scholarly journals Development of a homology model for clade A human immunodeficiency virus type 1 gp120 to localize temporal substitutions arising in recently infected women

2004 ◽  
Vol 85 (6) ◽  
pp. 1479-1484
Author(s):  
Mary Poss ◽  
David C. Holley ◽  
Roman Biek ◽  
Harold Cox ◽  
John Gerdes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Gene ◽  
Virus Population ◽  
Gene Sequences ◽  
Virus Diversity ◽  
Immunodeficiency Virus ◽  
Hiv 1

The virus population transmitted by a human immunodeficiency virus type 1 (HIV-1) infected individual undergoes restriction and subsequent diversification in the new host. However, in contrast to men, who have limited virus diversity at seroconversion, there is measurable diversity in viral envelope gene sequences in women infected with clade A HIV-1. In this study, virus sequence diversity in three unrelated, clade A infected women preceding and shortly after seroconversion was evaluated. It was demonstrated that there is measurable evolution of envelope gene sequences over this time interval. Furthermore, in each of the three individuals, amino acid substitutions arose at five or six positions in sequences derived at or shortly after seroconversion relative to sequences obtained from the seronegative sample. Presented here is a model of clade A gp120 to determine the location of substitutions that appeared as the virus population became established in three clade A HIV-1 infected women.

scholarly journals Mucosal and Systemic Immune Responses to a Human Immunodeficiency Virus Type 1 Epitope Induced upon Vaginal Infection with a Recombinant Influenza A Virus

2004 ◽  
Vol 78 (2) ◽  
pp. 1020-1025 ◽  
Author(s):  
Bruno Garulli ◽  
Yoshihiro Kawaoka ◽  
Maria R. Castrucci
Keyword(s):  
Human Immunodeficiency Virus ◽  
Influenza Virus ◽  
Immune Responses ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Gene ◽  
Vaginal Infection ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The humoral and cellular immune responses in the genital mucosa likely play an important role in the prevention of sexually transmitted infections, including infection with human immunodeficiency virus type 1 (HIV-1). Here we show that vaginal infection of progesterone-treated BALB/c mice with a recombinant influenza virus bearing the immunodominant P18IIIB cytotoxic T-lymphocyte (CTL) epitope of the gp160 envelope protein from an HIV-1 IIIB isolate (P18IIIB; RIQRGPGRAFVTIGK) can induce a specific immune response in regional mucosal lymph nodes, as well as in a systemic site (the spleen). A single inoculation of mice with the recombinant influenza virus induced long-lasting (at least 5 months) antigen-specific CTL memory detectable as a rapid recall of effector CTLs upon vaginal infection with recombinant vaccinia virus expressing HIV-1 IIIB envelope gene products. Long-term antigen-specific CTL memory was also induced and maintained in distant mucosal tissues when mice were intranasally immunized with the recombinant influenza virus. These results indicate that mucosal immunization and, in particular, local vaginal immunization with recombinant influenza virus can provide strong, durable immune responses in the female genital tract of mice.

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 Reversal of Human Immunodeficiency Virus Type 1 IIIB to a Neutralization-Resistant Phenotype in an Accidentally Infected Laboratory Worker with a Progressive Clinical Course

2001 ◽  
Vol 75 (5) ◽  
pp. 2246-2252 ◽  
Author(s):  
Tim Beaumont ◽  
Ad van Nuenen ◽  
Silvia Broersen ◽  
William A. Blattner ◽  
Vladimir V. Lukashov ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Gene ◽  
Nucleotide Substitutions ◽  
Laboratory Worker ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The role of humoral immunity in controlling human immunodeficiency virus type 1 (HIV-1) is still controversial. The resistance of primary HIV-1 variants to neutralization by antibodies, sera from HIV-1-infected patients, and soluble CD4 protein has been suggested to be a prerequisite for the virus to establish persistence in vivo. To further test this hypothesis, we studied the neutralization sensitivity of two IIIB/LAV variants that were isolated from a laboratory worker who accidentally was infected with the T-cell-line-adapted neutralization-sensitive IIIB isolate. Compared to the original virus in the inoculum, the reisolated viruses showed an increased resistance to neutralization over time. The ratio of nonsynonymous to synonymous nucleotide substitutions in the envelope gene pointed to strong positive selection. The emergence of neutralization-resistant HIV preceded disease development in this laboratory worker. Our results imply that the neutralization resistance of primary HIV may indeed be considered an escape mechanism from humoral immune control.

scholarly journals Different evolutionary patterns are found within human immunodeficiency virus type 1-infected patients

2001 ◽  
Vol 82 (10) ◽  
pp. 2495-2508 ◽  
Author(s):  
Concepción Casado ◽  
Soledad García ◽  
Carmen Rodríguez ◽  
Jorge del Romero ◽  
Gonzalo Bello ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleotide Sequencing ◽  
Virus Population ◽  
Evolutionary Patterns ◽  
Evolutionary Forces ◽  
Immunodeficiency Virus ◽  
Hiv 1

In order to study the evolution in vivo of human immunodeficiency virus type 1 (HIV-1) in patients with normal clinical evolution, six individuals were selected from a group of 46 patients followed for 1 to 4 years. Patients were selected not by clinical progression characteristics but on the basis of virus genetic variability, as analysed by heteroduplex mobility assay and RNase A mismatch cleavage method. Two patients displayed a homogeneous virus population, two showed very heterogeneous quasispecies and two presented two distinct variants within the virus population. Virus quasispecies were studied by nucleotide sequencing of the C2-fusion domain of the env gene. Virus evolution was approached by analysing the distribution of genetic distances, calculation of divergence and heterogeneity as well as the K a/K s ratio and by the construction of the phylogenetic trees. Three patients displayed the same tree topology, characterized by the presence of independent clades supported by high bootstrap values, whereas this pattern was not present in the other three patients. In the three patients displaying independent clades, a recombination analysis was carried out between distinct subpopulations and recombinant variants were identified. In one patient of this group, different selective pressures were detected in distinct virus clades, measured by their corresponding K a/K s ratios, revealing that different evolutionary forces are occurring at the same time within the same patient. These results show that multiple evolutionary patterns can be found in typical HIV-1-infected patients.

scholarly journals Elicitation of Neutralizing Antibodies with DNA Vaccines Expressing Soluble Stabilized Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Conjugated to C3d

2004 ◽  
Vol 78 (9) ◽  
pp. 4710-4719 ◽  
Author(s):  
Joseph F. Bower ◽  
Xinzhen Yang ◽  
Joseph Sodroski ◽  
Ted M. Ross
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
Dna Vaccines ◽  
Envelope Gene ◽  
Immunodeficiency Virus ◽  
Monomeric Gp120 ◽  
Hiv 1

ABSTRACT DNA vaccines expressing the envelope (Env) of human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting immune responses. Oligomeric or trimeric (gp140) forms of Env that more closely mimic the native proteins on the virion are often more effective immunogens than monomeric (gp120) envelopes. In this study, several forms of Env constructed from the HIV-1 isolate YU-2 (HIV-1YU-2) were tested for their immunogenic potential: a trimeric form of uncleaved (−) Env stabilized with a synthetic trimer motif isolated from the fibritin (FT) protein of the T4 bacteriophage, sgp140YU-2(−/FT), was compared to sgp140YU-2(−) without a synthetic trimerization domain, as well as to monomeric gp120YU-2. DNA plasmids were constructed to express Env alone or fused to various copies of murine C3d (mC3d). BALB/c mice were vaccinated (day 1 and week 4) with DNA expressing a codon-optimized envelope gene insert, alone or fused to mC3d. Mice were subsequently boosted (week 8) with the DNA or recombinant Env protein. All mice had high anti-Env antibody titers regardless of the use of mC3d. Sera from mice vaccinated with DNA expressing non-C3d-fused trimers elicited neutralizing antibodies against homologous HIV-1YU-2 virus infection in vitro. In contrast, sera from mice inoculated with DNA expressing Env-C3d protein trimers elicited antibody that neutralized both homologous HIV-1YU-2 and heterologous HIV-1ADA, albeit at low titers. Therefore, DNA vaccines expressing trimeric envelopes coupled to mC3d, expressed in vivo from codon-optimized sequences, elicit low titers of neutralizing antibodies against primary isolates of HIV-1.

scholarly journals Trafficking through the Rev/RRE Pathway Is Essential for Efficient Inhibition of Human Immunodeficiency Virus Type 1 by an Antisense RNA Derived from the Envelope Gene

