and SCID mutant mice to the disease induced by the murine AIDS defective virus.

Murine AIDS (MAIDS) is induced by a defective retrovirus that infects lymphocyte cells of the B lineage. To determine whether functional T cells are required for the infection of B cells, T-cell-deficient mice (nude, CD4 knockout, and SCII)) were infected with helper-free stocks of the MAIDS defective virus. Infection of B cells was monitored by Northern blot analysis and in situ hybridization. The C57BL/6 nude mice contained clusters of infected B cells, but less so than did the euthymic mice. In contrast, the (C57BL/6 x BALB/c)F1 nude mice harbored more infected B cells than did their euthymic littermates when maintained in a pathogen-free environment. Clusters of infected B cells were also detected in the MAIDS virus-infected CD4-/- knockout mice despite the total absence of CD4+ T cells in these mice. However, infected cells were not detected in SCID mice (deficient in mature T and B cells) inoculated with the same virus, indicating that precursor B cells are not a target of the virus in the absence of mature CD4+ T cells. These data confirm that the primary event in the development of MAIDS is the infection of relatively mature peripheral B cells and that CD4+ T cells are required to promote the expansion of these infected B cells.     

Induction of B-Cell Lymphoma in BALB/c Nude Mice with an Ecotropic, B-Tropic Helper Virus Present in the Murine AIDS Virus Stock

The pathogenicities of the murine AIDS (MAIDS) virus complex (LP-BM5) and ecotropic helper virus (BM5eco) isolated from the complex to BALB/c nude mice were studied to elucidate the possible role of replication-competent helper virus in inducing the monoclonal outgrowth of lymphoid cells. Neither LP-BM5 nor BM5eco was pathogenic in adult BALB/c nude mice. However, B-cell lymphoma developed with a very high frequency when either virus was inoculated into newborn BALB/c nude (nu/nu) mice. The cells from the B-cell lymphoma were easily transplanted into nude mice. These results suggested that ecotropic helper virus in the MAIDS virus complex plays an important role in inducing the monoclonal outgrowth of lymphoid cells under immunodeficient conditions caused by defective virus.     

小鼠艾滋病模型的建立及用鹿肠道病毒治疗的实验研究

用小鼠白血病病毒ＬＰ－ＢＭ５ＭｕＬＶ接种新生ＢＡＬＢ／Ｃ小鼠,感染后４～６个月可出现与人类ＡＩＤＳ极为相似的病理变化和免疫缺陷的症状,包括血免疫球蛋白增高、淋巴结肿大、Ｔ辅助淋巴细胞减少和淋巴细胞转化功能降低等。通常作为小鼠获得性免疫缺陷综合症即小鼠艾滋病（ＭＡＩＤＳ）的模型使用。本实验采用已证实具有溶瘤作用的鹿肠道病毒ＥＣＣＯ－１８株对小鼠艾滋病进行实验性治疗,结果表明鹿肠道病毒ＥＣＣＯ－１８可明显缓解艾滋病小鼠的淋巴结肿大和延长艾滋病小鼠的生存时间。提示鹿肠道病毒ＥＣＣＯ－１８治疗小鼠艾滋病有效。     

Impaired calcium mobilization in CD4+ and CD8+ T cells in a retrovirus-induced immunodeficiency syndrome, murine AIDS.

After infection with LP-BM5 murine leukemia viruses, susceptible strains of mice develop a severe and progressive immunodeficiency disease, termed murine AIDS (MAIDS), features of which include markedly impaired T cell response to mitogens or specific Ag stimulation and decreased production of IL-2. Since an elevation of intracellular calcium concentration resulting from binding of Ag to the TCR is associated with IL-2 production, T cells from mice either uninfected or infected with LP-BM5 murine leukemia viruses were examined by a calcium mobilization assay. Both CD4+ and CD8+ T cells from infected mice manifested impaired calcium mobilization responses upon in vitro stimulation with anti-CD3 mAb or Con A. The abnormalities appeared early after virus inoculation and showed no difference in time course between subsets of T cells. Frequencies of prestimulation calcium-positive cells among both CD4+ and CD8+ cells in mice with MAIDS were significantly higher than those for uninfected mice. These abnormalities were associated with presence of the MAIDS-inducing defective virus genome, but were not induced by infection of mice genetically resistant to development of MAIDS or with nonpathogenic helper murine leukemia virus, a virus component that induces high spontaneous proliferation of T cells, even in MAIDS-resistant mice.     

