scholarly journals Analysis of the Critical Domain in the V3 Loop of Human Immunodeficiency Virus Type 1 gp120 Involved in CCR5 Utilization

1999 ◽  
Vol 73 (10) ◽  
pp. 8216-8226 ◽  
Author(s):  
Chia-Suei Hung ◽  
Nancy Vander Heyden ◽  
Lee Ratner
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequence Motif ◽  
V3 Loop ◽  
Immunodeficiency Virus ◽  
Chemokine Receptor Ccr5 ◽  
T Cell Lines ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection of CD4+ lymphocytes and macrophages involves interaction of the surface subunit of the envelope protein (gp120) with coreceptors. Isolates have been found with specific tropism for macrophages and/or T-cell lines, through the utilization of chemokine receptor CCR5 (R5) or CXCR4 (X4). The third hypervariable loop (V3 loop) of gp120 is the major determinant of tropism. Using chimeric envelopes between HXB2 (X4) and ADA (R5), we found that the C-terminal half of the V3 loop was sufficient to confer on HXB2 the ability to infect CCR5-expressing cells. A sequence motif was identified at positions 289 to 292 allowing 30% of wild-type levels of infection, whereas full activity was achieved with the conversion of Lys to Glu at position 287 in addition to the above motif. Moreover, V3 loops from either SF2 (X4R5) or SF162 (R5) also allowed infection of CCR5-expressing cells, supporting the importance of V3 loops in influencing CCR5 utilization. The effects of amino acid changes at position 287 on the level of infection via CCR5 showed that negatively charged residues (Glu and Asp) were optimal for efficient interaction whereas only bulky hydrophobic residues drastically reduced infection. In addition, sequences at the N terminus of the V3 loop independently modulated the level of infection via CCR5. This study also examined the susceptibility of chimeric envelopes to neutralization by anticoreceptor antibodies and suggested the presence of differential interaction between the chimeric envelopes and CCR5. These findings highlight the critical residues in the V3 loop that mediate HIV-1 infection.

scholarly journals Selection for Human Immunodeficiency Virus Type 1 Recombinants in a Patient with Rapid Progression to AIDS

2002 ◽  
Vol 76 (21) ◽  
pp. 10674-10684 ◽  
Author(s):  
Shan-Lu Liu ◽  
John E. Mittler ◽  
David C. Nickle ◽  
Thera M. Mulvania ◽  
Daniel Shriner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequence Motif ◽  
V3 Loop ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Although human immunodeficiency virus type 1 (HIV-1) recombinants have been found with high frequency, little is known about the forces that select for these viruses or their importance to pathogenesis. Here we document the emergence and dynamics of 11 distinct HIV-1 recombinants in a man who was infected with two subtype B HIV-1 strains and progressed rapidly to AIDS without developing substantial cellular or humoral immune responses. Although numerous frequency oscillations were observed, a single recombinant lineage eventually came to dominate the population. Numerical simulations indicate that the successive recombinant forms displaced each other too rapidly to be explained by any simple model of random genetic drift or sampling variation. All of the recombinants, including several resulting from independent recombination events, possessed the same sequence motif in the V3 loop, suggesting intense selection on this segment of the viral envelope protein. The outgrowth of the predominant V3 loop recombinants was not, however, associated with changes in coreceptor utilization. The final variant was instead notable for having lost 3 of 14 potential glycosylation sites. We also observed high ratios of synonymous-to-nonsynonymous nucleotide changes—suggestive of purifying selection—in all viral populations, with particularly high ratios in newly arising recombinants. Our study, therefore, illustrates the unusual and important patterns of viral adaptation that can occur in a patient with weak immune responses. Although it is hard to tease apart cause and effect in a single patient, the correlation with disease progression in this patient suggests that recombination between divergent viruses, with its ability to create chimeras with increased fitness, can accelerate progression to AIDS.

scholarly journals UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein.

