Post-exposure prophylaxis with highly active antiretroviral therapy could not protect macaques from infection with SIV/HIV chimera

Grand, Roger Le; Vaslin, Bruno; Larghero, Jérôme; Neidez, O; Thiébot, Hugues; Sellier, Pierre; Clayette, Pascal; Dereuddre‐Bosquet, Nathalie; Dormont, Dominique

doi:10.1097/00002030-200008180-00029

Cited by 46 publications

(36 citation statements)

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“…In the same manner as in HIV-positive patients, hematological alterations are commonly found in SIV-infected macaques (16,17). We recently reported that treatment of macaques with a combination of zidovudine, lamivudine, and indinavir, initiated as early as 4 h after intravenous exposure to SHIV 89.6P and maintained for 4 weeks, failed to prevent infection but has long-lasting beneficial effects on the plasma viral load and blood CD4 ϩ cell counts (21). Here, we extended our study to the consequences on bone marrow hematopoiesis of early HAART in macaques infected with pathogenic SHIV 89.6P.…”

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confidence: 96%

Early and Persistent Bone Marrow Hematopoiesis Defect in Simian/Human Immunodeficiency Virus-Infected Macaques despite Efficient Reduction of Viremia by Highly Active Antiretroviral Therapy during Primary Infection

Thiébot

Louache

Vaslin

et al. 2001

J Virol

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The hematological abnormalities observed in human immunodeficiency virus (HIV)-infected patients appear to be mainly due to bone marrow dysfunction. A macaque models of AIDS could greatly facilitate an in vivo approach to the pathogenesis of such dysfunction. Here, we evaluated in this model the impact of infection with a pathogenic simian/human immunodeficiency virus (SHIV) on bone marrow hematopoiesis. Three groups of macaques were inoculated with 50 50% median infective doses of pathogenic SHIV 89.P, which expresses env of dual-tropic HIV type 1 (HIV-1) 89.6 primary isolate. During the primary phase of infection, animals were treated with either a placebo or highly active antiretroviral therapy (HAART) combining zidovudine, lamivudine, and indinavir, initiated 4 or 72 h postinfection (p.i.) and administered twice a day until day 28 p.i. In both placebo-treated and HAART-treated animals, bone marrow colony-forming cells (CFC) progressively decreased quite early, during the first month p.i. One year p.i., both placebo-and HAART-treated animals displayed decreases in CFC to about 56% of preinfection values. At the same time, a dramatic decrease (greater than 77%) of bone marrow CD34؉ long-term culture-initiating cells was noted in all animals were found. No statistically significant differences between placebo-and HAART-treated monkeys were found. These data argue for an early and profound alteration of myelopoiesis at the level of the most primitive CD34 ؉ progenitor cells during SHIV infection, independently of the level of viremia, circulating CD4 ؉ cell counts, or antiviral treatment.

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Early and Persistent Bone Marrow Hematopoiesis Defect in Simian/Human Immunodeficiency Virus-Infected Macaques despite Efficient Reduction of Viremia by Highly Active Antiretroviral Therapy during Primary Infection

Thiébot

Louache

Vaslin

et al. 2001

J Virol

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“…The reverse transcriptase (RT) inhibitor tenofovir {9-[2-(phosphonomethoxy)propyl]adenine} has been used extensively in this macaque model of AIDS because of its unprecedented efficacy, compared to other compounds, to prevent infection or suppress viremia (33, 55, 64, 69-71, 75-79, 80, 82, 85, 88). Most other commonly used antiviral drugs that have been tested in the macaque model were usually able to delay or reduce the peak of primary viremia if given early during infection, but in contrast to tenofovir, these other drugs were not very efficient in suppressing viremia once virus dissemination was already well established or the emergence of drug-resistant viral mutants inevitably led to increased virus replication and disease (22,30,35,47,70,84,87,90,102).The reasons for this high efficacy of tenofovir in the macaque model have been unclear but warrant further investigation, as this could lead to the development of additional antiviral strategies. The experiments described here demonstrate that suppression of viremia during tenofovir treatment of SIV-infected macaques requires CD8 ϩ -cell-mediated antiviral immune responses.…”

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CD8⁺-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

