Mutations in Multiple Domains of Gag Drive the Emergence of
            <i>In Vitro</i>
            Resistance to the Phosphonate-Containing HIV-1 Protease Inhibitor GS-8374

Stray, Kirsten M.; Callebaut, Christian; Glass, Bärbel; Tsai, Luke Y.; Xu, Lianhong; Müller, Bárbara; Kräusslich, Hans‐Georg; Cihlář, Tomáš

doi:10.1128/jvi.01211-12

Cited by 9 publications

(6 citation statements)

References 37 publications

(46 reference statements)

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“…R41G is present in 1/3083 isolates in the LANL database and is not a primary PI resistance substitution [11, 44]. A related change, R41K, is a common polymorph (26% in subtype B and 68% of all Gag genes in the LANL database), and may be involved in the emergence of protease resistance to an investigational protease inhibitor [45, 46]. R41 is located in a loop proximal to the HIV-1 protease substrate binding site and might act allosterically to facilitate closing the pocket over the substrate, thereby allowing catalysis.…”

Section: Discussionmentioning

confidence: 99%

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

Dicker¹,

Zhang²,

Ray

et al. 2019

PLoS ONE

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GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants.

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Section: Discussionmentioning

confidence: 99%

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

Dicker¹,

Zhang²,

Ray

et al. 2019

PLoS ONE

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“…Importantly, the aptamers specifically target CD4, which is a stable host cell receptor, instead of viral gp120. Using this approach, one can overcome the major obstacle for prevention of HIV-1 transmission, which is the high mutation rate of virus (Cabrera and Clotet, 2005; Holtz and Mansky, 2013; Stray et al, 2013; Wainberg et al, 2012). The aptamers may also be useful for emergency treatment of patients that have accidental exposure of HIV-1 via needlstick or bodily fluid transfer by temporarily blocking CD4 receptors on host blood cells.…”

Section: Discussionmentioning

confidence: 99%

Blocking interaction of viral gp120 and CD4-expressing T cells by single-stranded DNA aptamers

Zhao¹,

Pei²,

Parekh³

et al. 2014

The International Journal of Biochemistry & Cell Biology

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To investigate the potential clinical application of aptamers to prevention of HIV infection, single- stranded DNA (ssDNA) aptamers specific for CD4 were developed using the systematic evolution of ligands by exponential enrichment approach and next generation sequencing. In contrast to RNA-based aptamers, the developed ssDNA aptamers were stable in human serum up to 12 hr. Cell binding assays revealed that the aptamers specifically targeted CD4-expressing cells with high binding affinity (Kd=1.59 nM), a concentration within the range required for therapeutic application. Importantly, the aptamers selectively bound CD4 on human cells and disrupted the interaction of viral gp120 to CD4 receptors, which is a prerequisite step of HIV-1 infection. Functional studies showed that the aptamer polymers significantly blocked binding of viral gp120 to CD4-expressing cells by up to 70% inhibition. These findings provide a new approach to prevent HIV-1 transmission using oligonucleotide aptamers.

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“…Moreover, Gag mutations such as V128I, Y132F, K415R, Q430R, A431V, L449FV, S451GT, R452S, and P453TL are significantly associated with protease drug resistance (502,505). As new PI-associated Gag mutations have been consistently reported (558,570), further studies are required to map all PI-associated Gag mutations and to evaluate their impacts in studies with large patient populations.…”

Section: Novel Mechanisms Of Hiv Drug Resistancementioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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Mutations in Multiple Domains of Gag Drive the Emergence of In Vitro Resistance to the Phosphonate-Containing HIV-1 Protease Inhibitor GS-8374

Cited by 9 publications

References 37 publications

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

Blocking interaction of viral gp120 and CD4-expressing T cells by single-stranded DNA aptamers

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

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