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This corrects the article DOI: 10.1038/nature12519.
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Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69-172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.
Assuntos
Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/imunologia , Animais , Citomegalovirus/genética , Citomegalovirus/imunologia , Feminino , Macaca mulatta , Masculino , Dados de Sequência Molecular , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Fatores de Tempo , Vacinas Atenuadas/imunologia , Carga Viral , Replicação Viral/fisiologiaRESUMO
Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence and immune evasion. We now demonstrate that B22 proteins, encoded by the largest genes of these viruses, render human T cells unresponsive to stimulation of the T cell receptor by MHC-dependent antigen presentation or by MHC-independent stimulation. In contrast, stimuli that bypass TCR-signaling are not inhibited. In a non-human primate model of monkeypox, virus lacking the B22R homologue (MPXVΔ197) caused only mild disease with lower viremia and cutaneous pox lesions compared to wild type MPXV which caused high viremia, morbidity and mortality. Since MPXVΔ197-infected animals displayed accelerated T cell responses and less T cell dysregulation than MPXV US2003, we conclude that B22 family proteins cause viral virulence by suppressing T cell control of viral dissemination.
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Evasão da Resposta Imune , Infecções por Poxviridae/imunologia , Poxviridae/patogenicidade , Linfócitos T/imunologia , Linfócitos T/virologia , Proteínas Virais/fisiologia , Animais , Células CHO , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Cricetulus , Feminino , Células HEK293 , Humanos , Evasão da Resposta Imune/genética , Células Jurkat , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Mpox/imunologia , Poxviridae/genética , Poxviridae/imunologiaRESUMO
The strict tropism of many pathogens for man hampers the development of animal models that recapitulate important microbe-host interactions. We developed a rhesus macaque model for studying Neisseria-host interactions using Neisseria species indigenous to the animal. We report that Neisseria are common inhabitants of the rhesus macaque. Neisseria isolated from the rhesus macaque recolonize animals after laboratory passage, persist in the animals for at least 72 d, and are transmitted between animals. Neisseria are naturally competent and acquire genetic markers from each other in vivo, in the absence of selection, within 44 d after colonization. Neisseria macacae encodes orthologs of known or presumed virulence factors of human-adapted Neisseria, as well as current or candidate vaccine antigens. We conclude that the rhesus macaque model will allow studies of the molecular mechanisms of Neisseria colonization, transmission, persistence, and horizontal gene transfer. The model can potentially be developed further for preclinical testing of vaccine candidates.
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Transferência Genética Horizontal , Infecções por Bactérias Gram-Negativas/microbiologia , Neisseria/patogenicidade , Animais , Marcadores Genéticos , Infecções por Bactérias Gram-Negativas/genética , Infecções por Bactérias Gram-Negativas/transmissão , Interações Hospedeiro-Patógeno , Macaca mulatta , Dados de Sequência Molecular , Neisseria/classificação , Neisseria/genética , Filogenia , VirulênciaRESUMO
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Memória Imunológica/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD4-Positivos/virologia , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Doença Crônica , Citotoxicidade Imunológica , Homeostase , Imunidade Celular , Cinética , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Masculino , Fatores de Tempo , Carga ViralRESUMO
Monkeypox virus (MPXV) is an orthopoxvirus closely related to variola virus, the causative agent of smallpox. Human MPXV infection results in a disease that is similar to smallpox and can also be fatal. Two clades of MPXV have been identified, with viruses of the central African clade displaying more pathogenic properties than those within the west African clade. The monkeypox inhibitor of complement enzymes (MOPICE), which is not expressed by viruses of the west African clade, has been hypothesized to be a main virulence factor responsible for increased pathogenic properties of central African strains of MPXV. To gain a better understanding of the role of MOPICE during MPXV-mediated disease, we compared the host adaptive immune response and disease severity following intrabronchial infection with MPXV-Zaire (n = 4), or a recombinant MPXV-Zaire (n = 4) lacking expression of MOPICE in rhesus macaques (RM). Data presented here demonstrate that infection of RM with MPXV leads to significant viral replication in the peripheral blood and lungs and results in the induction of a robust and sustained adaptive immune response against the virus. More importantly, we show that the loss of MOPICE expression results in enhanced viral replication in vivo, as well as a dampened adaptive immune response against MPXV. Taken together, these findings suggest that MOPICE modulates the anti-MPXV immune response and that this protein is not the sole virulence factor of the central African clade of MPXV.
