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

Abstract

Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does notclear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.

Ultrasensitive Allele-Specific PCR Reveals Rare Preexisting Drug-Resistant Variants and a Large Replicating Virus Population in Macaques Infected with a Simian Immunodeficiency Virus Containing Human Immunodeficiency Virus Reverse Transcriptase

“…We applied the UsASP technique to better understand the evolution of resistance in two RT-SHIV-infected macaques, both of which developed resistance (K103N) following a 4-day course of EFV monotherapy and one of which (M03250) developed resistance (K65R and M184I) during a subsequent period of cART (2). The effect of the monotherapy is shown in Fig.…”

“…Three weeks after the first dose of EFV (week 16), the frequency of the 103N AAC allele was similar (9%), corresponding to an average of 139,500 copies of mutant genomes/ml due to a 30-fold increase in plasma HIV-1 total RNA (Table 2), but the AAT allele had declined to 2.6% of the virus population, corresponding to 39,000 mutant copies/ml (Table 2). Seventeen weeks postinoculation (week 17), the animals were started on cART (TNV plus FTC plus EFV), and as published previously (2,20), but not tested by UsASP in this study, at week 26, the 103N AAC mutation and the 184I mutation were fixed at 100% in macaque M03250.…”

“…The treatment regimens for six pigtail macaques inoculated with RT-SHIV mne has been described (2). In short, animals were treated with three doses of EFV over 4 days starting 13 weeks postinoculation; two of these animals developed EFV resistance as detected by ASP and SGS (M03250 and M04008) (2).…”

“…As described by Ambrose et al (2), plasma was collected and allele-specific PCR (ASP) and single-genome sequencing (SGS) were conducted on samples prior to and following EFV monotherapy and after cART. In samples collected after the initiation of cART, M184I and K65R, which encode FTC and TNV resistance, were detected in one of the macaques, which experienced virologic failure.…”

Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4 + T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2 −/− γ c −/− Mouse

“…NHPs infected with a chimeric simianhuman immunodeficiency virus (SHIV) encoding human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT-SHIV) can be used to test reverse transcriptase inhibitors; however, NHP resources are limited (2,18). BLT (bone marrow liver thymic) mice have been successfully used to model antiretroviral preexposure prophylaxis, but have not yet been used to model ART (7).…”