scholarly journals The HIV-1 gp120 Major Variable Regions Modulate Cold Inactivation

2013 ◽  
Vol 87 (7) ◽  
pp. 4103-4111 ◽  
Author(s):  
H. Medjahed ◽  
B. Pacheco ◽  
A. Desormeaux ◽  
J. Sodroski ◽  
A. Finzi
Keyword(s):  
Variable Regions ◽  
Major Variable ◽  
Cold Inactivation ◽  
Hiv 1

scholarly journals Rapid Escape from Preserved Cross-Reactive Neutralizing Humoral Immunity without Loss of Viral Fitness in HIV-1-Infected Progressors and Long-Term Nonprogressors

2010 ◽  
Vol 84 (7) ◽  
pp. 3576-3585 ◽  
Author(s):  
Marit J. van Gils ◽  
Evelien M. Bunnik ◽  
Judith A. Burger ◽  
Yodit Jacob ◽  
Becky Schweighardt ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Clinical Course ◽  
Viral Envelope ◽  
Viral Fitness ◽  
Viral Escape ◽  
Autologous Serum ◽  
Variable Regions ◽  
Neutralizing Activity ◽  
Hiv 1

ABSTRACT A substantial proportion of human immunodeficiency virus type 1 (HIV-1)-infected individuals has cross-reactive neutralizing activity in serum, with a similar prevalence in progressors and long-term nonprogressors (LTNP). We studied whether disease progression in the face of cross-reactive neutralizing serum activity is due to fading neutralizing humoral immunity over time or to viral escape. In three LTNP and three progressors, high-titer cross-reactive HIV-1-specific neutralizing activity in serum against a multiclade pseudovirus panel was preserved during the entire clinical course of infection, even after AIDS diagnosis in progressors. However, while early HIV-1 variants from all six individuals could be neutralized by autologous serum, the autologous neutralizing activity declined during chronic infection. This could be attributed to viral escape and the apparent inability of the host to elicit neutralizing antibodies to the newly emerging viral escape variants. Escape from autologous neutralizing activity was not associated with a reduction in the viral replication rate in vitro. Escape from autologous serum with cross-reactive neutralizing activity coincided with an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites in the viral envelope. Positive selection pressure was observed in the variable regions in envelope, suggesting that, at least in these individuals, these regions are targeted by humoral immunity with cross-reactive potential. Our results may imply that the ability of HIV-1 to rapidly escape cross-reactive autologous neutralizing antibody responses without the loss of viral fitness is the underlying explanation for the absent effect of potent cross-reactive neutralizing humoral immunity on the clinical course of infection.

scholarly journals P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Alexandra Y. Soare ◽  
Hagerah S. Malik ◽  
Natasha D. Durham ◽  
Tracey L. Freeman ◽  
Raymond Alvarez ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Chronic Inflammation ◽  
Neutralizing Antibody ◽  
Extracellular Nucleotides ◽  
Productive Infection ◽  
Variable Regions ◽  
Viral Membrane ◽  
P2x1 Receptor ◽  
Viral Membrane Fusion ◽  
Hiv 1

ABSTRACT Purinergic receptors are well-established modulators of inflammatory processes, primarily through detection of extracellular nucleotides that are released by dying or infected cells. Emerging literature has demonstrated that inhibition of these inflammatory receptors can block HIV-1 productive infection and HIV-1-associated inflammation. The specificity of receptor type and mechanism of interaction has not yet been determined. Here, we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449, in cell lines, primary cells, and a variety of HIV-1 envelope (Env) clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion, with a range of inhibitory activities against different HIV-1 Env isolates. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 Env glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules may be modulated by Env conformation. In contrast, a P2X7 antagonist, A438079, had a limited effect on productive infection and fusion. NF279 and NF449 interfered with the ability of the gp120 variable regions 1 and 2 (V1V2)-targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and the development of small molecules to block HIV-1 entry via this mechanism. IMPORTANCE While effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of noncommunicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation, but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.

scholarly journals Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models

2020 ◽  
Vol 117 (14) ◽  
pp. 7929-7940
Author(s):  
Ming Tian ◽  
Kelly McGovern ◽  
Hwei-Ling Cheng ◽  
Peyton Waddicor ◽  
Lisa Rieble ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mouse Models ◽  
Negative Selection ◽  
Cell Development ◽  
B Cell Development ◽  
Affinity Maturation ◽  
Variable Regions ◽  
Conditional Expression ◽  
Hiv 1

HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1–infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models is that bnAb expression often hinders B cell development. Such developmental blocks may be attributed to the unusual properties of bnAb variable regions, such as poly-reactivity and long antigen-binding loops, which are usually under negative selection during primary B cell development. To address this problem, we devised a method to circumvent such B cell developmental blocks by expressing bnAbs conditionally in mature B cells. We validated this method by expressing the unmutated common ancestor (UCA) of the human VRC26 bnAb in transgenic mice. Constitutive expression of the VRC26UCA led to developmental arrest of B cell progenitors in bone marrow; poly-reactivity of the VRC26UCA and poor pairing of the VRC26UCA heavy chain with the mouse surrogate light chain may contribute to this phenotype. The conditional expression strategy bypassed the impediment to VRC26UCA B cell development, enabling the expression of VRC26UCA in mature B cells. This approach should be generally applicable for expressing other bnAbs that are under negative selection during B cell development.

Short Communication: Severe Immune Suppression in Patients Infected with R5-Tropic HIV-1 Strains Is Associated with Increased gp120 Net Charge at Variable Regions

2011 ◽  
Vol 27 (9) ◽  
pp. 965-967 ◽  
Author(s):  
Eduardo Seclén ◽  
Vincent Soriano ◽  
María del Mar González ◽  
Juan González-Lahoz ◽  
Eva Poveda
Keyword(s):  
Immune Suppression ◽  
Short Communication ◽  
Net Charge ◽  
Variable Regions ◽  
Hiv 1

scholarly journals Compartmentalization and Clonal Amplification of HIV-1 Variants in the Cerebrospinal Fluid during Primary Infection

2009 ◽  
Vol 84 (5) ◽  
pp. 2395-2407 ◽  
Author(s):  
Gretja Schnell ◽  
Richard W. Price ◽  
Ronald Swanstrom ◽  
Serena Spudich
Keyword(s):  
Cerebrospinal Fluid ◽  
Neurological Disease ◽  
Primary Infection ◽  
Genetic Adaptation ◽  
Variable Regions ◽  
Single Genome ◽  
Immunodeficiency Virus ◽  
The Central Nervous System ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is a severe neurological disease that affects a subset of HIV-1-infected individuals. Increased compartmentalization has been reported between blood and cerebrospinal fluid (CSF) HIV-1 populations in subjects with HAD, but it is still not known when compartmentalization arises during the course of infection. To assess HIV-1 genetic compartmentalization early during infection, we compared HIV-1 populations in the peripheral blood and CSF in 11 primary infection subjects, with analysis of longitudinal samples over the first 18 months for a subset of subjects. We used heteroduplex tracking assays targeting the variable regions of env and single-genome amplification and sequence analysis of the full-length env gene to identify CSF-compartmentalized variants and to examine viral genotypes within the compartmentalized populations. For most subjects, HIV-1 populations were equilibrated between the blood and CSF compartments. However, compartmentalized HIV-1 populations were detected in the CSF of three primary infection subjects, and longitudinal analysis of one subject revealed that compartmentalization during primary HIV-1 infection was resolved. Clonal amplification of specific HIV-1 variants was identified in the CSF population of one primary infection subject. Our data show that compartmentalization can occur in the central nervous system (CNS) of subjects in primary HIV-1 infection in part through persistence of the putative transmitted parental variant or via viral genetic adaptation to the CNS environment. The presence of distinct HIV-1 populations in the CSF indicates that independent HIV-1 replication can occur in the CNS, even early after HIV-1 transmission.

scholarly journals Turnover of env Variable Region 1 and 2 Genotypes in Subjects with Late-Stage Human Immunodeficiency Virus Type 1 Infection

