Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection

Rompay, Koen K. A. Van; Johnson, Jeffrey A.; Blackwood, Emily J; Singh, Raman P.; Lipscomb, Jonathan; Matthews, Timothy B.; Marthas, Marta; Pedersen, Niels C; Bischofberger, Norbert; Heneine, Walid; North, Thomas W.

doi:10.1186/1742-4690-4-25

Cited by 51 publications

(66 citation statements)

References 87 publications

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“…Previous studies have shown that SIV and HIV share similar resistance patterns against different classes of ARVs (10,36,37). Additionally, tissue culture studies by our group demonstrated that SIV substitutions confer resistance against INSTIs in a similar fashion to HIV (12).…”

Section: Discussionmentioning

confidence: 65%

“…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). In another study, macaques treated during preexposure prophylaxis with emtricitabine (FTC) or Truvada (TFV and FTC) and later infected by SIV sometimes developed the M184V substitution in RT, which is associated with resistance to FTC in HIV (11).…”

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confidence: 99%

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

Hassounah

Liu

Quashie

et al. 2015

J Virol

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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...

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Section: Discussionmentioning

confidence: 65%

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

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“…To further substantiate that conclusion, and to determine if the atypical course of infection in the 3 animals with transient viremia was due to strong cell-mediated antiviral immune responses, an in vivo CD8 ϩ cell depletion experiment was performed. At 58 weeks after SIV inoculation, the three animals were administered an anti-CD8 antibody that in previous studies induced a transient increase in viremia in SIV-infected animals (31,55,56). Following a single infusion of anti-CD8 antibody M-T807R1, the CD3 ϩ CD8 ϩ T cell and CD3 Ϫ CD8 ϩ NK cell counts in peripheral blood were undetectable or very low (Յ5 per l) for 3, 8, and 9 weeks in animals 32787, 30285, and 32214, respectively (Fig.…”

Section: Cd4mentioning

confidence: 99%

A Vaccine against CCR5 Protects a Subset of Macaques upon Intravaginal Challenge with Simian Immunodeficiency Virus SIVmac251

Rompay

Hunter

Jayashankar

et al. 2014

J Virol

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eAs an alternative to targeting human immunodeficiency virus (HIV), we have developed vaccines targeting CCR5, a self-protein critically involved in HIV replication and pathogenesis. By displaying peptides derived from CCR5 at high density on the surface of virus-like particles, we can efficiently induce high-titer IgG antibodies against this self-molecule. Here, we investigated whether prophylactic immunization of rhesus macaques with a particle-based vaccine targeting two regions of macaque CCR5 could prevent or suppress vaginal infection with highly virulent SIVmac251. Twelve macaques were vaccinated with a bacteriophage Qß-based vaccine targeting macaque CCR5 (Qß.CCR5). Six control animals were immunized with the Qß platform alone. All animals immunized with Qß.CCR5 developed high-titer anti-CCR5 antibody responses. Macaques were vaginally challenged with a high dose of SIVmac251. The mean peak viral RNA levels in the vaccinated groups were 30-fold lower than in the control group (10 6.8 versus 10 8.3 copies/ml plasma). Three of the 12 vaccinated macaques dramatically suppressed simian immunodeficiency virus (SIV) replication: peak viral loads were low (10 3 to 10 4 RNA copies/ml), and SIV RNA became undetectable from 6 weeks onward. No viral RNA or DNA could be detected in colon and lymph node biopsy specimens collected 13 months after challenge. In vivo depletion of CD8 ؉ cells failed to induce a viral rebound. However, once anti-CCR5 antibody responses had waned, the 3 animals became infected after intravaginal and/or intravenous rechallenge. In conclusion, vaccination against CCR5 was associated with dramatic suppression of virus replication in a subset (25%) of macaques. These data support further research of vaccination against CCR5 to combat HIV infection.

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“…The primary resistance mutation to FTC has been studied for its effects on in vivo viral virulence and fitness (Van Rompay et al, 2002a). Similarly, mutations conferring resistance to tenofovir were studied in SIV for their emergence and suppression in vivo during tenofovir monotherapy (Van Rompay et al, 2007). Resistant viruses were identified in macaques with breakthrough infections after intermittent tenofovir/FTC pre-exposure prophylaxis with intrarectal challenge (Garcia-Lerma et al, 2008).…”

Section: Drug Resistancementioning

confidence: 99%

Use of Animal Models for Anti-HIV Drug Development

Ambrose¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection

Cited by 51 publications

References 87 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

A Vaccine against CCR5 Protects a Subset of Macaques upon Intravaginal Challenge with Simian Immunodeficiency Virus SIVmac251

Use of Animal Models for Anti-HIV Drug Development

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