scholarly journals Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity

2015 ◽  
Vol 90 (2) ◽  
pp. 636-649 ◽  
Author(s):  
Susan Zolla-Pazner ◽  
Sandra Sharpe Cohen ◽  
David Boyd ◽  
Xiang-Peng Kong ◽  
Michael Seaman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hiv Infection ◽  
Chemokine Receptors ◽  
Variable Region ◽  
Single Amino Acid ◽  
V3 Loop ◽  
Infection Rates ◽  
Neutralization Sensitivity ◽  
The Stability ◽  
Hiv 1

ABSTRACTAntibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop.IMPORTANCEThe levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.

scholarly journals Species-specific valid ternary interactions of HIV-1 Env-gp120, CD4, and CCR5 as revealed by an adaptive single-amino acid substitution at the V3 loop tip

2021 ◽  
Author(s):  
Takaaki Koma ◽  
Masaru Yokoyama ◽  
Osamu Kotani ◽  
Naoya Doi ◽  
Nina Nakanishi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Molecular Interactions ◽  
Md Simulations ◽  
Single Amino Acid ◽  
V3 Loop ◽  
Cell Tropism ◽  
Binding Ability ◽  
Ternary Interactions ◽  
Species Specific ◽  
Hiv 1

Molecular interactions of the variable envelope gp120 subunit of HIV-1 with two cellular receptors are the first step of viral infection, thereby playing pivotal roles in determining viral infectivity and cell tropism. However, the underlying regulatory mechanisms for interactions under gp120 spontaneous variations largely remain unknown. Here we show an allosteric mechanism in which a single gp120 mutation remotely controls the ternary interactions between gp120 and its receptors for the switch of viral cell tropism. Virological analyses showed that a G310R substitution at the tip of the gp120 V3 loop selectively abolished the viral replication ability in human cells, despite evoking enhancement of viral replication in macaque cells. Molecular dynamics (MD) simulations predicted that the G310R substitution at a site away from the CD4 interaction site selectively impeded the binding ability of gp120 to human CD4. Consistently, virions with the G310R substitution exhibited a reduced binding ability to human lymphocyte cells. Furthermore, the G310R substitution influenced the gp120-CCR5 interaction in a CCR5-type dependent manner as assessed by MD simulations and an infectivity assay using exogenously expressed CCR5s. Interestingly, an I198M mutation in human CCR5 restored the infectivity of the G310R virus in human cells. Finally, MD simulation predicted amino acid interplays that physically connect the V3 loop and gp120 elements for the CD4 and CCR5 interactions. Collectively, these results suggest that the V3 loop tip is a cis-allosteric regulator that remotely controls intra- and inter-molecular interactions of HIV-1 gp120 for balancing ternary interactions with CD4 and CCR5. IMPORTANCE Understanding molecular bases for viral entry into cells leads to the elucidation of one of major viral survival strategies, and thus to the development of new effective antiviral measures. As experimentally shown recently, HIV-1 is highly mutable and adaptable in growth-restrictive cells such as those of macaque origin. HIV-1 initiates its infection by sequential interactions of Env-gp120 with two cell surface receptors, CD4 and CCR5. A recent epoch-making structural study has disclosed that CD4-induced conformation of gp120 is stabilized upon binding of CCR5 to the CD4-gp120 complex, whereas its biological significance remains totally unknown. Here, from a series of mutations found in our extensive studies, we identified a single-amino acid adaptive mutation at the V3 loop tip of Env-gp120 critical for its interaction with both CD4 and CCR5 in a host cell species-specific way. This remarkable finding would certainly provoke and accelerate studies to precisely clarify the HIV-1 entry mechanism.

scholarly journals A single amino acid substitution in the C4 region in gp120 confers enhanced neutralization of HIV-1 by modulating CD4 binding sites and V3 loop

Virology ◽  
2011 ◽  
Vol 418 (2) ◽  
pp. 123-132 ◽  
Author(s):  
Rajesh Ringe ◽  
Deepak Sharma ◽  
Susan Zolla-Pazner ◽  
Sanjay Phogat ◽  
Arun Risbud ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Binding Sites ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
V3 Loop ◽  
Hiv 1

Alteration of HIV-1 Infectivity and Neutralization by a Single Amino Acid Replacement in the V3 Loop Domain

1991 ◽  
Vol 7 (7) ◽  
pp. 595-603 ◽  
Author(s):  
LUCINDA A. IVANOFF ◽  
DAVID J. LOONEY ◽  
CHARLENE McDANAL ◽  
JANE F. MORRIS ◽  
FLOSSIE WONG-STAAL ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Replacement ◽  
Single Amino Acid ◽  
V3 Loop ◽  
Loop Domain ◽  
Hiv 1

scholarly journals Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120.