High frequency of transmission of murine AIDS virus in C57BL/10 mice via mother''s milk.

Maternal transmission of a murine leukemia virus (MuLV) mixture named LP-BM5 MuLV, which is knwon to induce murine AIDS (MAIDS), was investigated. Adult female C57BL/10 mice were inoculated intraperitoneally with LP-BM5 MuLV. When the virus-inoculated female mice developed splenomegaly or lymphadenopathy, they were mated with normal C57BL/10 male mice. Of 56 offspring born to MAIDS mothers, 14 appeared to develop MAIDS, as assessed by the occurrence of splenomegaly or lymphadenopathy as well as the mitogen response of spleen cells. The occurrence of MAIDS in offspring was found to be accompanied by the maternal transmission and expansion of a defective virus genome from which almost the entire pol and env regions are deleted. On the other hand, the ecotropic helper virus genome was detected in all offspring regardless of the occurrence of MAIDS. To examine the mode of maternal transmission of LP-BM5 MuLV, foster-nursing experiments were conducted. The ecotropic helper viruses were found in all normal offspring nursed by a MAIDS mother, and some of them developed MAIDS. In contrast, none of offspring born to a MAIDS mother that were nursed by an uninfected foster mother either carried the LP-BM5 MuLV or developed MAIDS. Finally, both the defective and the ecotropic helper viruses were detected in LP-BM5 MuLV-infected mother's milk. These results indicated that maternal transmission of LP-BM5 MuLV occurs with a high frequency and is mediated by mother's milk.     

The murine AIDS virus Gag precursor protein binds to the SH3 domain of c-Abl.

The Pr60gag protein of the murine AIDS (MAIDS) defective virus promotes the proliferation of the infected target B cells and is responsible for inducing a severe immunodeficiency disease. Using the yeast two-hybrid system, we identified the SH3 domain of c-Abl as interacting with the proline-rich p12 domain of Pr60gag. The two proteins were shown to associate in vitro and in vivo in MAIDS virus-infected B cells. Overexpression of Pr60(gag) in these cells led to a detectable increase of the levels of c-Abl protein and to its translocation at the membrane. These results suggest that this viral protein serves as a docking site for signaling molecules and that c-Abl may be involved in the proliferation of infected B cells.     

Mutational analysis of the murine AIDS-defective viral genome reveals a high reversion rate in vivo and a requirement for an intact Pr60gag protein for efficient induction of disease.

Pr60gag appears to be the only protein encoded by the murine AIDS (MAIDS)-defective virus. To study the role of Pr60gag or some other sequences of the viral genome in the pathogenicity of the virus, we have generated mutants of the defective viral genome. These mutant defective viruses, prepared as helper-free stocks, were inoculated into susceptible C57BL/6 mice. Mutant Du5H-A virus, which had a stop codon within gag MA(p15), did not induce target cell proliferation or MAIDS. Mutants Du5H-B and -C encoded truncated Pr60gag proteins containing, respectively, MA(p15)-p12 or MA(p15)-p12 and part of CA(p30). These mutants showed a very limited capacity to induce early cell expansion and were poorly pathogenic. Only recombinant (revertant) viruses were recovered from organs of diseased mice inoculated with these two mutants. Mutant Du5H-D was generated by deleting 1.4 kbp of the 3'-end sequences, outside the gag coding region. The levels of RNA and proteins made by this mutant were low. This mutant also reverting frequently but was nevertheless able to induce MAIDS at a low efficiency without reverting. Our results indicate that the Pr60gag protein is necessary and sufficient to induce MAIDS. These data also suggest that the Pr60gag protein needs to be relatively intact to be fully pathogenic. In addition, our study shows a very high reversion rate of some mutants and emphasizes the need to check for the presence of revertant (recombinant) viruses in diseased organs when working with mutants of the MAIDS-defective virus.     

