Effects of monotherapy with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) on the evolution of a primary Simian immunodeficiency virus (SIV) isolate

Abstract

Determining the impact of antiretroviral therapy on virus evolution could advance the development of improved therapeutics/vaccines against HIV. Toward this goal, we analyzed virus burden, quasispecies complexity, and T cell responses in SIV/DeltaB670-infected rhesus macaques+/-treatment for 7 months with PMPA (2-30 weeks postinfection). Treatment divided the animals into two groups: poor responders (a reduction of < or =1 log) and responders (> or =2 log reduction) in virus burden. Virus evolution in poor responders and untreated controls was characterized by expression of a complex quasispecies that evolved as the disease progressed. This included the universal loss of a viral genotype selected against by in vitro passage in monkey cells and selected for by propagation in human cells. In contrast, a good response to PMPA was characterized by infection with a less complex quasispecies that evolved more slowly. Interestingly, in 2 of the best responders, the human-preferred genotype persisted until the study was discontinued (89 weeks p.i.). Neither virus burden nor the magnitude of the T cell response at 2 weeks postinfection predicted PMPA responsiveness. However, responders expressed a less complex quasispecies than nonresponders prior to treatment. These data suggest a role for intrinsic host factors in treatment responsiveness, and lend support for therapeutic vaccination as an adjunct to effective therapy.

Response of Simian Immunodeficiency Virus to the Novel Nucleoside Reverse Transcriptase Inhibitor 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine In Vitro and In Vivo

“…Virion-associated RNA in plasma was quantified by real-time PCR in a Prism 7700 (Applied Biosystems, Inc., Foster City, CA) using primers specific for the SIV long terminal repeat (LTR) as described previously (4,5,6,21). This assay is linear over an 8-log range of template copy numbers and has a sensitivity threshold of 10 copies per reaction.…”

“…1). SIV/DeltaB670 is highly virulent in macaques (19), has been propagated in vitro only in rhPBMC, and is comprised of a well-characterized genetic swarm (1,2,21,22). A comparison of the percent inhibition and the 50 and 90% effective concentrations (EC 50 and EC 90 ) for each drug are shown in Fig.…”

“…Animals had been inoculated intravenously with the same SIV stock as that used for the in vitro experiments described above. Plasma virus burden was monitored by qRT-PCR (4,5,21). Fortyone days postinoculation (after the viral set point had been reached but while they were clinically asymptomatic), daily treatment with 20 mg/kg TFV and twice-daily administration of 16 mg/kg lopinavir-ritonavir was initiated; therapy was continued for 279 days and then discontinued.…”

Antiretroviral-based HIV prevention strategies for women

“…In rhesus macaques treated daily with subcutaneous phosonomethoxypropyl adenine (PMPA) for 28 weeks beginning 2 weeks postinfection, Taber and colleagues found an average viremia of more than 10 5 RNA copies/ml was required to maintain the TFV-resistant mutation K65R and compensatory mutation N69S/T [41]. In another study, 12 reverse transcriptase-SHIV-infected rhesus macaques were administered 10 mg/ml once-daily subcutaneous TFV beginning at 20 weeks postinfection.…”

Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques

“…In this respect, animal studies using SIV infection of non-human primates provide a useful tool to shed light on the mechanisms of immune-mediated control of infection, the impact of antiretroviral drugs on virus replication [12], and the emergence and evolution of drug-resistant variants [13]. SIV infection in rhesus macaques shares many of the immunopathogenic features of HIV-1 infection in humans, and this model has been used to evaluate the contribution of antiviral immune responses to suppression of virus replication during ART intervention.…”