1997 ◽  
Vol 41 (12) ◽  
pp. 2616-2620 ◽  
Author(s):  
K De Vreese ◽  
I Van Nerum ◽  
K Vermeire ◽  
J Anné ◽  
E De Clercq
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Single Amino Acid ◽  
Resistance Pattern ◽  
V3 Loop ◽  
Resistant Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Resistant Strains ◽  
Anti Hiv

The bicyclams are a new class of anti-human immunodeficiency virus (anti-HIV) compounds targeted at viral entry. From marker rescue experiments, it appears that the envelope gp120 glycoprotein plays an important role in the anti-HIV activity of the bicyclams. Bicyclam-resistant strains contain a number of amino acid changes scattered over the V2 to V5 region of gp120. Experiments aimed at estimating the relative importance of particular amino acid changes with regard to the overall resistance pattern are described. The sequences of some partially bicyclam-resistant virus strains, obtained during the resistance development process, were analyzed, and the corresponding 50% effective concentrations were determined. Selected mutations observed in bicyclam-resistant strains were introduced in the wild-type background by site-directed mutagenesis. In addition, some amino acids were back-mutated to their wild-type counterparts in an otherwise JM3100-resistant strain. The sensitivities of these mutant viruses to bicyclams were determined. Construction of chimeric viruses, carrying the V3 loop of JM3100-resistant virus in a wild-type HIV type 1 HXB2 background, enabled us to investigate the importance of the mutations in the V3 loop of JM3100-resistant virus. From the results described in the report, it can be concluded that single amino acid substitutions do not influence the observed resistance to JM3100. Also, the mutations in the V3 loop are not sufficient to engender even a partially resistant phenotype. We postulate that the overall conformation of gp120 determines the degree of sensitivity or resistance of HIV strains to bicyclams.

scholarly journals A Single Amino Acid in Human APOBEC3F Alters Susceptibility to HIV-1 Vif

2010 ◽  
Vol 285 (52) ◽  
pp. 40785-40792 ◽  
Author(s):  
John S. Albin ◽  
Rebecca S. LaRue ◽  
Jessalyn A. Weaver ◽  
William L. Brown ◽  
Keisuke Shindo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Single Amino Acid ◽  
Hiv 1

scholarly journals A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer

2010 ◽  
Vol 84 (7) ◽  
pp. 3147-3161 ◽  
Author(s):  
Shi-Hua Xiang ◽  
Andrés Finzi ◽  
Beatriz Pacheco ◽  
Kevin Alexander ◽  
Wen Yuan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Receptor Binding ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Envelope Glycoproteins ◽  
V3 Loop ◽  
Virus Envelope ◽  
Hydrophobic Patch ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 β2, β19, β20, and β21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

scholarly journals Mechanism of Darunavir (DRV)’s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Manabu Aoki ◽  
Debananda Das ◽  
Hironori Hayashi ◽  
Hiromi Aoki-Ogata ◽  
Yuki Takamatsu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Critical Role ◽  
Viral Fitness ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Genetic Barrier ◽  
High Level ◽  
Hiv 1