Therapeutic effects of glycyrrhizin in mice infected with LP-BM5 murine retrovirus and mechanisms involved in the prevention of disease progression

Glycyrrhizin (GL), a plant extract, has been evaluated for its inhibitory effect on HIV replicationin vitro and for its improvement of clinical symptoms in HIV-infected patients. In this study, we used GL in a murine AIDS model (MAIDS) to evaluate these effects. C57BL/6 mice were inoculated with LP-BM5 murine leukemia virus to cause MAIDS. Treatment with GL supplemented with glycine and cysteine (Stronger Neo-Minophagen C, SNMC) was then begun on day 0 or 4 wks after virus inoculation. SNMC was administered three times a week for up to 19 wks. Immunological abnormalities were monitored with respect to the surface phenotype identified by two-color staining for CD3 and IL-2 receptorβ-chain. All mice infected with the virus alone developed MAIDS and died by 14 wks after infection. The immunopathogenesis was estimated to be an abnormal expansion of intermediate CD3 cells (i.e., extrathymic T cells) as well as other types of lymphocytes. SNMC did not change the total mortality rate. However, some mice that began the treatment on day 0 or 4 wks after infection survived 3 wks longer. Splenomegaly and lymphadenopathy in such mice were suppressed. These mice showed normal phenotypic features and normal responses to Con A. These results suggest that SNMC is effective in some MAIDS mice in preventing the progression of disease. When lymphocytes isolated from the liver, spleen and lymph nodes of diseased mice were culturedin vitro, they showed a spontaneous proliferation. Interestingly, such proliferation was inhibited by addition of liver lymphocytes, but not splenic lymphocytes, obtained from normal or SNMC-treated mice. Since liver lymphocytes contains intermediate CD3 cells with autoreactivity, they may possibly suppress the progression of disease.     

Characteristics and contributions of defective, ecotropic, and mink cell focus-inducing viruses involved in a retrovirus-induced immunodeficiency syndrome of mice.

LP-BM5 murine leukemia virus, a derivative of Duplan-Laterjet virus, contains a mixture of replication-competent B-tropic ecotropic and mink cell focus-inducing (MCF) viruses and a defective genome that is the proximal cause of a syndrome, murine AIDS (MAIDS), characterized by lymphoproliferation and immunodeficiency. The defective (BM5d) and ecotropic components of this mixture were molecularly cloned, and complete (BM5d) or partial (ecotropic) nucleotide sequences were determined. BM5d closely resembled the Du5H genome cloned from the Duplan virus, featuring a highly divergent p12 sequence in the gag open reading frame. In MAIDS-sensitive C57BL/6 mice, BM5d was detected in tissues within 2 weeks of infection but was absent from tissues of the MAIDS-resistant strain, A/J, 12 weeks after infection. B-cell-lineage tumors from mice with MAIDS contained and expressed BM5d, and clonal integrations of this genome were variably associated with clonal expansions of B cells in infected mice. Finally, mRNA crosshybridizing with a probe for BM5d was present in spleen but not kidney cells of uninfected B6 mice.     

Control of immunodeficiency and lymphoproliferation in mouse AIDS: studies of mice deficient in CD8+ T cells or perforin.

CD8+ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8+ T cells or deficient in perforin due to knockout of the beta2-microglobulin (beta2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the beta2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8+ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.     

Accelerated Progression of a Murine Retrovirus-Induced Immunodeficiency Syndrome In Fas Mutant C57BL/6/lpr/lpr Mice

We reported previously that CD4⁺ T cells and B cells in mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) caused by LP-BM5 murine leukemia virus (MuLV) mixtures increased the expression of Fas antigen (Fas) during progression of the disease. However, the contribution of the Fas/Fas ligand (Fas L) system to the pathogenesis of MAIDS remained unknown. Here, we examined the susceptibility of C57BL/6 (B6) lpr/lpr mice, which has been reported to be defective for the expression of Fas, to MAIDS. We found that the Thy 1.2^? CD4 T cells and IgK dull B220⁺ cells, which are characteristic of MAIDS, increased after the inoculation of LP-BM5 MuLV in B6 lpr/lpr mice. B22⁺ TCR αβ T cells, unique to lupus prone mice, also increased in the B6 lpr/lpr mice after infection. CD4⁺ B220⁺ TCR αβ T cells increased profoundly among the B220⁺ TCR αβ T cells from LP-BM5 MuLV-infected B6 lpr/lpr mice, while the B220⁺ TCR αβ T cells observed in non-infected B6 lpr/lpr mice were largely of the CD4^? CD8^? phenotype. A DNA PCR analysis of the LP-BM5 MuLV-infected B6 lpr/lpr mice revealed the genome integration of defective LP-BM5 virus, further confirming that MAIDS is inducible to B6 lpr/lpr mice. LP-BM5 MuLV-infected lpr/lpr mice died within 3 months, while MAIDS-infected B6 +/+ mice usually died within 5 to 6 months, and B6 lpr/lpr mice not infected with LP-BM5 MuLV lived more than 6 months. Taken together, these results suggest that MAIDS is inducible independently with functional Fas expression and the possibility of accelerated progression of murine AIDS and lpr-associated autoimmune disease in B6 lpr/lpr mice infected with LP-BM5 MuLV.     

