Retrovirus-infected Mice Research Articles

PD-1 knockout on cytotoxic primary murine CD8+ T cells improves their motility in retrovirus infected mice.

Cytotoxic T lymphocyte (CTL) motility is an important feature of effective CTL responses and is impaired when CTLs become exhausted, e.g. during chronic retroviral infections. A prominent T cell exhaustion marker is programmed cell death protein 1 (PD-1) and antibodies against the interaction of PD-1 and PD-ligand 1 (PD-L1) are known to improve CTL functions. However, antibody blockade affects all PD-1/PD-L1-expressing cell types, thus, the observed effects cannot be attributed selectively to CTLs. To overcome this problem, we performed CRISPR/Cas9 based knockout of the PD-1 coding gene PDCD1 in naïve Friend Retrovirus (FV)-specific CTLs. We transferred 1,000 of these cells into mice where they proliferated upon FV-infection. Using intravital two-photon microscopy we visualized CTL motility in the bone marrow and evaluated cytotoxic molecule expression by flow cytometry. Knockout of PDCD1 improved the CTL motility at 14 days post infection and enhanced the expression of cytotoxicity markers. Our data show the potential of genetic tuning of naive antiviral CTLs and might be relevant for future designs of improved T cell-mediated therapies.

Regulatory T cells suppress the motility of cytotoxic T cells in Friend retrovirus–infected mice

Regulatory T cells suppress the motility of cytotoxic T cells in Friend retrovirus–infected mice

Differential and sequential immunomodulatory role of neutrophils and Ly6Chi inflammatory monocytes during antiviral antibody therapy

ABSTRACT Antiviral monoclonal antibodies (mAbs) can generate protective immunity through Fc-FcγRs interactions. We previously showed a role for immune complexes (ICs) in the enhancement of antiviral T-cell responses through FcγR-mediated activation of dendritic cells (DCs). Here we addressed how mAb therapy in retrovirus-infected mice affects the activation of neutrophils and inflammatory monocytes, two FcγR-expressing innate effector cells rapidly recruited to sites of infection. We found that both cell-types activated in vitro by viral ICs secreted chemokines able to recruit monocytes and neutrophils themselves. Moreover, inflammatory cytokines potentiated chemokines and cytokines release by IC-activated cells and induced FcγRIV upregulation. Similarly, infection and mAb-treatment upregulated FcγRIV on neutrophils and inflammatory monocytes and enhanced their cytokines/chemokines secretion. Notably, upon antibody therapy neutrophils and inflammatory monocytes displayed distinct functional activation states and sequentially modulated the antiviral immune response by secreting Th1-type polarizing cytokines and chemokines, which occurred in a FcγRIV-dependent manner. Consistently, FcγRIV- blocking in mAb-treated, infected mice led to reduced immune protection. Our work provides new findings on the immunomodulatory role of neutrophils and monocytes in the enhancement of immune responses upon antiviral mAb therapy.

I-152, a supplier of N-acetyl-cysteine and cysteamine, inhibits immunoglobulin secretion and plasma cell maturation in LP-BM5 murine leukemia retrovirus-infected mice by affecting the unfolded protein response

Excessive production of immunoglobulins (Ig) causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR). Hypergammaglobulinemia and lymphadenopathy are hallmarks of murine AIDS that develops in mice infected with the LP-BM5 murine leukemia retrovirus complex. In these mice, Th2 polarization and aberrant humoral response have been previously correlated to altered intracellular redox homeostasis. Our goal was to understand the role of the cell's redox state in Ig secretion and plasma cell (PC) maturation. To this aim, LP-BM5-infected mice were treated with I-152, an N-acetyl-cysteine and cysteamine supplier. Intraperitoneal I-152 administration (30 μmol/mouse three times a week for 9 weeks) decreased plasma IgG and increased IgG/Syndecan 1 ratio in the lymph nodes where IgG were in part accumulated within the ER. PC containing cytoplasmic inclusions filled with IgG were present in all animals, with fewer mature PC in those treated with I-152. Infection induced up-regulation of signaling molecules involved in the UPR, i.e. CHAC1, BiP, sXBP-1 and PDI, that were generally unaffected by I-152 treatment except for PDI and sXBP-1, which have a key role in protein folding and PC maturation, respectively. Our data suggest that one of the mechanisms through which I-152 can limit hypergammaglobulinemia in LP-BM5-infected mice is by influencing IgG folding/assembly as well as secretion and affecting PC maturation.

Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology.

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied.

Enhanced immunoglobulin somatic hypermutation in human APOBEC3 transgenic mice

Abstract Eliciting a broadly neutralizing antibody (bNAb) response remains a major hurdle in HIV-1 vaccine development, as a majority of these bNAbs are heavily mutated. Immunoglobulin (Ig) somatic hypermutation (SHM) is primarily driven by AID. However, our previous data in Friend retrovirus (FV) infected mice revealed that an evolutionarily-related deaminase, mouse APOBEC3 (mA3), may complement AID in mutating virus-specific Abs (Halemano et al, PNAS 2014). AID mutates primarily in an RC context (R=purine), whereas the A3s mutate in a YC context (Y=pyrimidine). Of note, mice encode only one A3 gene, but humans encode seven. To date, it remains unclear if the human APOBEC3 (hA3) deaminases can directly mutate Ig genes. To study the role of hA3s in Ig SHM, bacterial artificial chromosome (BAC)-transgenic mice expressing the 7 hA3s (hA3-Tg) were crossed onto an mA3 KO background. All hA3s were expressed in hA3-Tg B cells during FV infection. hA3-Tg (n=13) and mA3 KO (n=12) mice were vaccinated with live-attenuated FV and analyzed at 28 d. Surprisingly, the hA3-Tg mice have an impaired plasma NAb response (p=0.0003) despite similar virus-specific binding IgG titers (p>0.1). Illumina sequencing of bone marrow IgG transcripts showed increased deamination mutations (C to T or G to A) in hA3-Tg versus mA3 KO mice (p=0.0043). Interestingly, this increase was accounted for by AID-type (RC), but not hA3-type (YC), mutations. Our findings reveal that hA3 can increase IgG SHM rates following vaccination, but the initial impact on the vaccine NAb response may be detrimental. Studies are ongoing to monitor the development of virus-specific antibodies in hA3-Tg mice, as harmful mutations may be more prominent during early time points post-vaccination.

Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection.

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/−) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections.

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells.

Natural killer (NK) cells belong to the innate immune system and protect against cancers and a variety of viruses including retroviruses by killing transformed or infected cells. They express activating and inhibitory receptors on their cell surface and often become activated after recognizing virus-infected cells. They have diverse antiviral effector functions like the release of cytotoxic granules, cytokine production and antibody dependent cellular cytotoxicity. The importance of NK cell activity in retroviral infections became evident due to the discovery of several viral strategies to escape recognition and elimination by NK cells. Mutational sequence polymorphisms as well as modulation of surface receptors and their ligands are mechanisms of the human immunodeficiency virus-1 to evade NK cell-mediated immune pressure. In Friend retrovirus infected mice the virus can manipulate molecular or cellular immune factors that in turn suppress the NK cell response. In this model NK cells lack cytokines for optimal activation and can be functionally suppressed by regulatory T cells. However, these inhibitory pathways can be overcome therapeutically to achieve full activation of NK cell responses and ultimately control dissemination of retroviral infection. One effective approach is to modulate the crosstalk between NK cells and dendritic cells, which produce NK cell-stimulating cytokines like type I interferons (IFN), IL-12, IL-15, and IL-18 upon retrovirus sensing or infection. Therapeutic administration of IFNα directly increases NK cell killing of retrovirus-infected cells. In addition, IL-2/anti-IL-2 complexes that direct IL-2 to NK cells have been shown to significantly improve control of retroviral infection by NK cells in vivo. In this review, we describe novel approaches to improve NK cell effector functions in retroviral infections. Immunotherapies that target NK cells of patients suffering from viral infections might be a promising treatment option for the future.

