RESUMO
Differences in immune activation were identified as the most significant difference between AIDS-susceptible and resistant species. p38 MAPK, activated in HIV infection, is key to induction of interferon-stimulated genes and cytokine-mediated inflammation and is associated with some of the pathology produced by HIV or SIV infection in AIDS-susceptible primates. As small molecule p38 MAPK inhibitors are being tested in human trials for inflammatory diseases, we evaluated the effects of treating SIV-infected macaques with the p38 MAPK inhibitor PH-797804 in conjunction with ART. PH-797804 had no side effects, did not impact negatively the antiviral immune response and, used alone, had no significant effect on levels of immune activation and did not reduced the viremia. When administered with ART, it significantly reduced numerous immune activation markers compared to ART alone. CD38+/HLA-DR+ and Ki-67+ T-cell percentages in blood, lymph node and rectal CD4+ and CD8+ T cells, PD-1 expression in CD8+ T cells and plasma levels of IFNα, IFNγ, TNFα, IL-6, IP-10, sCD163 and C-reactive protein were all significantly reduced. Significant preservation of CD4+, CD4+ central memory, CD4+/IL-22+ and CD4+/IL-17+ T-cell percentages and improvement of Th17/Treg ratio in blood and rectal mucosa were also observed. Importantly, the addition of PH-797804 to ART initiated during chronic SIV infection reduced immune activation and restored immune system parameters to the levels observed when ART was initiated on week 1 after infection. After ART interruption, viremia rebounded in a similar fashion in all groups, regardless of when ART was initiated. We concluded that the inhibitor PH-797804 significantly reduced, even if did not normalized, the immune activation parameters evaluated during ART treatment, improved preservation of critical populations of the immune system targeted by SIV, and increased the efficacy of ART treatment initiated in chronic infection to levels similar to those observed when initiated in acute infection but did not affect positively or negatively viral reservoirs.
Assuntos
Antirretrovirais/administração & dosagem , Benzamidas/administração & dosagem , Citoproteção/efeitos dos fármacos , Piridonas/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Antirretrovirais/farmacologia , Benzamidas/farmacologia , Citoproteção/imunologia , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Macaca mulatta , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Linfócitos T/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
PURPOSE OF REVIEW: Early studies have cast doubt on the utility of animal models for predicting success or failure of HIV-prevention strategies, but results of multiple human phase 3 microbicide trials, and interrogations into the discrepancies between human and animal model trials, indicate that animal models were, and are, predictive of safety and efficacy of microbicide candidates. RECENT FINDINGS: Recent studies have shown that topically applied vaginal gels, and oral prophylaxis using single or combination antiretrovirals are indeed effective in preventing sexual HIV transmission in humans, and all of these successes were predicted in animal models. Further, prior discrepancies between animal and human results are finally being deciphered as inadequacies in study design in the model, or quite often, noncompliance in human trials, the latter being increasingly recognized as a major problem in human microbicide trials. SUMMARY: Successful microbicide studies in humans have validated results in animal models, and several ongoing studies are further investigating questions of tissue distribution, duration of efficacy, and continued safety with repeated application of these, and other promising microbicide candidates in both murine and nonhuman primate models. Now that we finally have positive correlations with prevention strategies and protection from HIV transmission, we can retrospectively validate animal models for their ability to predict these results, and more importantly, prospectively use these models to select and advance even safer, more effective, and importantly, more durable microbicide candidates into human trials.
Assuntos
Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos Locais/toxicidade , Antirretrovirais/farmacologia , Antirretrovirais/toxicidade , Modelos Animais de Doenças , Animais , Transmissão de Doença Infecciosa/prevenção & controle , Avaliação Pré-Clínica de Medicamentos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Macaca mulatta , Projetos de Pesquisa , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controleRESUMO
There have been encouraging recent successes in the development of safe and effective topical microbicides to prevent vaginal or rectal HIV-1 transmission, based on the use of anti-retroviral drugs. However, much work remains to be accomplished before a microbicide becomes a standard element of prevention science strategies. Animal models should continue to play an important role in pre-clinical testing, with emphasis on safety, pharmacokinetic and efficacy testing.
Assuntos
Anti-Infecciosos Locais/uso terapêutico , Antirretrovirais/uso terapêutico , Modelos Animais de Doenças , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Administração Tópica , Animais , Anti-Infecciosos Locais/administração & dosagem , Antirretrovirais/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Infecções por HIV/transmissão , Macaca mulatta , Camundongos , Coelhos , RatosRESUMO
After disappointing results from all efficacy trials conducted to date, the field of microbicides research now faces substantial challenges. Poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies have hampered progress and created mistrust about the use of microbicides as a method to prevent HIV-1 sexual transmission. Although new promising strategies are available, there will need to be serious reappraisals of how decisions are made to advance the next generations of candidates into clinical trials, and the use of appropriate animal models in this process will be critical.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Polímeros/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Doenças Vaginais/prevenção & controle , Administração Intravaginal , Animais , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos Locais/uso terapêutico , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Humanos , Masculino , Cooperação do Paciente , Polieletrólitos , Polímeros/farmacologia , Polímeros/uso terapêutico , Primatas , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Doenças Vaginais/tratamento farmacológicoRESUMO
Topical agents, such as microbicides, that can protect against human immunodeficiency virus (HIV) transmission are urgently needed. Using a chimeric simian/human immunodeficiency virus (SHIV SF162), which is tropic for the chemokine receptor CCR5, we report that topical application of high doses of PSC-RANTES, an amino terminus-modified analog of the chemokine RANTES, provided potent protection against vaginal challenge in rhesus macaques. These experimental findings have potentially important implications for understanding vaginal transmission of HIV and the design of strategies for its prevention.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Antagonistas dos Receptores CCR5 , Quimiocina CCL5/análogos & derivados , Quimiocina CCL5/uso terapêutico , Infecções por HIV/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vagina/virologia , Administração Intravaginal , Animais , Fármacos Anti-HIV/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Anticorpos Antivirais/sangue , Quimiocina CCL5/administração & dosagem , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Macaca mulatta , Receptores CCR5/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/imunologiaRESUMO
Human immunodeficiency virus type 1 (HIV-1) fusion with its target cells is initiated by sequential interactions between its envelope glycoprotein, CD4, and a co-receptor, usually CCR5 or CXCR4. Small molecules that bind to CCR5 and prevent its use by R5 HIV-1 strains are now being developed clinically as antiviral drugs. To test whether a block to CCR5 promotes the replication of viruses that enter cells via CXCR4 and are associated with accelerated disease progression, we administered a small molecule CCR5 inhibitor, CMPD 167, to three macaques dual-infected with both R5 (SIVmac251) and X4 (SHIV-89.6P) viruses. CMPD 167 caused a rapid and substantial (on average, 50-fold) suppression of R5 virus replication in each animal. In two of the animals, but not in the third, a rapid, transient, 8- to 15-fold increase in the amount of plasma X4 virus occurred. In neither animal was the increase in X4 viral load sustained throughout therapy, however. These observations may have relevance for the development of CCR5 inhibitors for treatment of HIV-1 infection of humans.