2003 ◽  
Vol 77 (12) ◽  
pp. 6811-6822 ◽  
Author(s):  
Kathryn M. Kitrinos ◽  
Noah G. Hoffman ◽  
Julie A. E. Nelson ◽  
Ronald Swanstrom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Late Stage ◽  
Virus Population ◽  
Variable Regions ◽  
Discrete Transition ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The env gene of human immunodeficiency virus type 1 (HIV-1) includes some of the most genetically diverse regions of the viral genome, which are called variable regions 1 through 5 (V1 through V5). We have developed a heteroduplex tracking assay to detect changes in variable regions 1 and 2 of env (V1/V2-HTA). Using sequences from two molecular clones as probes, we have studied the nature of longitudinal virus population changes in a cohort of HIV-1-infected subjects. Viral sequences present in 21 subjects with late-stage HIV-1 infection were initially screened for stability of the virus population by V1/V2-HTA. The virus populations at entry comprised an average of five coexisting V1/V2 genotypic variants (as identified by HTA). Eight of the 21 subjects were examined in detail because of the dynamic behavior of their env variants over an approximately 9-month period. In each of these cases we detected a single discrete transition of V1/V2 genotypes based on monthly sampling. The major V1/V2 genotypes (those present at >10% abundance) from the eight subjects were cloned and sequenced to define the nature of V1/V2 variability associated with a discrete transition. Based on a comparison of V1/V2 genotypic variants present at entry with the newly emerged variants we categorized the newly emerged variants into two groups: variants without length differences and variants with length differences. Variants without length differences had fewer nucleotide substitutions, with the changes biased to either V1 or V2, suggestive of recent evolutionary events. Variants with length differences included ones with larger numbers of changes that were distributed, suggestive of recall of older genotypes. Most length differences were located in domains where the codon motif AVT (V = A, G, C) had become enriched and fixed. Finally, recombination events were detected in two subjects, one of which resulted in the reassortment of V1 and V2 regions. We suggest that turnover in V1/V2 populations was largely driven by selection on either V1 or V2 and that escape was accomplished either through changes focused in the region under selection or by the appearance of a highly divergent variant.

scholarly journals Vaccine Induction of Antibodies against a Structurally Heterogeneous Site of Immune Pressure within HIV-1 Envelope Protein Variable Regions 1 and 2

Immunity ◽  
2013 ◽  
Vol 38 (1) ◽  
pp. 176-186 ◽  
Author(s):  
Hua-Xin Liao ◽  
Mattia Bonsignori ◽  
S. Munir Alam ◽  
Jason S. McLellan ◽  
Georgia D. Tomaras ◽  
...  
Keyword(s):  
Envelope Protein ◽  
Variable Regions ◽  
Immune Pressure ◽  
Hiv 1

scholarly journals Phylogenetic measures of indel rate variation among the HIV-1 group M subtypes

2018 ◽  
Author(s):  
John Palmer ◽  
Art Poon
Keyword(s):  
Sequence Data ◽  
Poisson Model ◽  
Nucleotide Composition ◽  
Rate Variation ◽  
Flanking Sequence ◽  
Nucleotide Substitutions ◽  
Virus Surface ◽  
Variable Regions ◽  
Subtype B ◽  
Hiv 1

The transmission and pathogenesis of human immunodeficiency virus type 1 (HIV-1) is disproportionately influenced by evolution in the five variable regions of the virus surface envelope glycoprotein (gp120). Insertions and deletions (indels) are a significant source of evolutionary change in these regions. However, the influx of indels relative to nucleotide substitutions has not yet been quantified through a comparative analysis of HIV-1 sequence data. Here we develop and report results from a phylogenetic method to estimate indel rates for the gp120 variable regions across five major subtypes and two circulating recombinant forms (CRFs) of HIV-1 group M. We processed over 26,000 published HIV-1 gp120 sequences, from which we extracted 6,605 sequences for phylogenetic analysis. In brief, our method employs maximum likelihood to reconstruct phylogenies scaled in time and fits a Poisson model to the observed distribution of indels between closely related pairs of sequences in the tree (cherries). The rate estimates ranged from 3.0e-5 to 1.5e-3 indels/nt/year and varied significantly among variable regions and subtypes. Indel rates were significantly lower in the region encoding variable loop V3, and also lower for HIV-1 subtype B relative to other subtypes. We also found that variable loops V1, V2 and V4 tended to accumulate significantly longer indels. Further, we observed that the nucleotide composition of indel sequences was significantly distinct from that of the flanking sequence in HIV-1 gp120. Indels affected potential N-linked glycosylation sites substantially more often in V1 and V2 than expected by chance, which is consistent with positive selection on glycosylation patterns within these regions of gp120. These results represent the first comprehensive measures of indel rates in HIV-1 gp120 across multiple subtypes and CRFs, and identifies novel and unexpected patterns for further research in the molecular evolution of HIV-1.

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