Checkpoint Regulator VISTA plays a role in Suppression of B-Cell Responsiveness by Monocytic Myeloid Derived Suppressor Cells from LP-BM5 retrovirus-infected Mice

Abstract MDSC inhibition of tumor directed T cell responses is well described. We have reported an increase of monocytic MDSC (M-MDSC) during infection of B6 mice by LP-BM5 immunodeficiency causing retrovirus. These M-MDSCs suppressed T, and B cell responsiveness ex vivo. M-MDSC inhibition of stimulated T-cell proliferation and IFN-gamma production was ~100% iNOS/NO dependent; whereas suppression of B-cells was only ~50% dependent on iNOS/NO. An additional mechanism(s) for M-MDSC inhibition of B cell responsiveness involved V-domain Ig Suppressor of T cell Activation (VISTA), negative checkpoint regulator. Using anti-VISTA blocking mAb, ~50% of total MDSC suppression of B-cell responses was dependent on MDSC-expressed VISTA. The combination of iNOS/NO inhibitors and VISTA lead to additive, if not synergistic, blockade of M-MDSC suppression of B cell responsiveness. Regarding the LP-BM5-infection dependency of M-MDSCs, spleens from uninfected mice yielded ~3-fold fewer enriched M-MDSCs; and on a per-cell basis, the M-MDSCs from uninfected mice were also substantially less suppressive (4.3 fold); than those from infected mice. Consistent with a direct role of VISTA, in the absence of M-MDSCs, a VISTA-Ig fusion protein also partially inhibited B-cell responsiveness. Initial experiments show differential VISTA expression for the LP-BM5 M-MDSC CD11b+hiLy6C+hi subpopulations we have recently defined (O’Connor et al, 2015, Virology). Thus, LP-BM5 infected, when compared to analogous subsets from uninfected mice, contain substantially more VISTA+ cells. These results suggest an unique role for M-MDSCs in LP-BM5 induced immunodeficiency, and highlight multiple suppressive pathways in the area of MDSC suppression of B cell responses.

Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-viral immunity during chronic retroviral infection.

BackgroundRegulatory T cells (Tregs) have been shown to limit anti-viral immunity during chronic retroviral infection and to restrict vaccine-induced T cell responses. The objective of the study was to assess whether a combinational therapy of nanoparticle-based therapeutic vaccination and concomitant transient ablation of Tregs augments anti-viral immunity and improves virus control in chronically retrovirus-infected mice. Therefore, chronically Friend retrovirus (FV)-infected mice were immunized with calcium phosphate (CaP) nanoparticles functionalized with TLR9 ligand CpG and CD8+ or CD4+ T cell epitope peptides (GagL85–93 or Env gp70123–141) of FV. In addition, Tregs were ablated during the immunization process. Reactivation of CD4+ and CD8+ effector T cells was analysed and the viral loads were determined.ResultsTherapeutic vaccination of chronically FV-infected mice with functionalized CaP nanoparticles transiently reactivated cytotoxic CD8+ T cells and significantly reduced the viral loads. Transient ablation of Tregs during nanoparticle-based therapeutic vaccination strongly enhanced anti-viral immunity and further decreased viral burden.ConclusionOur data illustrate a crucial role for CD4+ Foxp3+ Tregs in the suppression of anti-viral T cell responses during therapeutic vaccination against chronic retroviral infection. Thus, the combination of transient Treg ablation and therapeutic nanoparticle-based vaccination confers robust and sustained anti-viral immunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0258-9) contains supplementary material, which is available to authorized users.

Expanded regulatory T cells in chronically friend retrovirus-infected mice suppress immunity to a murine cytomegalovirus superinfection.

It is still unclear whether expanded and activated regulatory T cells (Tregs) in chronic viral infections can influence primary immune responses against superinfections with unrelated viruses. Expanded Tregs found in the spleens of chronically Friend virus (FV)-infected mice decreased murine cytomegalovirus (mCMV)-specific CD8(+) T cell responses during acute mCMV superinfection. This suppression of mCMV-specific T cell immunity was found only in organs with FV-induced Treg expansion. Surprisingly, acute mCMV infection itself did not expand or activate Tregs.