ABSTRACTDarunavir (DRV) has bimodal activity against HIV-1 protease, enzymatic inhibition and protease dimerization inhibition, and has an extremely high genetic barrier against development of drug resistance. We previously generated a highly DRV-resistant HIV-1 variant (HIVDRVRP51). We also reported that four amino acid substitutions (V32I, L33F, I54M, and I84V) identified in the protease of HIVDRVRP51are largely responsible for its high-level resistance to DRV. Here, we attempted to elucidate the role of each of the four amino acid substitutions in the development of DRV resistance. We found that V32I is a key substitution, which rarely occurs, but once it occurs, it predisposes HIV-1 to develop high-level DRV resistance. When two infectious recombinant HIV-1 clones carrying I54M and I84V (rHIVI54Mand rHIVI84V, respectively) were selected in the presence of DRV, V32I emerged, and the virus rapidly developed high-level DRV resistance. rHIVV32Ialso developed high-level DRV resistance. However, wild-type HIVNL4-3(rHIVWT) failed to acquire V32I and did not develop DRV resistance. Compared to rHIVWT, rHIVV32Iwas highly susceptible to DRV and had significantly reduced fitness, explaining why V32I did not emerge upon selection of rHIVWTwith DRV. When the only substitution is at residue 32, structural analysis revealed much stronger van der Waals interactions between DRV and I-32 than between DRV and V-32. These results suggest that V32I is a critical amino acid substitution in multiple pathways toward HIV-1’s DRV resistance development and elucidate, at least in part, a mechanism of DRV’s high genetic barrier to development of drug resistance. The results also show that attention should be paid to the initiation or continuation of DRV-containing regimens in people with HIV-1 containing the V32I substitution.IMPORTANCEDarunavir (DRV) is the only protease inhibitor (PI) recommended as a first-line therapeutic and represents the most widely used PI for treating HIV-1-infected individuals. DRV possesses a high genetic barrier to development of HIV-1’s drug resistance. However, the mechanism(s) of the DRV’s high genetic barrier remains unclear. Here, we show that the preexistence of certain single amino acid substitutions such as V32I, I54M, A71V, and I84V in HIV-1 protease facilitates the development of high-level DRV resistance. Interestingly, allin vitro-selected highly DRV-resistant HIV-1 variants acquired V32I but never emerged in wild-type HIV (HIVWT), and V32I itself rendered HIV-1 more sensitive to DRV and reduced viral fitness compared to HIVWT, strongly suggesting that the emergence of V32I plays a critical role in the development of HIV-1’s resistance to DRV. Our results would be of benefit in the treatment of HIV-1-infected patients receiving DRV-containing regimens.

scholarly journals Coreceptor Tropism Can Be Influenced by Amino Acid Substitutions in the gp41 Transmembrane Subunit of Human Immunodeficiency Virus Type 1 Envelope Protein

2008 ◽  
Vol 82 (11) ◽  
pp. 5584-5593 ◽  
Author(s):  
Wei Huang ◽  
Jonathan Toma ◽  
Signe Fransen ◽  
Eric Stawiski ◽  
Jacqueline D. Reeves ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Protein ◽  
Variable Region ◽  
Single Amino Acid ◽  
Coreceptor Tropism ◽  
Immunodeficiency Virus

ABSTRACT Many studies have demonstrated that the third variable region (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) is a major determinant of coreceptor tropism. Other regions in the surface gp120 subunit of Env can modulate coreceptor tropism in a manner that is not fully understood. In this study, we evaluated the effect of env determinants outside of V3 on coreceptor usage through the analysis of (i) patient-derived env clones that differ in coreceptor tropism, (ii) chimeric env sequences, and (iii) site-directed mutants. The introduction of distinct V3 sequences from CXCR4-using clones into an R5-tropic env backbone conferred the inefficient use of CXCR4 in some but not all cases. Conversely, in many cases, X4- and dual-tropic env backbones containing the V3 sequences of R5-tropic clones retained the ability to use CXCR4, suggesting that sequences outside of the V3 regions of these CXCR4-using clones were responsible for CXCR4 use. The determinants of CXCR4 use in a set of dual-tropic env sequences with V3 sequences identical to those of R5-tropic clones mapped to the gp41 transmembrane (TM) subunit. In one case, a single-amino-acid substitution in the fusion peptide of TM was able to confer CXCR4 use; however, TM substitutions associated with CXCR4 use varied among different env sequences. These results demonstrate that sequences in TM can modulate coreceptor specificity and that env sequences other than that of V3 may facilitate efficient CXCR4-mediated entry. We hypothesize that the latter plays an important role in the transition from CCR5 to CXCR4 coreceptor use.

