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

Abstract

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mutations but acquired the K65R mutation in reverse transcriptase at 11 weeks after efavirenz treatment was withdrawn.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.

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

“…Experiments with RT-SHIV mac239 , a direct antecedent to RT-SHIV mne , first demonstrated that substitution of SIV RT with HIV-1 RT yielded a virus with the desirable characteristics of robust replication within animals and susceptibility to antiviral agents which structurally recognize an HIV-1 protein (44,51). We developed a similar infection model with pigtail macaques to investigate questions of viral dynamics and the evolution of drug resistance in response to therapy.…”

Novel Pathway for Induction of Latent Virus from Resting CD4+T Cells in the Simian Immunodeficiency Virus/Macaque Model of Human Immunodeficiency Virus Type 1 Latency

“…An AIDS-like disease was first noted in rhesus macaques infected with SIV from sooty mangabeys (29). Although SIV infection of macaques is an excellent model for HIV-1 pathogenesis, it has only recently been used to model the treatment of HIV-1 infection (11,34,47,57), including the SIV/macaque model that we recently developed to study HIV latency under suppressive therapy (47). We showed that SIV established latent infection in resting macaque CD4…”

Use of Animal Models for Anti-HIV Drug Development

“…In an animal model, antiretroviral suppression should be as good as what is observed in humans on combination antiretroviral therapy. Standard assays detect down to 50 copies of viral RNA per milliliter of plasma, but even with typical three drug regimens it has been difficult to completely inhibit plasma viremia in some macaques to undetectable levels (Ambrose et al, 2007;Dinoso et al, 2009;Lugli et al, 2011;North et al, 2005). The ability to achieve complete suppression generally correlates with the level of plasma viremia prior to treatment, such that higher viral loads are more difficult to completely suppress (Kearney et al, 2011).…”

“…Efavirenz monotherapy leads to the emergence of common resistance mutations that are seen in patients (Ambrose et al, 2007;Hofman et al, 2004). Efavirenz combined with tenofovir and FTC is a commonly prescribed combination therapy for HIV-infected individuals and was shown to be effective in reducing RT-SHIV plasma viremia in two species of macaques (Ambrose et al, 2007;North et al, 2005). Prior efavirenz resistance was shown to compromise combination therapy in one animal, leading to accumulation of FTC-resistant mutations in the virus and, ultimately, failure of therapy (Ambrose et al, 2007).…”