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Monkeypox virus/imunologia , Monkeypox virus/patogenicidade , Mpox/imunologia , Mpox/patologia , Proteínas Virais/metabolismo , Fatores de Virulência/metabolismo , Imunidade Adaptativa , Animais , Linfócitos B/imunologia , Sangue/virologia , DNA Viral/química , DNA Viral/genética , Modelos Animais de Doenças , Feminino , Deleção de Genes , Pulmão/virologia , Macaca mulatta , Masculino , Dados de Sequência Molecular , Mpox/virologia , Doenças dos Primatas/imunologia , Doenças dos Primatas/patologia , Doenças dos Primatas/virologia , Análise de Sequência de DNA , Pele/patologia , Linfócitos T/imunologia , Proteínas Virais/genética , Fatores de Virulência/genéticaRESUMO
Simian varicella virus (SVV), the etiologic agent of naturally occurring varicella in primates, is genetically and antigenically closely related to human varicella zoster virus (VZV). Early attempts to develop a model of VZV pathogenesis and latency in nonhuman primates (NHP) resulted in persistent infection. More recent models successfully produced latency; however, only a minority of monkeys became viremic and seroconverted. Thus, previous NHP models were not ideally suited to analyze the immune response to SVV during acute infection and the transition to latency. Here, we show for the first time that intrabronchial inoculation of rhesus macaques with SVV closely mimics naturally occurring varicella (chickenpox) in humans. Infected monkeys developed varicella and viremia that resolved 21 days after infection. Months later, viral DNA was detected only in ganglia and not in non-ganglionic tissues. Like VZV latency in human ganglia, transcripts corresponding to SVV ORFs 21, 62, 63 and 66, but not ORF 40, were detected by RT-PCR. In addition, as described for VZV, SVV ORF 63 protein was detected in the cytoplasm of neurons in latently infected monkey ganglia by immunohistochemistry. We also present the first in depth analysis of the immune response to SVV. Infected animals produced a strong humoral and cell-mediated immune response to SVV, as assessed by immunohistology, serology and flow cytometry. Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.
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Modelos Animais de Doenças , Infecções por Herpesviridae , Macaca mulatta/virologia , Varicellovirus/patogenicidade , Animais , Linfócitos B/imunologia , Proliferação de Células , DNA Viral/análise , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Herpesvirus Humano 3 , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Varicellovirus/genética , Carga ViralRESUMO
The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G(1)-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.
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Envelhecimento/imunologia , Imunidade Inata/imunologia , Macaca mulatta/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Proliferação de Células , Feminino , Homeostase/imunologia , Memória Imunológica/imunologia , Antígeno Ki-67/metabolismo , Cinética , Masculino , Linfócitos T/metabolismoRESUMO
HIV infection selectively targets CD4+ effector memory T (T EM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the T EM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ T EM cells with little effect on the naive or central memory T (T CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ T EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4 + T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.
