Functional conservation of HIV-1 Gag: implications for rational drug design

Li, Guangdi; Verheyen, Jens; Rhee, Soo-Yon; Voet, Arnout; Vandamme, Anne‐Mieke; Theys, Kristof

doi:10.1186/1742-4690-10-126

Cited by 57 publications

(74 citation statements)

References 33 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although it is easier to detect immune responses to conserved proteins such as p24 in cohorts of HIV-infected persons, the discrepancies between the abundance of p15 MHC-bound peptides and the lesser density of p15-specific immune responses in HIV infection cannot be solely explained by the degree of conservation of these HIV Gag subproteins. Gag p15 is, on average, as conserved as Gag p17 but less conserved than p24 and contains both highly and poorly conserved subproteins (47). Yet Gag p15-derived MHC-bound peptides are far more abundant than p17-derived peptides.…”

Section: Discussionmentioning

confidence: 98%

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Ručević

Kourjian

Boucau

et al. 2016

J Virol

View full text Add to dashboard Cite

H IV-specific T cells play an important role in the containment of infection as evidenced by the concurrent drop of viral load and the appearance of HIV-specific CD8 T cells in acute infection, T cell-driven immune pressure leading to predictable HLA-restricted HIV mutations, and the association between specific HLAs and epitopes or immune responses to specific proteins and spontaneous control of HIV. However, the lack of clear correlates of immune protection hampers efficient vaccine design (1).Screening and functional studies of T cells from HIV-infected persons or vaccinees use high nonphysiological concentrations of long HIV peptides exogenously pulsed onto cells or soluble major histocompatibility complex (MHC)-peptide multimers presenting peptides of optimal size (2, 3). These approaches bypass all steps required for intracellular antigen processing and presentation of HIV peptides by MHC class I (MHC-I) molecules (4). Determination of the amounts and sequences of peptides presented by an infected cell remains largely elusive despite the role of the peptides in immune recognition.Direct mass spectrometry (MS)-based sequencing has become a preferred and yet difficult approach for the unbiased identification and characterization of peptides naturally presented by MHC-I molecules displayed by healthy and cancerous cells or in the context of pathogen infection. However, considering the relatively low number of MHC-peptide complexes per cell and the

show abstract

Section: Discussionmentioning

confidence: 98%

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Ručević

Kourjian

Boucau

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…7A). Among HIV-1 proteins, CA is relatively highly conserved and Arg132 is nearly invariant, being substituted for only by Lys, thus preserving the positive charge (43). Thus, while a single codon change (Arg to Thr) at this position is sufficient to confer resistance to C1, the high degree of conservation across circulating strains suggests that the Arg-to-Thr change is deleterious to HIV-1 fitness in vivo.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HIV-1 Maturation via Small-Molecule Targeting of the Amino-Terminal Domain in the Viral Capsid Protein

Wang

Zhou

Halambage

et al. 2017

J Virol

View full text Add to dashboard Cite

The human immunodeficiency virus type 1 (HIV-1) capsid protein is an attractive therapeutic target, owing to its multifunctionality in virus replication and the high fitness cost of amino acid substitutions in capsids to HIV-1 infectivity. To date, small-molecule inhibitors have been identified that inhibit HIV-1 capsid assembly and/or impair its function in target cells. Here, we describe the mechanism of action of the previously reported capsid-targeting HIV-1 inhibitor, BoehringerIngelheim compound 1 (C1). We show that C1 acts during HIV-1 maturation to prevent assembly of a mature viral capsid. However, unlike the maturation inhibitor bevirimat, C1 did not significantly affect the kinetics or fidelity of Gag processing. HIV-1 particles produced in the presence of C1 contained unstable capsids that lacked associated electron density and exhibited impairments in early postentry stages of infection, most notably reverse transcription. C1 inhibited assembly of recombinant HIV-1 CA in vitro and induced aberrant cross-links in mutant HIV-1 particles capable of spontaneous intersubunit disulfide bonds at the interhexamer interface in the capsid lattice. Resistance to C1 was conferred by a single amino acid substitution within the compound-binding site in the N-terminal domain of the CA protein. Our results demonstrate that the binding site for C1 represents a new pharmacological vulnerability in the capsid assembly stage of the HIV-1 life cycle. IMPORTANCEThe HIV-1 capsid protein is an attractive but unexploited target for clinical drug development. Prior studies have identified HIV-1 capsid-targeting compounds that display different mechanisms of action, which in part reflects the requirement for capsid function at both the efferent and afferent phases of viral replication. Here, we show that one such compound, compound 1, interferes with assembly of the conical viral capsid during virion maturation and results in perturbations at a specific protein-protein interface in the capsid lattice. We also identify and characterize a mutation in the capsid protein that confers resistance to the inhibitor. This study reveals a novel mechanism by which a capsid-targeting small molecule can inhibit HIV-1 replication.

show abstract

“…Although the fulllength structure of Gag in complex with viral protease has not been resolved, the tertiary structures of protease in complex with peptides near the Gag cleavage sites reveal that protease or Gag substitutions contribute to weak binding (499), low interaction energies (500), and reduced van der Waals contacts (501). Recent findings also suggest that amino acid substitutions in Gag induce significant resistance to protease inhibitors (PIs), causing treatment failure in patients receiving PI-based therapies (502)(503)(504)(505). In the presence of protease drug-resistant mutations, cleavage site mutations in Gag and GagPol compensate for impaired proteasemediated cleavages (497,505).…”

Section: Protease-gag/gagpol Interactionmentioning

confidence: 99%

“…Among 16 viral proteins, only HIV-1 Vpu and structural proteins are unlikely to interact with other viral proteins due to their functional roles (see Text S1 in the supplemental material). HIV-1 Vpu is known to interact with host proteins for CD4 downregulation and tetherin antagonism (585), while structural proteins (e.g., capsid) are expected to maintain stable HIV structures with lesser associations (503). In comparison, HIV-1 regulatory and accessory proteins (Tat, Rev, Vpr, Vif, and Nef) have more opportunities to engage in a dialogue with other viral and host proteins in many cell compartments, because they undertake multiple activities during the HIV life cycle (Fig.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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

Clercq

2016

Microbiol Mol Biol Rev

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Functional conservation of HIV-1 Gag: implications for rational drug design

Cited by 57 publications

References 33 publications

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Inhibition of HIV-1 Maturation via Small-Molecule Targeting of the Amino-Terminal Domain in the Viral Capsid Protein

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

Contact Info

Product

Resources

About