Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

Higgins

et al. 2005

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We have modeled highly active antiretroviral therapy (HAART) for AIDS in rhesus macaques infected with a chimera (RT-SHIV) of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type-1 (HIV-1). Seven RT-SHIV-infected macaques were treated with a combination of efavirenz (200 mg orally once daily), lamivudine (8 mg/kg subcutaneously once daily), and tenofovir (30 mg/kg subcutaneously once daily). Plasma viral RNA levels in all animals were reduced by more than 1,000-fold after 4 weeks and, in six of the seven animals, were reduced to undetectable levels after 10 weeks. Virus loads increased slightly between 12 and 16 weeks of treatment, associated with problems with the administration of efavirenz. After a change in the method of efavirenz administration, virus loads declined again and remained undetectable in the majority of animals for the duration of therapy. Treatment was stopped for three animals after 36 weeks of therapy, and virus loads increased rapidly. Posttreatment RT-SHIV isolates had no mutations associated with resistance to any of the three drugs. Efavirenz treatment was stopped, but lamivudine and tenofovir treatment for two other macaques was continued. The virus load in one of these two animals rebounded; virus from this animal was initially free of drug-resistance mutations but acquired the K65R mutation in reverse transcriptase at 11 weeks after efavirenz treatment was withdrawn. These results mimic HAART of HIV-1-infected humans. The RT-SHIV/rhesus macaque model should be useful for studies of tissue reservoirs and sites of residual replication that are not possible or practical with humans.

Section: Methodsmentioning

confidence: 99%

Suppression of Virus Load by Highly Active Antiretroviral Therapy in Rhesus Macaques Infected with a Recombinant Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

North

Higgins

et al. 2005

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“…Our SIVmac251 isolates are very difficult to control in vivo. Of the more than 180 rhesus macaques (including 54 previously vaccinated animals) that became persistently infected after inoculation with these SIVmac251 virus stocks over the past decade at CNPRC, none suppressed viremia to persistently low or undetectable levels (19,43,65,79,80,82,83,85,87,88,(90)(91)(92).…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Singh

Pahar

et al. 2004

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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...

“…Infected cells were harvested as soon as culture supernatant results were positive by p27 antigen capture ELISA. Genomic DNA was extracted and used for nested PCR according to methods and with primers described previously; amplicons were sequenced by Davis Sequencing (Davis, California) with primers 239-2786 and SIV-RT3 (67,72). This method can detect the presence of a 20% subpopulation.…”

Section: Methodsmentioning

confidence: 99%

Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques

Singh

Heneine

et al. 2006

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We demonstrated previously that prolonged tenofovir treatment of infant macaques, starting early during infection with virulent simian immunodeficiency virus (SIVmac251), can lead to persistently low or undetectable viremia even after the emergence of mutants with reduced in vitro susceptibility to tenofovir as a result of a K65R mutation in reverse transcriptase; this control of viremia was demonstrated to be mediated by the generation of effective antiviral immune responses. To determine whether structured treatment interruptions (STI) can induce similar immunologic control of viremia, eight newborn macaques were infected with highly virulent SIVmac251 and started on a tenofovir STI regimen 5 days later. Treatment was withdrawn permanently at 33 weeks of age. All animals receiving STI fared much better than 22 untreated SIVmac251-infected infant macaques. However, there was a high variability among animals in the viral RNA set point after complete drug withdrawal, and none of the animals was able to achieve long-term immunologic suppression of viremia to persistently low levels. Early immunologic and viral markers in blood (including the detection of the K65R mutation) were not predictive of the viral RNA set point after drug withdrawal. These results, which reflect the complex interactions between drug resistance mutations, viral virulence, and drug-and immunemediated inhibition of virus replication, highlight the difficulties associated with trying to develop STI regimens with predictable efficacy for clinical practice.