1989 ◽  
Vol 9 (11) ◽  
pp. 5169-5181 ◽  
Author(s):  
B Stein ◽  
H J Rahmsdorf ◽  
A Steffen ◽  
M Litfin ◽  
P Herrlich
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dna Damage ◽  
Uv Radiation ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequence Motif ◽  
Nf Kappa B ◽  
Immunodeficiency Virus ◽  
Hiv 1

UV irradiation of human and murine cells enhances the transcription of several genes. Here we report on the primary target of relevant UV absorption, on pathways leading to gene activation, and on the elements receiving the UV-induced signal in the human immunodeficiency virus type 1 (HIV-1) long terminal repeat, in the gene coding for collagenase, and in the cellular oncogene fos. In order to induce the expression of genes. UV radiation needs to be absorbed by DNA and to cause DNA damage of the kind that cannot be repaired by cells from patients with xeroderma pigmentosum group A. UV-induced activation of the three genes is mediated by the major enhancer elements (located between nucleotide positions -105 and -79 of HIV-1, between positions -72 and -65 of the collagenase gene, and between positions -320 and -299 of fos). These elements share no apparent sequence motif and bind different trans-acting proteins; a member of the NF kappa B family binds to the HIV-1 enhancer, the heterodimer of Jun and Fos (AP-1) binds to the collagenase enhancer, and the serum response factors p67 and p62 bind to fos. DNA-binding activities of the factors recognizing the HIV-1 and collagenase enhancers are augmented in extracts from UV-treated cells. The increase in activity is due to posttranslational modification. While AP-1 resides in the nucleus and must be modulated there, NF kappa B is activated in the cytoplasm, indicating the existence of a cytoplasmic signal transduction pathway triggered by UV-induced DNA damage. In addition to activation, new synthesis of AP-1 is induced by UV radiation.

scholarly journals Enhancement of human immunodeficiency virus type 1 infection by antisera to peptides from the envelope glycoproteins gp120/gp41.

1991 ◽  
Vol 174 (6) ◽  
pp. 1557-1563 ◽  
Author(s):  
S B Jiang ◽  
K Lin ◽  
A R Neurath
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Envelope Glycoproteins ◽  
V3 Loop ◽  
Immunodeficiency Virus ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (gp120 and gp41) elicit virus-neutralizing antibodies (VNAB) and also antibodies enhancing HIV-1 infection (EAB). Several epitopes eliciting VNAB have been defined, the principal virus-neutralizing determinant being assigned to the V3 loop of gp120. To provide a background for a rational design of anti-HIV vaccines, it also appears important to define domains eliciting EAB. This was accomplished by screening antisera against synthetic peptides covering almost the entire sequence of gp120/gp41 for their enhancing effects on HIV-1 infection of MT-2 cells, a continuous T cell line. Many (16/30) of the antisera significantly enhanced HIV-1 in the presence of human complement. Antibodies to complement receptor type 2 (CR2) abrogated the antibody-mediated enhancement of HIV-1 infection. Antisera to V3 hypervariable loops of 21 distinct HIV-1 isolates were also tested for their enhancing effects on HIV-1IIIB infection. 11 of these sera contained VNAB and 10 enhanced HIV-1IIIB infection. All antisera with virus-enhancing activity contained antibodies crossreactive with the V3 loop of HIV-1IIIB, and the virus-enhancing activity increased with increasing serological crossreactivity. These results suggest that immunization with antigens encompassing V3 loops may elicit EAB rather than protective antibodies if epitopes on the immunogen and the predominant HIV-1 isolate infecting a population are insufficiently matched, i.e., crossreactive serologically but not at the level of virus neutralization.

scholarly journals Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer.

1995 ◽  
Vol 182 (1) ◽  
pp. 185-196 ◽  
Author(s):  
Q J Sattentau ◽  
J P Moore
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Line ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Neutralization ◽  
V3 Loop ◽  
Immunodeficiency Virus ◽  
Monomeric Gp120 ◽  
Hiv 1