Isothiocyanates Ameliorate the Symptom of Heart Dysfunction and Mortality in a Murine AIDS Model by Inhibiting Apoptosis in the Left Ventricle

Cardiac involvement has been reported in as many as 45-55% of patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), and significant cardiac morbidity is reported in 6-7% of HIV patients. We investigated the inhibitory effects of isothiocyanates (ITCs) on heart dysfunction and mortality by regulating apoptosis in the left ventricle of the heart in a murine AIDS model. Mice were divided into six groups: an uninfected group, an untreated LP-BM5 retrovirus-infected group, and four LP-BM5 retrovirus-infected groups treated with one of four ITCs (sulforaphane [SUL], indolo[3,2-b]carbazole, benzyl isothiocyanate [BITC], or phenethyl isothiocyanate [PEITC]). After 16 weeks, the median survival time of the LP-BM5 retrovirus-infected mice was 87 days, whereas that of the uninfected control group and all ITC treatment groups was over 112 days. SUL, PEITC, and BITC significantly inhibited apoptosis in the left ventricle by increasing the Bcl-2/Bax ratio compared with LP-BM5-infected mice. In addition, SUL and PEITC suppressed inducible nitric oxide synthase (iNOS) expression at both the mRNA and protein levels in the left ventricle of heart tissue infected with the LP-BM5 retrovirus by inactivating cytoplasmic nuclear factor κB (NF-κB). In conclusion, LP-BM5 retrovirus infection was related to survival of murine AIDS mice, and NF-κB-mediated iNOS expression may be an important mediator of left ventricle dysfunction of the heart. Furthermore, certain ITCs may have the potential to improve AIDS-related heart dysfunction due to their inhibition of apoptosis by decreasing iNOS and Bax expression through suppression of NF-κB.

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8+T Cells by Adenovirus-Based Immunization

While Friend retrovirus-infected mice readily mount a vigorous CD8(+) T cell response to the leader-gag-derived peptide GagL(85-93), no GagL(85-93)-specific T cells were detectable in mice immunized against Friend virus (FV) with viral vectors or DNA vaccines. By exchanging one epitope-flanking amino acid or using a scaffold protein we were able to demonstrate for the first time the induction of GagL(85-93)-specific CD8(+) T cells by genetic vaccination and show their high protective effect against FV challenge infection.

Polyinosinic-Polycytidylic Acid Treatment of Friend Retrovirus-Infected Mice Improves Functional Properties of Virus-Specific T Cells and Prevents Virus-Induced Disease

The induction of type I IFN is the most immediate host response to viral infections. Type I IFN has a direct antiviral activity mediated by antiviral enzymes, but it also modulates the function of cells of the adaptive immune system. Many viruses can suppress type I IFN production, and in retroviral infections, the initial type I IFN is weak. Thus, one strategy of immunotherapy in viral infection is the exogenous induction of type I IFN during acute viral infection by TLR ligands. Along these lines, the TLR3/MDA5 ligand polyinosinic-polycytidylic acid [poly(I:C)] has already been used to treat viral infections. However, the immunological mechanisms underlying this successful therapy have not been defined until now. In this study, the Friend retrovirus (FV) mouse model was used to investigate the mode of action of poly(I:C) in antiretroviral immunotherapy. Postexposure, poly(I:C) treatment of FV-infected mice resulted in a significant reduction in viral loads and protection from virus-induced leukemia. This effect was IFN dependent because type I IFN receptor-deficient mice could not be protected by poly(I:C). The poly(I:C)-induced IFN response resulted in the expression of antiviral enzymes, which suppressed FV replication. Also, the virus-specific T cell response was augmented. Interestingly, it did not enhance the number of virus-specific CD4(+) and CD8(+) T cells, but rather the functional properties of these cells, such as cytokine production and cytotoxic activity. The results demonstrate a direct antiviral and immunomodulatory effect of poly(I:C) and, therefore, suggests its potential for clinical treatment of retroviral infections.