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Linfócitos T CD4-Positivos/imunologia , Movimento Celular/fisiologia , Memória Imunológica , Interleucina-15/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antirretrovirais/imunologia , Antirretrovirais/uso terapêutico , Antígenos CD28/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Infecções por HIV/imunologia , Humanos , Interleucina-15/uso terapêutico , Interleucina-2/imunologia , Interleucina-7/imunologia , Ativação Linfocitária , Macaca mulatta , Masculino , Receptores CCR7 , Receptores de Quimiocinas/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Carga Viral , Replicação ViralRESUMO
The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While sporozoite vaccines targeting the pre-erythrocytic stage show great promise, it has not been possible to maintain efficacy long-term, likely due to an inability of these vaccines to maintain effector memory T cell responses in the liver. Vaccines based on human cytomegalovirus (HCMV) might overcome this limitation since vectors based on rhesus CMV (RhCMV), the homologous virus in rhesus macaques (RM), elicit and indefinitely maintain high frequency, non-exhausted effector memory T cells in extralymphoid tissues, including the liver. Moreover, RhCMV strain 68-1 elicits CD8+ T cells broadly recognizing unconventional epitopes exclusively restricted by MHC-II and MHC-E. To evaluate the potential of these unique immune responses to protect against malaria, we expressed four Plasmodium knowlesi (Pk) antigens (CSP, AMA1, SSP2/TRAP, MSP1c) in RhCMV 68-1 or in Rh189-deleted 68-1, which additionally elicits canonical MHC-Ia-restricted CD8+ T cells. Upon inoculation of RM with either of these Pk Ag expressing RhCMV vaccines, we obtained T cell responses to each of the four Pk antigens. Upon challenge with Pk sporozoites we observed a delayed appearance of blood stage parasites in vaccinated RM consistent with a 75-80% reduction of parasite release from the liver. Moreover, the Rh189-deleted RhCMV/Pk vectors elicited sterile protection in one RM. Once in the blood, parasite growth was not affected. In contrast to T cell responses induced by Pk infection, RhCMV vectors maintained sustained T cell responses to all four malaria antigens in the liver post-challenge. The delayed appearance of blood stage parasites is thus likely due to a T cell-mediated inhibition of liver stage parasite development. As such, this vaccine approach can be used to efficiently test new T cell antigens, improve current vaccines targeting the liver stage and complement vaccines targeting erythrocytic antigens.
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Antígenos de Protozoários/imunologia , Citomegalovirus/genética , Vacinas Antimaláricas/imunologia , Malária/imunologia , Parasitemia/imunologia , Plasmodium knowlesi/imunologia , Esporozoítos/imunologia , Animais , Anopheles/imunologia , Anopheles/parasitologia , Feminino , Vetores Genéticos/administração & dosagem , Memória Imunológica , Fígado/imunologia , Fígado/parasitologia , Macaca mulatta , Malária/sangue , Malária/parasitologia , Malária/prevenção & controle , Masculino , Parasitemia/sangue , Parasitemia/parasitologia , Parasitemia/prevenção & controle , Plasmodium knowlesi/genética , Proteínas de Protozoários/imunologia , Linfócitos T/imunologia , Linfócitos T/parasitologiaRESUMO
Despite widespread use of the bacille Calmette-Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)-which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4+ and CD8+ memory T cell responses-can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at â¼1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.
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Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Vacina BCG/imunologia , Citomegalovirus/imunologia , Macaca mulatta/imunologiaRESUMO
Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1-specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8(+) T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.
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Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Modelos Animais de Doenças , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Macaca/virologia , Relações Mãe-Filho , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidadeRESUMO
Simian hemorrhagic fever virus is an arterivirus that naturally infects species of African nonhuman primates causing acute or persistent asymptomatic infections. Although it was previously estimated that 1% of baboons are SHFV-positive, more than 10% of wild-caught and captive-bred baboons tested were SHFV positive and the infections persisted for more than 10 years with detectable virus in the blood (100-1000 genomes/ml). The sequences of two baboon SHFV isolates that were amplified by a single passage in primary macaque macrophages had a high degree of identity to each other as well as to the genome of SHFV-LVR, a laboratory strain isolated in the 1960s. Infection of Japanese macaques with 100PFU of a baboon isolate consistently produced high level viremia, pro-inflammatory cytokines, elevated tissue factor levels and clinical signs indicating coagulation defects. The baboon virus isolate provides a reliable BSL2 model of viral hemorrhagic fever disease in macaques.