The major target of the neutralizing antibody response to infection by the human immunodeficiency virus type 1 (HIV-1) is the outer envelope glycoprotein, gp120. The spectrum of HIV-1 neutralization specificity is currently represented by monoclonal antibodies (mAbs) that can be divided broadly into five groups. We have studied the binding of these mAbs to functional oligomeric and soluble monomeric gp120 derived from the molecular clone of a cell line-adapted isolate of HIV-1, and compared these binding properties with virus neutralization. Binding of all mAbs except those reactive with the V3 loop was much weaker to oligomeric than to monomeric gp120. This reduction in binding to oligomeric gp120 was determined mostly by a slower relative rate of association, although the dissociation rate also had some influence on relative variation in mAb affinity. Virus neutralization correlated broadly with mAb binding to the oligomeric rather than to the monomeric form of gp120, and neutralization potency was related to the estimated association rate. Thus, with the exception of the hypervariable V3 loop, regions of HIV-1 gp120 with the potential to induce a neutralization response are likely to be poorly presented for antibody recognition on the surface of cell line-adapted virions.

scholarly journals Anti-Human Immunodeficiency Virus Type 1 Activity of R-95288, a Phosphodiester Hexadeoxyribonucleotide Modified by Dibenzyloxybenzyl and Hydroxyethyl Residues at the 5′- and 3′-Ends

1997 ◽  
Vol 8 (5) ◽  
pp. 429-438 ◽  
Author(s):  
T Agatsuma ◽  
H Furukawa ◽  
H Hotoda ◽  
M Koizumi ◽  
R Koga ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Specific Interaction ◽  
V3 Loop ◽  
Virus Envelope ◽  
Immunodeficiency Virus ◽  
Hiv 1

The phosphodiester hexadeoxyribonucleotide R-95288 is a potent anti-human immunodeficiency virus type 1 (HIV-1) agent in vitro which consists or a TGGGAG nucleoside sequence with dibenzyloxybenzyl and hydroxyethyl substituents at the 5′- and 3′-ends, respectively. In this study, the antiviral activity of R-95288 against various strains of HIV-1 in vitro was assessed and its mechanism of action was analysed. R-95288 inhibited replication of all strains of HIV-1 used including laboratory strains with the syncytium-inducing (SI) phenotype and clinical isolates with both SI and non-SI (NSI) phenotypes. The 50% inhibitory concentrations (IC50s) were 0.62–18 μg mL−1 (0.21–6.2 μM). R-95288 inhibited the binding and fusion of HIV-1-infected T cells with CD4+ cells. In addition, R-95288 specifically blocked the binding of monoclonal antibodies, recognizing the anti-V3 loop or the CD4-binding site of the virus envelope glycoprotein gp120. Furthermore, the target site of R-95288 within the V3 loop was found in the putative heparin-binding region by binding inhibition assays using various anti-V3 loop antibodies. These results suggest that R-95288 can inhibit various strains of HIV-1, possibly by specific interaction with gp120.

scholarly journals Patterns of Changes in Human Immunodeficiency Virus Type 1 V3 Sequence Populations Late in Infection

2000 ◽  
Vol 74 (18) ◽  
pp. 8494-8501 ◽  
Author(s):  
Julie A. E. Nelson ◽  
Frédéric Baribaud ◽  
Terri Edwards ◽  
Ronald Swanstrom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequence Motif ◽  
Total Change ◽  
Evolutionary Pathway ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have used a V3-specific heteroduplex tracking assay (V3-HTA) with probes from two different human immunodeficiency virus type 1 (HIV-1) subtypes to examine the extent and pace of HIV-1 evolution late in infection. Twenty-four subjects with advanced HIV-1 infection (CD4+ T-cell count, <100/μl) and stable viral loads were studied using blood plasma samples collected over a study period of approximately 9 months, during which time most of the subjects were treated with reverse transcriptase inhibitors. The V3-HTA patterns from the first and last time points were evaluated initially to determine the amounts of change in V3 sequence populations, which were primarily changes in abundance in preexisting sequence populations. Three of the 24 subjects had major changes (greater than 50% total change in the relative abundance of the sequence populations), 11 subjects had intermediate changes (10 to 50% total change), and 10 subjects had minimal changes (less than 10% total change). The average total amount of change was between two- and threefold greater in subjects with X4-like variants, although there was no correlation between average viral load and the presence of X4-like variants. V3-HTA patterns in monthly samples from 11 of the subjects were also compared. In two subjects, the amount of change exceeded 40% in a 1-month period. Overall, the pace of change in V3 populations varied between subjects and was not constant within a subject over time. Sequence analysis of the V3 variants showed that R5-like variants (not containing any X4-associated substitutions) continued to be maintained in three subjects in the presence of X4-like variants, indicating that X4 variants do not always outgrow R5 variants. The coreceptor usage of the V3 sequences from two subjects was determined using a cell fusion assay. One subject had an X4 variant that was maintained at a low level for at least 9 months, during which time the predominant variants were R5X4 (dualtropic), while in the second subject the reverse situation was observed. One of the dualtropic variants had a novel sequence motif in V3, suggesting another evolutionary pathway to altered tropism. These studies begin to probe the complexities and pace of V3 evolution in vivo, revealing dynamic patterns of change among multiple V3 sequence variants in a subset of subjects.