Human herpesvirus 6 infects dendritic cells and suppresses human immunodeficiency virus type 1 replication in coinfected cultures

Human herpesvirus 6 (HHV-6) has been implicated as a cofactor in the progressive loss of CD4(+) T cells observed in AIDS patients. Because dendritic cells (DC) play an important role in the immunopathogenesis of human immunodeficiency virus (HIV) disease, we studied the infection of DC by HHV-6 and coinfection of DC by HHV-6 and HIV. Purified immature DC (derived from adherent peripheral blood mononuclear cells in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4) could be infected with HHV-6, as determined by PCR analyses, intracellular monoclonal antibody staining, and presence of virus in culture supernatants. However, HHV-6-infected DC demonstrated neither cytopathic changes nor functional defects. Interestingly, HHV-6 markedly suppressed HIV replication and syncytium formation in coinfected DC cultures. This HHV-6-mediated anti-HIV effect was DC specific, occurred when HHV-6 was added either before or after HIV, and was not due to decreased surface expression or function of CD4, CXCR4, or CCR5. Conversely, HIV had no demonstrable effect on HHV-6 replication. These findings suggest that HHV-6 may protect DC from HIV-induced cytopathicity in AIDS patients. We also demonstrate that interactions between HIV and herpesviruses are complex and that the observable outcome of dual infection is dependent on the target cell type.     

The role of CD4 T cells in the pathogenesis of murine AIDS

LP-BM5, a retroviral isolate, induces a disease featuring retrovirus-induced immunodeficiency, designated murine AIDS (MAIDS). Many of the features of the LP-BM5-induced syndrome are shared with human immunodeficiency virus-induced disease. For example, CD4 T cells are critical to the development of MAIDS. In vivo depletion of CD4 T cells before LP-BM5 infection rendered genetically susceptible B6 mice MAIDS resistant. Similarly, MAIDS did not develop in B6.nude mice. However, if reconstituted with CD4 T cells, B6.nude mice develop full-blown MAIDS. Our laboratory has shown that the interaction of B and CD4 T cells that is central to MAIDS pathogenesis requires ligation of CD154 on CD4 T cells with CD40 on B cells. However, it is not clear which additional characteristics of the phenotypically and functionally heterogeneous CD4 T-cell compartment are required. Here, in vivo adoptive transfer experiments using B6.nude recipients are employed to compare the pathogenic abilities of CD4 T-cell subsets defined on the basis of cell surface phenotypic or functional differences. Th1 and Th2 CD4 T cells equally supported MAIDS induction. The rare Thy1.2(-) CD4 subset that expands upon LP-BM5 infection was not necessary for MAIDS. Interestingly, CD45RB(low) CD4 T cells supported significantly less disease than CD45RB(high) CD4 T cells. Because the decreased MAIDS pathogenesis could not be attributed to inhibition by CD45RB(low) CD25(+) natural T-regulatory cells, an intrinsic property of the CD45RB(low) cells appeared responsible. Similarly, there was no evidence that natural T-regulatory cells played a role in LP-BM5-induced pathogenesis in the context of the intact CD4 T-cell population.     

Apoptosis by CD95 (Fas)-dependent and -independent mechanisms in Peyer's patch lymphocytes in murine retrovirus-induced immunodeficiency syndrome.

CD95 (Fas)/CD95 ligand (CD95 L)-mediated apoptosis is thought to be involved in the delayed progression of murine AIDS (MAIDS) induced by LP-BM5 murine leukemia virus (MuLV). We show evidence of apoptosis in lymphocytes of Peyer's patches (PP) at the early stage of MAIDS. Both T and B cells in PP expressed CD95 at the early stage of MAIDS and decreased in number thereafter. The decrease in T cells was not evident in CD95-mutated lpr mice with MAIDS, suggesting that CD95/CD95 L interaction is involved in the apoptosis of T cells in PP during the course of MAIDS. On the other hand, the number of B cells was also decreased in PP of lpr mice with MAIDS. The proliferative ability of B cells in PP of MAIDS mice in response to immunoglobulin M cross-linking or lipopolysaccharide was severely impaired, while the B cells normally proliferated in response to anti-CD40 monoclonal antibody. These findings imply that aberrantly activated B cells in PP undergo apoptosis independently of the CD95/CD95 L system during the course of infection with MAIDS virus.