Monosodium luminol upregulates the expression of Bcl-2 and VEGF in retrovirus-infected mice through downregulation of corresponding miRNAs

The retrovirus ts1 is a mutant of Moloney murine leukemia virus (MoMuLV) that causes neurodegeneration (ND) in susceptible mice. Our previous studies showed that the antioxidant drug monosodium luminol (GVT) prevented the development of ND in ts1-infected mice. In this study, we analyzed effect of GVT on the expression of B-cell lymphoma-2 protein (Bcl-2) and vascular endothelial growth factor (VEGF) in central nervous system (CNS) tissues of these animals. Our data showed that GVT treatment of ts1-infected mice significantly increased their expression of Bcl-2 and VEGF in brainstem compared with ts1-infected untreated mice. We also studied the expression of specific microRNAs (miRNAs) such as miRNA-15 and -16 (targeting Bcl-2), and miRNA-20 (targeting VEGF). We found that the expression of miRNAs inversely correlated with the upregulation of their target proteins in ts1-infected untreated as well as in GVT-treated-ts1-infected mice. The data showed that GVT treatment prevented ts1-induced ND at least in part by upregulating Bcl-2 and VEGF expression, what likely occurred as a consequence of downregulation of their corresponding miRNAs.

Reduced micronutrient intake accentuates premature death caused by immune dysfunction in leukemia retrovirus-infected C57BL/6 mice

We investigated the effect of micronutrient deficiency on the survival and immune dysfunction of C57BL/6 mice during progression to murine AIDS. Survival of retrovirus-infected mice has been influenced by micronutrient deficiency although it alone could significantly reduce the median survival time. The premature death could be explained by dysregulation of the immune system and generation of free radicals. Dysfunction of T-cell and B-cell mitogenesis from primary cultured splenocytes has been observed with retrovirus infection and micronutrient deficiency in synergism. There was an abnormal shift of cytokine pattern that was designated by the decreased secretion of Th1 cytokines and increased secretion of Th2 cytokines. The hepatic vitamin E level was significantly decreased by retrovirus infection and micronutrient deficiency, in accordance with the increased hepatic lipid peroxidation level. This study suggests that micronutrient deficiency may accelerate premature death during progression to murine AIDS, implying that nutritional application would be the first line to consider for retarding the progression from HIV infection to AIDS.

CpG ODNs Treatments of HIV-1 Infected Patients May Cause the Decline of Transmission in High Risk Populations – A Review, Hypothesis and Implications

The Joint United Nations Program on HIV-1/AIDS (UNAIDS) announced its goal to stop HIV-1 transmission by antiviral (HAART) treatment of patients since at the end of 2003 the number of people living with HIV-1 was 38 million, 25 million in the sub-Saharan region of Africa. The present review deals with a new approach to simultaneously treat HIV-1/AIDS patients in HIV-1 endemic regions with CpG oligodeoxynucleotides (ODNs) and people at high risk of infection with a vaccine containing CpG ODNs combined with synthetic HIV-1 peptides by intranasal and intradermal applications.

Chronic methamphetamine exposure alters immune function in normal and retrovirus-infected mice

Methamphetamine (MA) abuse represents a growing problem in the USA with an increase of sudden death. To evaluate the immune function alterations due to chronic methamphetamine use, we examined C57BL/C mice with LP-BM5 retrovirus infection plus methamphetamine exposure. Mice were randomly assigned to the following groups: placebo, placebo retrovirus-infected, uninfected MA treated and retrovirus-infected MA treated. Placebo, MA-treated groups were intraperitoneally injected with saline, MA, respectively, with a gradually increasing dose from 15 to 40 mg/kg for 12 weeks (5 days/week). Con A- and LPS-induced mitogenesis of splenocytes, cytokine production by splenocytes culture and lipid peroxides in the liver were measured. Heart tissue histopathology was analyzed in all the groups with murine cytomegalovirus (CMV) superinfection. Our data showed that MA treatment significantly decreased production of IL-2 and interferon gamma (IFN-γ) in uninfected mice but did not further suppress the reduced Th1 cytokines in retrovirus-infected mice. There were no significant effects on cytokines IL-4 and IL-6. However, tumor necrosis factor (TNF-α) was significantly increased in both uninfected and infected mice due to MA treatment. Lipid peroxides in liver were significantly increased both in uninfected and retrovirus-infected mice due to MA exposure. Vitamin E levels in liver were significantly decreased in uninfected mice due to MA treatment. CMV superinfection greatly increased the cardiac lesions in retrovirus-infected mice while no significant histopathology changes were detected due to MA treatment. Our data suggest that MA has immunomodulation activity, suppressing Th1 cytokine production and enhancing some Th2 cytokine secretion, as well as increasing lipid peroxides in uninfected mice. The interaction between LP-BM5 and MA remains unclear.