scholarly journals Characterization of Antibody Responses Elicited by Human Immunodeficiency Virus Type 1 Primary Isolate Trimeric and Monomeric Envelope Glycoproteins in Selected Adjuvants

2006 ◽  
Vol 80 (3) ◽  
pp. 1414-1426 ◽  
Author(s):  
Y. Li ◽  
K. Svehla ◽  
N. L. Mathy ◽  
G. Voss ◽  
J. R. Mascola ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antibody Response ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
V3 Loop ◽  
Homologous Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric or monomeric immunogens. Consistent with our earlier studies, the YU2 gp140 immunogens elicited higher-titer neutralizing antibodies against homologous and heterologous isolates than those elicited by monomeric YU2 gp120. Additionally, the GlaxoSmithKline family of adjuvants AS01B, AS02A, and AS03 induced higher levels of neutralizing antibodies compared to emulsification of the same immunogens in Ribi adjuvant. Further analysis of vaccine sera indicated that homologous virus neutralization was not mediated by antibodies to the V3 loop, although V3 loop-directed neutralization could be detected for some heterologous isolates. In most gp120-inoculated animals, the homologous YU2 neutralization activity was inhibited by a peptide derived from the YU2 V1 loop, whereas the neutralizing activity elicited by YU2 gp140 trimers was much less sensitive to V1 peptide inhibition. Consistent with a less V1-focused antibody response, sera from the gp140-immunized animals more efficiently neutralized heterologous HIV-1 isolates, as determined by two distinct neutralization formats. Thus, there appear to be qualitative differences in the neutralizing antibody response elicited by YU2 gp140 compared to YU2 monomeric gp120. Further mapping analysis of more conserved regions of gp120/gp41 may be required to determine the neutralizing specificity elicited by the trimeric immunogens.

scholarly journals The tRNA Primer Activation Signal in the Human Immunodeficiency Virus Type 1 Genome Is Important for Initiation and Processive Elongation of Reverse Transcription

2002 ◽  
Vol 76 (5) ◽  
pp. 2329-2339 ◽  
Author(s):  
Nancy Beerens ◽  
Ben Berkhout
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcription ◽  
Sequence Motif ◽  
Immunodeficiency Virus ◽  
Trna Primer ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) reverse transcription is primed by the cellular tRNA3 Lys molecule, which binds, with its 3"-terminal 18 nucleotides (nt), to a complementary sequence in the viral genome, the primer-binding site (PBS). Besides PBS-anti-PBS pairing, additional interactions between viral RNA sequences and the tRNA primer are thought to regulate the process of reverse transcription. We previously identified a novel 8-nt sequence motif in the U5 region of the HIV-1 RNA genome that is critical for tRNA3 Lys-mediated initiation of reverse transcription in vitro. This motif activates initiation from the natural tRNA3 Lys primer but is not involved in tRNA placement and was therefore termed primer activation signal (PAS). It was proposed that the PAS interacts with the anti-PAS motif in the TΨC arm of tRNA3 Lys. In this study, we analyzed several PAS-mutated viruses and performed reverse transcription assays with virion-extracted RNA-tRNA complexes. Mutation of the PAS reduced the efficiency of tRNA-primed reverse transcription. In contrast, mutations in the opposing leader sequence that trigger release of the PAS from base pairing stimulated reverse transcription. These results are similar to the reverse transcription effects observed in vitro. We also selected revertant viruses that partially overcome the reverse transcription defect of the PAS deletion mutant. Remarkably, all revertants acquired a single nucleotide substitution that does not restore the PAS sequence but that stimulates elongation of reverse transcription. These combined results indicate that the additional PAS-anti-PAS interaction is needed to assemble an initiation-competent and processive reverse transcription complex.