2008 ◽  
Vol 83 (2) ◽  
pp. 940-952 ◽  
Author(s):  
Alex M. Ward ◽  
David Rekosh ◽  
Marie-Louise Hammarskjold
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antisense Rna ◽  
Envelope Gene ◽  
Antisense Inhibition ◽  
Rev Response Element ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A human immunodeficiency virus type 1 (HIV-1)-based vector expressing an antisense RNA directed against HIV-1 is currently in clinical trials. This vector has shown a remarkable ability to inhibit HIV-1 replication, in spite of the fact that therapeutic use of unmodified antisense RNAs has generally been disappointing. To further analyze the basis for this, we examined the effects of different plasmid-based HIV-1 long-terminal-repeat-driven constructs expressing antisense RNA to the same target region in HIV-1 but containing different export elements. Two of these vectors were designed to express antisense RNA containing either a Rev response element (RRE) or a Mason-Pfizer monkey virus (MPMV) constitutive transport element (CTE). In the third vector, no specific transport element was provided. Efficient inhibition of HIV-1 virus production was obtained with the RRE-driven antisense RNA. This construct also efficiently inhibited p24 production from a pNL4-3 provirus that used the MPMV CTE for RNA export. In contrast, little inhibition was observed with the constructs lacking an RRE. Furthermore, when the RRE-driven antisense RNA was redirected to the Tap/Nxf1 pathway, utilized by the MPMV CTE, through the expression of a RevM10-Tap fusion protein, the efficiency of antisense inhibition was greatly reduced. These results indicate that efficient inhibition requires trafficking of the antisense RNA through the Rev/RRE pathway. Mechanistic studies indicated that the Rev/RRE-mediated inhibition did not involve either nuclear retention or degradation of target mRNA, since target RNA was found to export and associate normally with polyribosomes. However, protein levels were significantly reduced. Taken together, our results suggest a new mechanism for antisense inhibition of HIV mediated by Rev/RRE.

scholarly journals Role of the Human Immunodeficiency Virus Type 1 Envelope Gene in Viral Fitness

2003 ◽  
Vol 77 (16) ◽  
pp. 9069-9073 ◽  
Author(s):  
Hector R. Rangel ◽  
Jan Weber ◽  
Bikram Chakraborty ◽  
Arantxa Gutierrez ◽  
Michael L. Marotta ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Fitness ◽  
Envelope Gene ◽  
Wild Type ◽  
Recombinant Viruses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A human host offers a variety of microenvironments to the infecting human immunodeficiency virus type 1 (HIV-1), resulting in various selective pressures, most of them directed against the envelope (env) gene. Therefore, it seems evident that the replicative capacity of the virus is largely related to viral entry. In this study we have used growth competition experiments and TaqMan real-time PCR detection to measure the fitness of subtype B HIV-1 primary isolates and autologous env-recombinant viruses in order to analyze the contribution of wild-type env sequences to overall HIV-1 fitness. A significant correlation was observed between fitness values obtained for wild-type HIV-1 isolates and those for the corresponding env-recombinant viruses (r = 0.93; P = 0.002). Our results suggest that the env gene, which is linked to a myriad of viral characteristics (e.g., entry into the host cell, transmission, coreceptor usage, and tropism), plays a major role in fitness of wild-type HIV-1. In addition, this new recombinant assay may be useful for measuring the contribution of HIV-1 env to fitness in viruses resistant to novel antiretroviral entry inhibitors.

scholarly journals Infection with Multiple Human Immunodeficiency Virus Type 1 Variants Is Associated with Faster Disease Progression

2003 ◽  
Vol 77 (23) ◽  
pp. 12921-12926 ◽  
Author(s):  
Manish Sagar ◽  
Ludo Lavreys ◽  
Jared M. Baeten ◽  
Barbra A. Richardson ◽  
Kishorchandra Mandaliya ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Primary Infection ◽  
Virus Population ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals develop a genetically diverse virus population over time, but often only a limited number of viral variants are transmitted from a chronic carrier to a newly infected person. Interestingly, many women but few men are infected by multiple HIV-1 variants from a single partner. To determine whether the complexity of the infecting virus population influences clinical outcome, we examined viral diversity in the HIV-1 envelope sequences present at primary infection in 156 women from Kenya for whom we had follow-up data on viral RNA levels and CD4 T-cell counts. Eighty-nine women had multiple viral genotypes, while 67 women had a single genotype at primary infection. Women who acquired multiple viral genotypes had a significantly higher viral load (median, 4.84 versus 4.64 log10 copies/ml, P = 0.04) and a significantly lower CD4+-T-cell count (median, 416 versus 617 cells/mm3, P = 0.01) 4 to 24 months after infection compared to women who were infected with a single viral genotype. These studies suggest that early HIV-1 genetic diversity is linked to faster disease progression.