Rompay

Singh

Pahar

et al. 2004

J Virol

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The ability of tenofovir to suppress viremia in simian immunodeficiency virus (SIV)-infected macaques for years despite the presence of virulent viral mutants with reduced in vitro susceptibility is unprecedented in this animal model. In vivo cell depletion experiments demonstrate that tenofovir's ability to suppress viremia during acute and chronic infection is significantly dependent on the presence of CD8 ؉ lymphocytes. Continuous tenofovir treatment was required to maintain low viremia. Although it is unclear whether this immunemediated suppression of viremia is linked to tenofovir's direct antiviral efficacy or is due to independent immunomodulatory effects, these studies prove the concept that antiviral immune responses can play a crucial role in suppressing viremia during anti-human immunodeficiency virus drug therapy.Although highly active antiretroviral therapy (HAART) regimens provide significant progress in the clinical management of human immunodeficiency virus (HIV) infection, their longterm use is often limited by problems such as incomplete virus suppression and drug resistance. To alleviate this problem, it is believed we need to invoke the help of the immune system to help limit virus replication and/or the virus-induced immune dysfunction.Immune responses, especially cell-mediated immune responses (CD4 ϩ -T-helper cells and CD8 ϩ T lymphocytes) are thought to play an important role in controlling virus replication and determining disease-free survival. Evidence for this comes from studies in untreated long-term nonprogressors (for a review, see reference 2). In addition, macaque data have shown conclusively that CD8 ϩ lymphocytes play an important role in limiting lentivirus replication because in vivo CD8ϩ -cell depletion of untreated macaques resulted in an increase in viremia (23,34,67).A number of dilemmas exist, however, for patients receiving HAART. HAART initiated during acute HIV infection can often preserve or increase antiviral immune responses, but episodes of transient viremia may be required to maintain these responses (54, 63). In contrast, when HAART is initiated during chronic HIV infection, HIV-specific immune responses are more difficult to restore (for a review, see reference 2).The goal of immunotherapeutic strategies is to augment these antiviral immune responses to prevent the emergence and/or the replication of drug-resistant mutants during HAART or to allow simplified regimens or periods without drug treatment. Although different approaches are investigated to stimulate antiviral immune responses (e.g., structured treatment interruptions, active immunizations, and cytokines), the results have been poor or success has been limited mainly to patients with acute infection with often transient results (2,3,25,63). Progress in this area may depend on a better understanding of the contribution of antiviral immune responses to the reduction of viremia during HAART and of the complex in vivo interactions of viral replication, drug resistance, immune responses, and drug pharmacok...

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“…One study showed that a combination of neutralizing antibodies given to neonates at 1 hour and 8 days post-challenge led to 100% protection in animals infected with a SHIV, but did not protect animals from a more pathogenic virus (Hofmann-Lehmann et al, 2001). This same highly pathogenic virus also failed to be controlled by triple therapy of AZT, 3TC, and the protease inhibitor indinavir when initiated 4 hours after intravenous infection and continued for 14-28 days (Bourry et al, 2009;Le Grand et al, 2000). These studies noted that although most of the animals became infected, plasma viremia was reduced compared to the control animals, suggesting a partial protective effect of the treatment regimens.…”

Section: Post-exposure Prophylaxismentioning

confidence: 96%

Use of Animal Models for Anti-HIV Drug Development

Ambrose¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Post-exposure prophylaxis with highly active antiretroviral therapy could not protect macaques from infection with SIV/HIV chimera

Cited by 46 publications

References 5 publications

Early and Persistent Bone Marrow Hematopoiesis Defect in Simian/Human Immunodeficiency Virus-Infected Macaques despite Efficient Reduction of Viremia by Highly Active Antiretroviral Therapy during Primary Infection

Early and Persistent Bone Marrow Hematopoiesis Defect in Simian/Human Immunodeficiency Virus-Infected Macaques despite Efficient Reduction of Viremia by Highly Active Antiretroviral Therapy during Primary Infection

CD8⁺-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

Use of Animal Models for Anti-HIV Drug Development

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Post-exposure prophylaxis with highly active antiretroviral therapy could not protect macaques from infection with SIV/HIV chimera

Cited by 46 publications

References 5 publications

Early and Persistent Bone Marrow Hematopoiesis Defect in Simian/Human Immunodeficiency Virus-Infected Macaques despite Efficient Reduction of Viremia by Highly Active Antiretroviral Therapy during Primary Infection

Early and Persistent Bone Marrow Hematopoiesis Defect in Simian/Human Immunodeficiency Virus-Infected Macaques despite Efficient Reduction of Viremia by Highly Active Antiretroviral Therapy during Primary Infection

CD8+-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

Use of Animal Models for Anti-HIV Drug Development

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CD8⁺-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment