Evolution and Biological Characterization of Human Immunodeficiency Virus Type 1 Subtype E gp120 V3 Sequences following Horizontal and Vertical Virus Transmission in a Single Family

ABSTRACT It has been suggested that immune-pressure-mediated positive selection operates to maintain the antigenic polymorphism on the third variable (V3) loop of the gp120 of human immunodeficiency virus type 1 (HIV-1). Here we present evidence, on the basis of sequencing 147 independently cloned env C2/V3 segments from a single family (father, mother, and their child), that the intensity of positive selection is related to the V3 lineage. Phylogenetic analysis and amino acid comparison of env C2/V3 and gagp17/24 regions indicated that a single HIV-1 subtype E source had infected the family. The analyses of unique env C2/V3 clones revealed that two V3 lineage groups had evolved in the parents. Group 1 was maintained with low variation in all three family members regardless of the clinical state or the length of infection, whereas group 2 was only present in symptomatic individuals and was more positively charged and diverse than group 1. Only virus isolates carrying the group 2 V3 sequences infected and induced syncytia in MT2 cells, a transformed CD4+-T-cell line. A statistically significant excess of nonsynonymous substitutions versus synonymous substitutions was demonstrated only for the group 2 V3 region. The data suggest that HIV-1 variants, possessing the more homogeneous group 1 V3 element and exhibiting the non-syncytium-inducing phenotype, persist in infected individuals independent of clinical status and appear to be more resistant to positive selection pressure.

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Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.7.1657 ◽

1996 ◽

Vol 40 (7) ◽

pp. 1657-1664 ◽

Cited By ~ 46

Author(s):

R T Davey ◽

D G Chaitt ◽

G F Reed ◽

W W Freimuth ◽

B R Herpin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Nucleoside Analogs ◽

Cd4 Counts ◽

Immunodeficiency Virus ◽

Group 2 ◽

To Receive ◽

Group 1

Delavirdine mesylate (DLV) is a potent nonnucleoside reverse transcriptase inhibitor with activity specific for human immunodeficiency virus type 1. In the present phase I/II study we evaluated the safety, toxicity, pharmacokinetics, and antiretroviral activities of two-drug and three-drug combinations of DLV and conventional doses of nucleoside analogs compared with those of both DLV monotherapy and two-drug nucleoside analog therapy. A total of 85 human immunodeficiency virus type 1 infected patients with CD4 counts of 100 to 300 cells per mm3 were enrolled in two periods: in the first period patients were randomized to receive either zidovudine (ZDV) plus didanosine (group 1) or ZDV plus didanosine plus escalating doses (400 to 1,200 mg/day) of DLV (group 2). In the second period, patients were randomized to receive either 1,200 mg of DLV alone per day (group 3) or ZDV plus 1,200 mg of DLV per day (group 4). DLV demonstrated good oral bioavailability at all five doses tested. The major toxicity was a transient mild rash which appeared in 44% of all DLV recipients. Overall, group 2 patients demonstrated more sustained improvements in CD4 counts, percent CD4 cells, branched DNA levels, p24 antigen levels, and virus titers in plasma than group 1, 3, or 4 patients. The magnitude of the response correlated with the intensity of prior nucleoside analog treatment, the non-syncytium-inducing or syncytium-inducing viral phenotype at baseline, and the presence of a wild-type codon at amino acid position 215 in the baseline reverse transcriptase genotype. Despite a transient rash, DLV therapy was well tolerated. Combination therapy with DLV and nucleoside analogs appears promising, with the three-drug combination appearing to be more potent that either two-drug combinations or monotherapy.

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QUASI analysis of host immune responses to Gag polyproteins of human immunodeficiency virus type 1 by a systematic bioinformatics approachThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o10-002 ◽

2010 ◽

Vol 88 (4) ◽

pp. 671-681 ◽

Cited By ~ 3

Author(s):

Binhua Liang ◽

Ma Luo ◽

T. Blake Ball ◽

Steven J.M. Jones ◽

Francis A. Plummer

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Positive Selection ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Peer Review Process ◽

Host Immune Responses ◽

Immunodeficiency Virus ◽

Hiv 1

There is a consensus that Gag-specific cytotoxic T lymphocyte (CTL) response plays a key role in the immune control of human immunodeficiency virus type 1 (HIV-1) infection. In this study, we analyzed all currently available gag sequences in the Los Alamos HIV sequence database and identified positive selection (PS) sites likely restricted by the host immune responses. We found that between 23.4% and 47.4% of PS sites were shared by clades A, B, and C of Gag, indicating similar positive selection pressure on Gag in different subtypes of HIV-1. Furthermore, a significant correlation was observed between the combined CTL and antibody responses and PS sites. The Gag regions of free from PS contained 9 CTL epitopes restricted by 11 HLA class I alleles associated with disease progression to acquired immune deficiency syndrome (AIDS). These analyses provide information important for the identification of cross-clade epitopes and development of a global HIV-1 vaccine.

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Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection

Journal of Virology ◽

10.1128/jvi.00575-06 ◽

2006 ◽

Vol 80 (19) ◽

pp. 9519-9529 ◽

Cited By ~ 97

Author(s):

Yi Liu ◽

John McNevin ◽

Jianhong Cao ◽

Hong Zhao ◽

Indira Genowati ◽

...