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Infecções por Arterivirus/veterinária , Arterivirus/isolamento & purificação , Arterivirus/patogenicidade , Febres Hemorrágicas Virais/veterinária , Doenças dos Macacos/virologia , Papio/virologia , Animais , Arterivirus/genética , Infecções por Arterivirus/patologia , Infecções por Arterivirus/virologia , Citocinas/sangue , Genoma Viral , Febres Hemorrágicas Virais/patologia , Febres Hemorrágicas Virais/virologia , Interações Hospedeiro-Patógeno , Macaca , Doenças dos Macacos/imunologia , Doenças dos Macacos/patologia , Especificidade de Órgãos , Viremia/veterinária , Viremia/virologiaRESUMO
Nonhuman primates are critical animal models for the study of human disorders and disease and offer a platform to assess the role of immune cells in pathogenesis via depletion of specific cellular subsets. However, this model is currently hindered by the lack of reagents that safely and specifically ablate myeloid cells of the monocyte/macrophage Lin. Given the central importance of macrophages in homeostasis and host immunity, development of a macrophage-depletion technique in nonhuman primates would open new avenues of research. Here, using LA at i.v. doses as low as 0.1 mg/kg, we show a >50% transient depletion of circulating monocytes and tissue-resident macrophages in RMs by an 11-color flow cytometric analysis. Diminution of monocytes was followed rapidly by emigration of monocytes from the bone marrow, leading to a rebound of monocytes to baseline levels. Importantly, LA was well-tolerated, as no adverse effects or changes in gross organ function were observed during depletion. These results advance the ex vivo study of myeloid cells by flow cytometry and pave the way for in vivo studies of monocyte/macrophage biology in nonhuman primate models of human disease.
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Alendronato/farmacologia , Separação Celular/métodos , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Macaca mulatta/imunologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Alendronato/administração & dosagem , Alendronato/toxicidade , Animais , Medula Óssea/efeitos dos fármacos , Contagem de Células , Movimento Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Lipossomos , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacosRESUMO
The development of AIDS in chronic HIV/simian immunodeficiency virus (SIV) infection has been closely linked to progressive failure of CD4(+) memory T cell (T(M)) homeostasis. CD4(+) naive T cells (T(N)) also decline in these infections, but their contribution to disease progression is less clear. We assessed the role of CD4(+) T(N) in SIV pathogenesis using rhesus macaques (RMs) selectively and permanently depleted of CD4(+) T(N) before SIV infection. CD4(+) T(N)-depleted and CD4(+) T(N)-repleted RMs were created by subjecting juvenile RMs to thymectomy versus sham surgery, respectively, followed by total CD4(+) T cell depletion and recovery from this depletion. Although thymectomized and sham-treated RMs manifested comparable CD4(+) T(M) recovery, only sham-treated RMs reconstituted CD4(+) T(N). CD4(+) T(N)-depleted RMs responded to SIVmac239 infection with markedly attenuated SIV-specific CD4(+) T cell responses, delayed SIVenv-specific Ab responses, and reduced SIV-specific CD8(+) T cell responses. However, CD4(+) T(N)-depleted and -repleted groups showed similar levels of SIV replication. Moreover, CD4(+) T(N) deficiency had no significant effect on CD4(+) T(M) homeostasis (either on or off anti-retroviral therapy) or disease progression. These data demonstrate that the CD4(+) T(N) compartment is dispensable for CD4(+) T(M) homeostasis in progressive SIV infection, and they confirm that CD4(+) T(M) comprise a homeostatically independent compartment that is intrinsically capable of self-renewal.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Imunidade Adaptativa , Animais , Progressão da Doença , Homeostase , Macaca mulatta , Masculino , Replicação ViralRESUMO
Depletion of CD8(+) lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8(+) lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8(+) lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4(+) effector memory T (T(EM)) cells and, to a lesser extent, transitional memory T (T(TrM)) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4(+)/CCR5(+) SIV "target" cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8(+) lymphocytes in SIV(-) RMs led to a sustained increase in the number of potential CD4(+) SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4(+) T(EM) cell proliferation of CD8(+) lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4(+) T(EM) and T(TrM) cell proliferation, it did not recapitulate the viral dynamics of CD8(+) lymphocyte depletion. These data suggest that CD8(+) lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.