The S230R Integrase Substitution Associated With Virus Load Rebound During Dolutegravir Monotherapy Confers Low-Level Resistance to Integrase Strand-Transfer Inhibitors

Pham, Hanh Thi; Labrie, Lydia; Wijting, Ingeborg E A; Hassounah, Said; Lok, Ka Yee; Portna, Inna; Goring, Mark E; Han, Ying-Shan; Lungu, Cynthia; Ende, Marchina E. van der; Brenner, Bluma G.; Boucher, Charles A.; Rijnders, Bart J. A.; Kampen, Jeroen J. A. van; Mésplède, Thibault; Wainberg, Mark A.

doi:10.1093/infdis/jiy175

Cited by 33 publications

(27 citation statements)

References 49 publications

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“…Several clinical reports have observed failure of DTG-containing therapy in the absence of IN mutations, suggesting that mutations outside IN may confer resistance in these patients (82,83). A recent study observed mutations in the nef gene that conferred INSTI resistance (84,85). However, to our knowledge, we present a unique instance of de novo selection of Env mutations that confer resistance to DTG in vitro.…”

Section: Discussionmentioning

confidence: 65%

Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Duyne

Kuo

Pham

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The p6 domain of HIV-1 Gag contains highly conserved peptide motifs that recruit host machinery to sites of virus assembly, thereby promoting particle release from the infected cell. We previously reported that mutations in the YPXnL motif of p6, which binds the host protein Alix, severely impair HIV-1 replication. Propagation of the p6–Alix binding site mutants in the Jurkat T cell line led to the emergence of viral revertants containing compensatory mutations not in Gag but in Vpu and the envelope (Env) glycoprotein subunits gp120 and gp41. The Env compensatory mutants replicate in Jurkat T cells and primary human peripheral blood mononuclear cells, despite exhibiting severe defects in cell-free particle infectivity and Env-mediated fusogenicity. Remarkably, the Env compensatory mutants can also rescue a replication-delayed integrase (IN) mutant, and exhibit reduced sensitivity to the IN inhibitor Dolutegravir (DTG), demonstrating that they confer a global replication advantage. In addition, confirming the ability of Env mutants to confer escape from DTG, we performed de novo selection for DTG resistance and observed resistance mutations in Env. These results identify amino acid substitutions in Env that confer broad escape from defects in virus replication imposed by either mutations in the HIV-1 genome or by an antiretroviral inhibitor. We attribute this phenotype to the ability of the Env mutants to mediate highly efficient cell-to-cell transmission, resulting in an increase in the multiplicity of infection. These findings have broad implications for our understanding of Env function and the evolution of HIV-1 drug resistance.

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Section: Discussionmentioning

confidence: 65%

Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Duyne

Kuo

Pham

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…After 48 h, culture supernatants were harvested, centrifuged, passed through a 0.45-m-pore-size filter to remove cellular debris, treated with Benzonase (EMD) to degrade the transfected plasmids, and stored at Ϫ80°C for future use. Reverse transcriptase (RT) activity quantification was performed using a previously described in vitro HIV RT assay (11) and used to normalize viral infections of PBMCs to 30,000 RT units of either WT or mutant viruses. The same RT quantification assay was used to measure the SIV replicative capacity over time (RT).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, several studies have investigated DTG monotherapy as a maintenance therapy in HIV-infected patients who have previously achieved virological suppression with combination ART regimens. Despite promising results in several initial small studies, in subsequent larger studies, including the DOMONO study, occasional virological failures associated with the detection of DTG resistance mutations have been reported, raising ethical concerns whether this strategy deserves further consideration (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

Dolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological Outcomes

Rompay

Hassounah

Keele

et al. 2019

J Virol

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Drug resistance remains a major concern for human immunodeficiency virus (HIV) treatment. To date, very few resistance mutations have emerged in first-line combination therapy that includes the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). In vitro, DTG selects for several primary mutations that induce low-level DTG resistance; secondary mutations, while increasing the level of resistance, however, further impair replication fitness, which raised the idea that DTG monotherapy may be feasible. The simian immunodeficiency virus (SIV) rhesus macaque model of HIV infection can be useful to explore this concept. Nine macaques were infected with virulent SIVmac251 and started on DTG monotherapy during either acute (n = 2) or chronic infection (n = 7). Within 4 weeks of treatment, all animals demonstrated a reduction in viremia of 0.8 to 3.5 log RNA copies/ml plasma. Continued treatment led to overall sustained benefits, but the outcome after 10 to 50 weeks of treatment was highly variable and ranged from viral rebound to near pretreatment levels to sustained suppression, with viremia being 0.5 to 5 logs lower than expected based on pretreatment viremia. A variety of mutations previously described to confer low-level resistance of HIV-1 to DTG or other INSTI were detected, and these were sometimes followed by mutations believed to be compensatory. Some mutations, such as G118R, previously shown to severely impair the replication capacity in vitro, were associated with more sustained virological and immunological benefits of continued DTG therapy, while other mutations, such as E92Q and G140A/Q148K, were associated with more variable outcomes. The observed variability of the outcomes in macaques warrants avoidance of DTG monotherapy in HIV-infected people. IMPORTANCE A growing number of anti-HIV drug combinations are effective in suppressing virus replication in HIV-infected persons. However, to reduce their cost and risk for toxicity, there is considerable interest in simplifying drug regimens. A major concern with single-drug regimens is the emergence of drug-resistant viral mutants. It has been speculated that DTG monotherapy may be a feasible option, because DTG may have a higher genetic barrier for the development of drug resistance than other commonly used antiretrovirals. To explore treatment initiation with DTG monotherapy, we started SIV-infected macaques on DTG during either acute or chronic infection. Although DTG initially reduced virus replication, continued treatment led to the emergence of a variety of viral mutations previously described to confer low-level resistance of HIV-1 to DTG, and this was associated with variable clinical outcomes. This unpredictability of mutational pathways and outcomes warns against using DTG monotherapy as initial treatment for HIV-infected people.