Keyword(s):

Amino Acids ◽

Human Immunodeficiency Virus ◽

Positive Selection ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Viral Fitness ◽

Ctl Epitopes ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Typically during human immunodeficiency virus type 1 (HIV-1) infection, a nearly homogeneous viral population first emerges and then diversifies over time due to selective forces that are poorly understood. To identify these forces, we conducted an intensive longitudinal study of viral genetic changes and T-cell immunity in one subject at ≤17 time points during his first 3 years of infection, and in his infecting partner near the time of transmission. Autologous peptides covering amino acid sites inferred to be under positive selection were powerful for identifying HIV-1-specific cytotoxic-T-lymphocyte (CTL) epitopes. Positive selection and mutations resulting in escape from CTLs occurred across the viral proteome. We detected 25 CTL epitopes, including 14 previously unreported. Seven new epitopes mapped to the viral Env protein, emphasizing Env as a major target of CTLs. One-third of the selected sites were associated with epitopic mutational escapes from CTLs. Most of these resulted from replacement with amino acids found at low database frequency. Another one-third represented acquisition of amino acids found at high database frequency, suggesting potential reversions of CTL epitopic sites recognized by the immune system of the transmitting partner and mutation toward improved viral fitness in the absence of immune targeting within the recipient. A majority of the remaining selected sites occurred in the envelope protein and may have been subjected to humoral immune selection. Hence, a majority of the amino acids undergoing selection in this subject appeared to result from fitness-balanced CTL selection, confirming CTLs as a dominant selective force in HIV-1 infection.

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Immune-Mediated Positive Selection Drives Human Immunodeficiency Virus Type 1 Molecular Variation and Predicts Disease Duration

Journal of Virology ◽

10.1128/jvi.76.22.11715-11720.2002 ◽

2002 ◽

Vol 76 (22) ◽

pp. 11715-11720 ◽

Cited By ~ 83

Author(s):

Howard A. Ross ◽

Allen G. Rodrigo

Keyword(s):

Human Immunodeficiency Virus ◽

Positive Selection ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Disease Duration ◽

Immune Recognition ◽

Short Term ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Using likelihood-based evolutionary methods, we demonstrate that the broad genetic diversity of human immunodeficiency virus type 1 (HIV-1) in an infected individual is a consequence of site-specific positive selection for diversity, a likely consequence of immune recognition. In particular, the extent of positive selection appears to be a good predictor of disease duration. Positively selected sites along HIV-1 partial env sequences are numerous but not distributed uniformly. In a sample of eight patients studied longitudinally, the proportion of sites per sample under positive selection was a statistically significant predictor of disease duration. Among long-term progressors, positive selection persisted at sites over time and appears to be associated with helper T-cell epitopes. In contrast, sites under positive selection shifted from one longitudinal sample to the next in short-term progressors. Our study is consistent with the hypothesis that a broad and persistent immunologic response is associated with a slower rate of disease progression. In contrast, narrow, shifting immune responses characterize short-term progressors.

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A Group of V3 Sequences from Human Immunodeficiency Virus Type 1 Subtype E Non-Syncytium-Inducing, CCR5-Using Variants Are Resistant to Positive Selection Pressure

Journal of Virology ◽

10.1128/jvi.74.3.1069-1078.2000 ◽

2000 ◽

Vol 74 (3) ◽

pp. 1069-1078 ◽

Cited By ~ 18

Author(s):

Teiichiro Shiino ◽

Kayoko Kato ◽

Noriko Kodaka ◽

Tuyoshi Miyakuni ◽

Yutaka Takebe ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Positive Selection ◽

Selection Pressure ◽

Cell Tropism ◽

Positive Selection Pressure ◽

Immunodeficiency Virus ◽

Group 2 ◽

Hiv 1 ◽

Group 1

ABSTRACT In a human immunodeficiency virus type 1 (HIV-1)-infected individual, immune-pressure-mediated positive selection operates to maintain the antigenic polymorphism on the gp120 third variable (V3) loop. Recently, we suggested on the basis of sequencing C2/V3 segments from an HIV-1 subtype E-infected family that a V3 sequence lineage group of the non-syncytium-inducing (NSI) variants (group 1) was relatively resistant to positive selection pressure (35). To better understand the relationship between the intensity of positive selection pressure and cell tropism of the virus, we determined the linkage between each V3 genotype and its function of directing coreceptor preference and MT2 cell tropism. The biological characterization of a panel of V3 recombinant viruses showed that all of the group 1 V3 sequences could confer an NSI/CCR5-using (NSI/R5) phenotype on HIV-1LAI, whereas the group 2 V3 sequence, which was more positively charged than the group 1 sequence, dictated mainly a syncytium-inducing, CXCR4-using (SI/X4) phenotype. Phylogenetic analysis of C2/V3 sequences encoding group 1 or 2 V3 suggested that the variants carrying group 1 V3 are the ancestors of the intrafamilial infection and persisted in the family, while the variants carrying group 2 V3 evolved convergently from the group 1 V3 variants during disease progression in the individuals. Finally, a statistical test showed that the V3 sequence that could dictate an NSI/R5 phenotype had a synonymous substitution rate significantly higher than the nonsynonymous substitution rate. These data suggest that V3 sequences of the subtype E NSI/R5 variants are more resistant to positive selection pressure than those of the SI/X4 variants.

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