scholarly journals Study of the V3 Loop as a Target Epitope for Antibodies Involved in the Neutralization of Primary Isolates versus T-Cell-Line-Adapted Strains of Human Immunodeficiency Virus Type 1

1998 ◽  
Vol 72 (12) ◽  
pp. 9855-9864 ◽  
Author(s):  
Catherine Spenlehauer ◽  
Sentob Saragosti ◽  
Hervé J. A. Fleury ◽  
André Kirn ◽  
Anne-Marie Aubertin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Cell Line ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
V3 Loop ◽  
Immunodeficiency Virus ◽  
Target Epitope ◽  
Hiv 1

ABSTRACT Previous studies characterized the third variable (V3) loop of the envelope gp120 as the principal neutralizing determinant for laboratory T-cell-line-adapted (TCLA) strains of human immunodeficiency virus type 1 (HIV-1). However, primary viruses isolated from infected individuals are more refractory to neutralization than TCLA strains, suggesting that qualitatively different neutralizing antibodies may be involved. In this study, we investigated whether the V3 loop constitutes a linear target epitope for antibodies neutralizing primary isolates. By using peptides representative of the V3 regions of various primary isolates, an early, relatively specific and persistent antibody response was detected in sera from HIV-infected patients. To assess the relationship between these antibodies and neutralization, the same peptides were used in competition and depletion experiments. Addition of homologous V3 peptides led to a competitive inhibition in the neutralization of the TCLA strain HIVMN/MT-4 but had no effect on the neutralization of the autologous primary isolate. Similarly, the removal of antibodies that bind to linear V3 epitopes resulted in a loss of HIVMN/MT-4 neutralization, whereas no decrease in the autologous neutralization was measured. The different roles of V3-specific antibodies according to the virus considered were thereby brought to light. This confirmed the involvement of V3 antibodies in the neutralization of a TCLA strain but emphasized a more pronounced contribution of either conformational epitopes or epitopes outside the V3 loop as targets for antibodies neutralizing primary HIV-1 isolates. This result underlines the need to focus on new vaccinal immunogens with epitopes able to induce broadly reactive and efficient antibodies that neutralize a wide range of primary HIV-1 isolates.

scholarly journals Evidence for Similar Recognition of the Conserved Neutralization Epitopes of Human Immunodeficiency Virus Type 1 Envelope gp120 in Humans and Macaques

2001 ◽  
Vol 75 (19) ◽  
pp. 9287-9296 ◽  
Author(s):  
Susan E. Malenbaum ◽  
David Yang ◽  
Cecilia Cheng-Mayer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
V3 Loop ◽  
Immune Recognition ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We compared the immune responses to the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins in humans and macaques with the use of clade A and clade B isogenic V3 loop glycan-possessing and -deficient viruses. We found that the presence or absence of the V3 loop glycan affects to similar extents immune recognition by a panel of anti-HIV human and anti-simian/human immunodeficiency virus (anti-SHIV) macaque sera. All sera tested neutralized the glycan-deficient viruses, in which the conserved CD4BS and CD4i epitopes are more exposed, better than the glycan-containing viruses. The titer of broadly neutralizing antibodies appears to be higher in the sera of macaques infected with glycan-deficient viruses. Collectively, our data add legitimacy to the use of SHIV-macaque models for testing the efficacy of HIV-1 Env-based immunogens. Furthermore, they suggest that antibodies to the CD4BS and CD4i sites of gp120 are prevalent in human and macaque sera and that the use of immunogens in which these conserved neutralizing epitopes are more exposed is likely to increase their immunogenicity.

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