Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus

Andrews, C. Webster; Spreen, William; Mohri, Hiroshi; Moss, Lee; Ford, Susan L.; Gettie, Agegnehu; Russell‐Lodrigue, Kasi; Bohm, Rudolf P.; Cheng‐Mayer, Cecilia; Hong, Zhi; Markowitz, Martin; Ho, David D.

doi:10.1126/science.1248707

Cited by 148 publications

(171 citation statements)

References 27 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…Macaque models of rectal and vaginal transmission of SIV and SHIV have provided data that support the use of topical gels with reverse transcriptase (RT) inhibitors such as tenofovir (TFV) and MIV150 (3)(4)(5) and integrase inhibitors such as L-870812, an analogue of RAL (6), toward reductions of viral transmission rates. A long-acting form of a new INSTI, cabotegravir (also known as S/GSK-1265744), which is a DTG analogue, was shown to protect macaques against repeated vaginal and rectal challenges using SHIV (7,8). Prolonged TFV monotherapy of macaques infected with SIV or SHIV resulted in the emergence of viral mutants with the K65R substitution in RT, the same mutation that is associated with TFV treatment failure (9,10).…”

mentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

View full text Add to dashboard Cite

We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3=-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased K m = and V max =/K m = for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV. IMPORTANCEOur goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.T he limitations of current highly active antiretroviral therapy (HAART) include the incidence of drug resistance observed in patients, issues of drug adherence, and numbers of newly acquired infections. The emergence of drug-resistant viruses can lead to increases in viral load and treatment failure, and such viruses can be transmitted to both healthy individuals as well as to untreated HIV-positive individuals, therefore threatening the long-term effica...

show abstract

mentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Taken these demonstrated properties of DTG, investigators have slightly modified its structure to [88] . In these preclinical studies, GSK744 provided high-level protection against repeated simian/human immunodeficiency virus challenge in rhesus macaques.…”

Section: Clinical Results Using Hiv In Stis and Drug Resistancementioning

confidence: 99%

Multifunctional facets of retrovirus integrase

Grandgenett¹

2015

WJBC

View full text Add to dashboard Cite

The retrovirus integrase (IN) is responsible for integration of the reverse transcribed linear cDNA into the host DNA genome. First, IN cleaves a dinucleotide from the 3' OH blunt ends of the viral DNA exposing the highly conserved CA sequence in the recessed ends. IN utilizes the 3' OH ends to catalyze the concerted integration of the two ends into opposite strands of the cellular DNA producing 4 to 6 bp staggered insertions, depending on the retrovirus species. The staggered ends are repaired by host cell machinery that results in a permanent copy of the viral DNA in the cellular genome. 83-94 ISSN 1949-8454 (online)

show abstract

“…The ARV drugs atazanavir and ritonavir, nanoformulated in poloxamer 188 excipient by high-pressure homogenization, were evaluated preclinically as LA-ART candidates in humanized mouse (28) and nonhuman primate models (29). Parenteral administration of the integrase strand-transfer inhibitor GSK1265744 (GSK744) fully protected rhesus macaques against repeated low-dose intrarectal challenges of SHIV162P3 (30). Monthly or bimonthly injections of longacting nanoparticulate formulations of GSK744 and the non- nucleoside reverse transcriptase inhibitor rilpivirine (RPV) are being investigated clinically as possible regimens for HIV therapy (25,27,31).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Injectable, Long-Acting Nevirapine for HIV Prophylaxis in Breastfeeding Infants

Cortez

Quintero

Moss

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

c Mother-to-child transmission (MTCT) of HIV-1 remains a global health problem. The World Health Organization (WHO) recommendations advise the administration of a once-daily, oral, prophylactic regimen of the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) from birth until 4 to 6 weeks of age for infants born to HIV-infected mothers in regions without access to safe and nutritionally adequate alternatives to breast milk. A critical factor driving the successful implementation of the WHO guidelines involves sustaining high adherence to the frequent dosing. With these challenges in mind, we have developed the first injectable, sustained-release NVP formulations with the goal of providing, for 6 weeks or longer, preventative plasma drug levels from a single subcutaneous administration at birth. The long-acting NVP consists of large (>50 m), monodisperse NVP particles coated with biocompatible polymers that control the drug release kinetics. Two lead formulations exhibiting burst-free, sustained-release kinetics for up to 75 days in vitro were developed. Subsequent in vivo studies in rats demonstrated no toxicity related to the formulations. Rat plasma NVP concentrations were above the analytical assay's limit of quantification for up to 28 days. Pharmacokinetic analysis of the rat plasma NVP concentration-time data allowed absorption rate constants to be calculated. These data then were used to simulate infant NVP exposure from a single injected dose (<200 mg) of our longacting formulations, demonstrating preliminary feasibility of the technology to maintain safe, preventative NVP plasma levels (0.2 to 3.0 g ml ؊1 ) for 6 weeks or longer.

show abstract

Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus

Cited by 148 publications

References 27 publications

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Multifunctional facets of retrovirus integrase

Pharmacokinetics of Injectable, Long-Acting Nevirapine for HIV Prophylaxis in Breastfeeding Infants

Contact Info

Product

Resources

About