Effects of chronic methamphetamine exposure on heart function in uninfected and retrovirus-infected mice

Methamphetamine (MA) increases catecholamine levels, which have detrimental effects on heart function through vasoconstriction, myocardial hypertrophy, and fibrosis. Murine retrovirus infection induces dilated cardiomyopathy (DCM). The present study investigated the cardiovascular effects of chronic MA treatment on uninfected and retrovirus-infected mice. C57BL/6 mice were studied after 12 weeks treatment. The four study groups were (group I) uninfected, MA placebo; (group II) infected, MA placebo; (group III) uninfected, MA treatment; and (group IV) infected and MA treatment. MA injections were given i.p. once a day for 5 days/week with a increasing dose from 15 mg/kg to 40 mg/kg. Left ventricular mechanics were measured in situ a using Millar conductance catheter system for pressure–volume loop analysis. Cardiac pathology was determined with histological analysis. In the uninfected mice, the load independent contractile parameters, pre-load recruitable stroke work (PRSW) and dP/dt max vs. Ved, significantly decreased by 32% and 35% in MA treated mice when compared to the saline injected mice. In retrovirus-infected mice, although there were no significant difference in Ees, PRSW, and dP/dt max vs. Ved due to MA treatment, they were increased 45%, 15% and 42% respectively when compared to saline treated mice. No further lowered heart function during murine AIDS may be due to the counteraction of the retroviral DCM and the MA induced myocardial fibrosis and hypertrophy (thickening of the ventricular walls). This is supported by increases in the End-diastolic volume (Ved, 38%) and End-systolic volume (Ves, 84%) in the retrovirus-infected saline injected mice, the decreases of 33% and 17% in the uninfected MA-treated mice, but no significant changes in the retrovirus-infected MA treated mice when compared to uninfected saline injected mice. These data suggest that MA induced myocardial cellular changes compensate for retrovirus induced DCM.

Side-stream cigarette smoke accentuates immunomodulation during murine AIDS

Side-stream cigarette smoke has become a hotly debated social, political, and scientific health and safety issue for nonsmokers. The harmful influences of side-stream cigarette smoke on human health are its adverse effects on the immune system, especially when already compromised by other agents. Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by human immunodeficiency virus (HIV). To facilitate studies, murine AIDS was induced in C57BL/6 mice by LP-BM5 murine leukemia virus infection, which mimics human AIDS. After 2 weeks of retroviral infection, the mice were exposed to side-stream cigarette smoke for 30 min, 5 days/week for 12 weeks using a side-stream cigarette smoke exposure system. Murine retrovirus infection reduced the in vitro proliferation of T lymphocytes stimulated by concanavalin A, increased the release of pro-inflammatory cytokine interleukin-6 (IL-6) tumor necrosis factor-alpha (TNF-α), increased the hepatic lipid peroxidation and decreased the α-tocopherol levels in liver, lung and heart. Concomitant side-stream cigarette smoke exposure for 12 weeks further inhibited the proliferation of T cells, increased the release of TNF-α, IL-6 cytokines and enhanced the hepatic lipid peroxidation from retrovirus infected mice. The loss of α-tocopherol was also further enhanced by side-stream cigarette smoke exposure during retrovirus infection. Our conclusions are that side-stream cigarette smoke induced increasing oxidative stress, reducing nutrient concentrations and suppressing immune function could make mice with murine AIDS more susceptible to opportunistic infections, potentially accelerating murine AIDS progression. Thus, the reduction of side-stream cigarette smoke exposure is an important health issue in AIDS patients to improve the quality and quantity of their lives.