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

2010 ◽  
Vol 2 ◽  
pp. CMT.S5420
Author(s):  
SL. Pett ◽  
S. Emery ◽  
AD. Kelleher ◽  
DA. Cooper
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors ◽  
Hiv Transmission ◽  
Hiv Therapy ◽  
Ccr5 Receptor ◽  
Tick Borne Encephalitis ◽  
Hiv Entry ◽  
Orally Bioavailable ◽  
Hiv Envelope ◽  
Hiv 1

Over a decade has passed since several groups identified the chemokine receptors CXCR4 and CCR5 as key co-receptors for HIV entry. CCR5 is more important in HIV transmission and during the early course of HIV infection. It is also apparent that protection from HIV infection is afforded to those lacking CCR5–-the so called delta-32 homozygotes; in those heterozygous for this mutation, an attenuated course of HIV-infection is observed. Provocatively, those with modified expression of CCR5 are physiologically normal with the exception of poorer outcomes with some of the viral encephalitides specifically West Nile virus and Tick Borne encephalitis. The small molecule, orally-bioavailable CCR5 receptor antagonists, including, maraviroc (MVC), are allosteric inhibitors that lock the CCR5 receptor into a conformation such that the receptor is not able to bind HIV envelope protein; the molecules also variably block intracellular signalling induced by different receptor-binding chemokines. The aims of this review on the CCR5 receptor inhibitors are to summarise information relevant to treatment in individuals with HIV-1 infection. Data from the licensing studies, the side-effect profile and putative long-term risks of CCR5 receptor inhibitor exposure, tropism testing and mechanisms of resistance will be reviewed. The potential for using this class of agent as an immunomodulating agent will be detailed. Given that MVC is the only licensed drug in this class at present and reflecting the greater body of work describing this agent, the majority of information in this review relates to MVC. Last, the authors propose the place of MVC in the hierarchy of HIV therapy and future opportunities for research.

scholarly journals HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Ludy Registre ◽  
Yvetane Moreau ◽  
Sila Toksoz Ataca ◽  
Surya Pulukuri ◽  
Timothy J. Henrich ◽  
...  
Keyword(s):  
Homology Modeling ◽  
Neutralizing Antibody ◽  
V3 Loop ◽  
Plasma Viremia ◽  
Neutralization Sensitivity ◽  
Variable Loop ◽  
Ccr5 Receptor ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1 ◽  
Homology Models

ABSTRACT In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia and delay virus reemergence. The presence of less neutralization-susceptible strains prior to treatment decreases the efficacy of these antibody-based treatments, but neutralization sensitivity often cannot be predicted by sequence analysis alone. We found that phenotypically confirmed CXCR4-utilizing strains are less neutralization sensitive, especially to variable loop 3 (V3 loop)-directed bnAbs, than exclusively CCR5-utilizing strains in some, but not all, cases. Homology modeling suggested that the primary V3 loop bnAb epitope is equally accessible among CCR5- and CXCR4-using strains, although variants that exclusively use CXCR4 have V3 loop protrusions that interfere with CCR5 receptor interactions. Homology modeling also showed that among some, but not all, envelopes with decreased neutralization sensitivity, V1 loop orientation interfered with V3 loop-directed bnAb binding. Thus, there are likely different structural reasons for the coreceptor usage restriction and the different bnAb susceptibilities. Importantly, we show that individuals harboring envelopes with higher likelihood of using CXCR4 or greater predicted V1 loop interference have faster virus rebound and a lower maximum decrease in plasma viremia, respectively, after treatment with a V3 loop bnAb. Knowledge of receptor usage and homology models may be useful in developing future algorithms that predict treatment efficacy with V3 loop bnAbs. IMPORTANCE The efficacy of HIV-1 broadly neutralizing antibody (bnAb) therapies may be compromised by the preexistence of less susceptible variants. Sequence-based methods are needed to predict pretreatment variants’ neutralization sensitivities. HIV-1 strains that exclusively use the CXCR4 receptor rather than the CCR5 receptor are less neutralization susceptible, especially to variable loop 3 (V3 loop) bnAbs in some, but not all, instances. While the inability to utilize the CCR5 receptor maps to a predicted protrusion in the envelope V3 loop, this viral determinant does not directly influence V3 loop bnAb sensitivity. Homology modeling predicts that contact between the envelope V1 loop and the antibody impacts V3 loop bnAb susceptibility in some cases. Among pretreatment envelopes, increased probability of using CXCR4 and greater predicted V1 interference are associated with faster virus rebound and a smaller decrease in the plasma virus level, respectively, after V3 loop bnAb treatment. Receptor usage information and homology models may be useful for predicting V3 loop bnAb therapy efficacy.

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