scholarly journals Phenotypic and Genotypic Comparisons of CCR5- and CXCR4-Tropic Human Immunodeficiency Virus Type 1 Biological Clones Isolated from Subtype C-Infected Individuals

2004 ◽  
Vol 78 (6) ◽  
pp. 2841-2852 ◽  
Author(s):  
Georgios Pollakis ◽  
Almaz Abebe ◽  
Aletta Kliphuis ◽  
Moustapha I. M. Chalaby ◽  
Margreet Bakker ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Gene ◽  
Subtype C ◽  
Subtype B ◽  
Immature Dendritic Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Individuals infected with human immunodeficiency virus type 1 (HIV-1) subtype C infrequently harbour X4 viruses. We studied R5 and X4 biological clones generated from HIV-1 subtype C-infected individuals. All subtype C R5 viruses demonstrated slower profiles of replication on CD4+ lymphocytes in comparison to subtype B viruses, whereas subtype C X4 viruses replicated with comparable efficiency to subtype B X4 viruses. No differences were identified in CC or CXC chemokine inhibitions (RANTES and SDF-1α, respectively) between subtype C and subtype B viruses. Immature dendritic cells were shown in coculture experiments to similarly enhance the infection of subtype C and subtype B R5 as well as X4 viruses. By amino acid sequence analysis, we showed that the R5 and X4 subtype C gp120 envelope gene alterations were similar to those for a switching subtype B virus, specifically with respect to the V3 charge and envelope N-linked glycosylation patterns. By phylogenetic analysis, we showed that one patient was infected with HIV-1 C′ and the other was infected with HIV-1 C" and that one of the patients harbored a virus that was a recombinant in the gp120 env gene between an R5 and an X4 virus, with the resultant virus being R5. No differences were identified between the long terminal repeat regions of the subtype C R5 and X4 biological clones. These results indicate that even though R5 subtype C viruses are restrictive for virus replication, the R5-to-X4 phenotype switch can occur and does so in a manner similar to that of subtype B viruses.

scholarly journals A Recombinant Sendai Virus Is Controlled by CD4+ Effector T Cells Responding to a Secreted Human Immunodeficiency Virus Type 1 Envelope Glycoprotein

2007 ◽  
Vol 81 (22) ◽  
pp. 12535-12542 ◽  
Author(s):  
Scott A. Brown ◽  
Julia L. Hurwitz ◽  
Amy Zirkel ◽  
Sherri Surman ◽  
Toru Takimoto ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sendai Virus ◽  
Envelope Gene ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The importance of antigen-specific CD4+ helper T cells in virus infections is well recognized, but their possible role as direct mediators of virus clearance is less well characterized. Here we describe a recombinant Sendai virus strategy for probing the effector role(s) of CD4+ T cells. Mice were vaccinated with DNA and vaccinia virus recombinant vectors encoding a secreted human immunodeficiency virus type 1 (HIV-1) envelope protein and then challenged with a Sendai virus carrying a homologous HIV-1 envelope gene. The primed mice showed (i) prompt homing of numerous envelope-primed CD4+ T cell populations to the virus-infected lung, (ii) substantial production of gamma interferon, and interleukin-2 (IL-2), IL-4, and IL-5 in that site, and (iii) significantly reduced pulmonary viral load. The challenge experiments were repeated with immunoglobulin−/− μMT mice in the presence or absence of CD8+ and/or CD4+ T cells. These selectively immunodeficient mice were protected by primed CD4+ T cells in the absence of antibody or CD8+ T cells. Together, these results highlight the role of CD4+ T cells as direct effectors in vivo and, because this protocol gives such a potent response, identify an outstanding experimental model for further dissecting CD4+ T-cell-mediated immunity in the lung.

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