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“…An overall DRM prevalence of 1.4%, 35.7%, and 15.7% was estimated for PR, RT, and int, respectively. The [40][41][42][43][44][45][46][47][48][49] year-olds in our study had the highest prevalence of DRMs (22.9%), while the [20][21][22][23][24][25][26][27][28][29] year-olds in our study did not show any DRMs. Overall, DRMs caused amino acid changes in only one codon position in PR, while 22 and 9 different codons positions changed in RT and int, respectively, when analyzing the consensus sequences.…”

mentioning

confidence: 55%

“…These sites were 64, 72, 77, and 93 for PR; 35,85,102,and 200 for RT;and 201,206,211,218,230,256,265,283, and 285 for int. The only codon position predicted by FUBAR in the haplotypes was 230 for int, and it is associated with reduced susceptibility to integrase inhibitors (INSTI) 27 . Seven (4,34,41,43,44,45,64) and eight (22,40,84,92,93,95,105,111) codons were inferred to be under positive selection for V1V2 and V3 haplotype sequences, respectively.…”

mentioning

confidence: 99%

A cross-sectional study to characterize local HIV-1 dynamics in Washington, DC using next-generation sequencing

Gibson

Jair

Castel

et al. 2020

Sci Rep

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the DC Cohort Executive Committee † Washington, DC continues to experience a generalized HIV-1 epidemic. We characterized the local phylodynamics of HIV-1 in DC using next-generation sequencing (NGS) data. Viral samples from 68 participants from 2016 through 2017 were sequenced and paired with epidemiological data. Phylogenetic and network inferences, drug resistant mutations (DRMs), subtypes and HIV-1 diversity estimations were completed. Haplotypes were reconstructed to infer transmission clusters. Phylodynamic inferences based on the HIV-1 polymerase (pol) and envelope genes (env) were compared. Higher HIV-1 diversity (n.s.) was seen in men who have sex with men, heterosexual, and male participants in DC. 54.0% of the participants contained at least one DRM. The 40-49 year-olds showed the highest prevalence of DRMs (22.9%). Phylogenetic analysis of pol and env sequences grouped 31.9-33.8% of the participants into clusters. HIV-TRACE grouped 2.9-12.8% of participants when using consensus sequences and 9.0-64.2% when using haplotypes. NGS allowed us to characterize the local phylodynamics of HIV-1 in DC more broadly and accurately, given a better representation of its diversity and dynamics. Reconstructed haplotypes provided novel and deeper phylodynamic insights, which led to networks linking a higher number of participants. Our understanding of the HIV-1 epidemic was expanded with the powerful coupling of HIV-1 NGS data with epidemiological data.Despite recent reductions in HIV-1 prevalence in Washington, DC from 2.5% in 2013 1 to 1.8% in 2018, the United States (US) capital is still experiencing a generalized HIV-1 epidemic -as defined by the World Health Organization 2-4 . There were 340 newly diagnosed cases in DC in 2018, and the DC rate is five times higher than the national rate 3 . Blacks, men, men who have sex with men (MSM), and heterosexuals (HRH) account for the majority of people living with HIV-1 (PLWH) in DC 2,3 . However, ~20% of the newly diagnosed persons had an unknown risk for transmission in both 2016 and 2017 2,3 . Furthermore, the leading group (33.3%) of newly diagnosed cases was between the ages of 20-29 years old 3 . This same age group had the highest percentage (27.5%) of drug resistance mutations (DRM) at diagnosis, suggesting broader spread of HIV-1 drug resistant variants and potential concern for future therapeutic options, especially if these mutations are against first line antiretroviral (ART) drugs for newly infected individuals. With blacks and young adults being the most impacted groups of individuals for HIV-1 in DC, understanding the current HIV-1 phylodynamics can provide informative data to guide programs that prevent and reduce the incidence of HIV-1. Moreover, identifying potential transmission clusters amongst individuals in DC and their associated epidemiological features may help infer otherwise 'unknown' transmission modes and provide insight for more targeted prevention and intervention strategies.In 2011, the DC Cohort, a longitudinal observational NIH-funded co...

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The S230R Integrase Substitution Associated With Virus Load Rebound During Dolutegravir Monotherapy Confers Low-Level Resistance to Integrase Strand-Transfer Inhibitors

Abstract: Our data indicate that the S230R substitution is comparable to the previously reported R263K substitution in some respects. Virologic failure during DTG monotherapy can occur through the development of the S230R or R263K mutation, without the need for high-level DTG resistance.

Cited by 33 publications

References 49 publications

Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Dolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological Outcomes

A cross-sectional study to characterize local HIV-1 dynamics in Washington, DC using next-generation sequencing

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