Reply to Das and Berkhout, “How Polypurine Tract Changes in the HIV-1 RNA Genome Can Cause Resistance against the Integrase Inhibitor Dolutegravir”

Abstract Background Little is known about HIV-1 integrase inhibitor resistance in the CNS. Objectives This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma. Methods HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. Results Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85–5.80) and 3.59 (2.16–4.50) log10 copies/mL versus 4.79 (3.56–5.25) and 3.80 (2.68–4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02_AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, n = 3; L74I/M, n = 1; T97A, n = 1; E157Q, n = 4) and ARV-treated (L74I, n = 6; L74M, n = 1; T97A, n = 1; N155H, n = 1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients. Conclusions This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients.

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Flavonol 7-O-Glucoside Herbacitrin Inhibits HIV-1 Replication through Simultaneous Integrase and Reverse Transcriptase Inhibition

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/1064793 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Éva Áy ◽

Attila Hunyadi ◽

Mária Mezei ◽

János Minárovits ◽

Judit Hohmann

Keyword(s):

Antiviral Activity ◽

Reverse Transcriptase ◽

Cell Cultures ◽

Core Protein ◽

Integrase Inhibitor ◽

Host Cells ◽

Cytotoxic Activities ◽

Protein Levels ◽

Hiv 1 ◽

Antiretroviral Activity

Here we report the evaluation of the antiretroviral effect of two flavonoid 7-O-glucosides, herbacitrin (1) and gossypitrin (2), together with quercetin (3), a well-studied flavonol. Antiviral activity of the flavonoids was assessed by analyzing HIV-1 p24 core protein levels in the supernatants of HIV-1 infected MT-4 and MT-2 cell cultures. The compounds showed mild to weak cytotoxic activities on the host cells; herbacitrin was the strongest in this regard (CC50=27.8 and 63.64 μM on MT-4 and MT-2 cells, respectively). In nontoxic concentrations, herbacitrin and quercetin reduced HIV-1 replication, whereas gossypitrin was ineffective. Herbacitrin was found to inhibit reverse transcriptase at 21.5 μM, while it was a more potent integrase inhibitor already active at 2.15 μM. Therefore, our observations suggest that herbacitrin exerts antiretroviral activity through simultaneously acting on these two targets of HIV-1 and that integrase inhibition might play a major role in this activity.

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Performance of the Abbott RealTime HIV-1 Viral Load Assay Is Not Impacted by Integrase Inhibitor Resistance-Associated Mutations

Journal of Clinical Microbiology ◽

10.1128/jcm.02253-10 ◽

2011 ◽

Vol 49 (4) ◽

pp. 1631-1634 ◽

Cited By ~ 3

Author(s):

T. P. Young ◽

G. Cloherty ◽

S. Fransen ◽

L. Napolitano ◽

P. Swanson ◽

...

Keyword(s):

Viral Load ◽

Integrase Inhibitor ◽

Viral Load Assay ◽

Inhibitor Resistance ◽

Hiv 1

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Purine analog substitution of the HIV-1 polypurine tract primer defines regions controlling initiation of plus-strand DNA synthesis

Nucleic Acids Research ◽

10.1093/nar/gkl909 ◽

2006 ◽

Vol 35 (1) ◽

pp. 256-268 ◽

Cited By ~ 16

Author(s):

J. W. Rausch ◽

S. F. J. Le Grice

Keyword(s):

Dna Synthesis ◽

Polypurine Tract ◽

Purine Analog ◽

Hiv 1

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Circularization of the HIV-1 RNA genome

Nucleic Acids Research ◽

10.1093/nar/gkm564 ◽

2007 ◽

Vol 35 (15) ◽

pp. 5253-5261 ◽

Cited By ~ 27

Author(s):

M. Ooms ◽

T. E. M. Abbink ◽

C. Pham ◽

B. Berkhout

Keyword(s):

Rna Genome ◽

Hiv 1

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Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection

Scientific Reports ◽

10.1038/s41598-021-90678-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna Prats ◽

Ignacio Martínez-Zalacaín ◽

Beatriz Mothe ◽

Eugènia Negredo ◽

Núria Pérez-Álvarez ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Integrase Inhibitor ◽

Strand Transfer ◽

Cognitive Differences ◽

Integrase Strand Transfer Inhibitors ◽

Initiation Of Therapy ◽

Main Component ◽

Living With Hiv ◽

The Impact ◽

Hiv 1

AbstractIntegrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

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PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex

Journal of Virology ◽

10.1128/jvi.01741-18 ◽

2018 ◽

Vol 93 (6) ◽

Cited By ~ 11

Author(s):

Muthukumar Balasubramaniam ◽

Jing Zhou ◽

Amma Addai ◽

Phillip Martinez ◽

Jui Pandhare ◽

...

Keyword(s):

Reverse Transcription ◽

Integrase Inhibitor ◽

Antiviral Effect ◽

Inhibitory Effect ◽

Clear Understanding ◽

Nuclear Entry ◽

Preintegration Complex ◽

Gradient Based ◽

Hiv 1

ABSTRACTThe HIV-1 capsid protein (CA) facilitates reverse transcription and nuclear entry of the virus. However, CA’s role in post-nuclear entry steps remains speculative. We describe a direct link between CA and integration by employing the capsid inhibitor PF74 as a probe coupled with the biochemical analysis of HIV-1 preintegration complexes (PICs) isolated from acutely infected cells. At a low micromolar concentration, PF74 potently inhibited HIV-1 infection without affecting reverse transcription. Surprisingly, PF74 markedly reduced proviral integration owing to inhibition of nuclear entry and/or integration. However, a 2-fold reduction in nuclear entry by PF74 did not quantitatively correlate with the level of antiviral activity. Titration of PF74 against the integrase inhibitor raltegravir showed an additive antiviral effect that is dependent on a block at the post-nuclear entry step. PF74’s inhibitory effect was not due to the formation of defective viral DNA ends or a delay in integration, suggesting that the compound inhibits PIC-associated integration activity. Unexpectedly, PICs recovered from cells infected in the presence of PF74 exhibited elevated integration activity. PF74’s effect on PIC activity is CA specific since the compound did not increase the integration activity of PICs of a PF74-resistant HIV-1 CA mutant. Sucrose gradient-based fractionation studies revealed that PICs assembled in the presence of PF74 contained lower levels of CA, suggesting a negative association between CA and PIC-associated integration activity. Finally, the addition of a CA-specific antibody or PF74 inhibited PIC-associated integration activity. Collectively, our results demonstrate that PF74’s targeting of PIC-associated CA results in impaired HIV-1 integration.IMPORTANCEAntiretroviral therapy (ART) that uses various combinations of small molecule inhibitors has been highly effective in controlling HIV. However, the drugs used in the ART regimen are expensive, cause side effects, and face viral resistance. The HIV-1 CA plays critical roles in the virus life cycle and is an attractive therapeutic target. While currently there is no CA-based therapy, highly potent CA-specific inhibitors are being developed as a new class of antivirals. Efforts to develop a CA-targeted therapy can be aided through a clear understanding of the role of CA in HIV-1 infection. CA is well established to coordinate reverse transcription and nuclear entry of the virus. However, the role of CA in post-nuclear entry steps of HIV-1 infection is poorly understood. We show that a CA-specific drug PF74 inhibits HIV-1 integration revealing a novel role of this multifunctional viral protein in a post-nuclear entry step of HIV-1 infection.

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