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  • American Society for Microbiology  (6)
  • 1
    Online Resource
    Online Resource
    Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection
    American Society for Microbiology ; 2006
    In:  Journal of Virology Vol. 80, No. 19 ( 2006-10), p. 9519-9529
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 80, No. 19 ( 2006-10), p. 9519-9529
    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.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00575-06
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2006
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  • 2
    Online Resource
    Online Resource
    Analysis of HLA A*02 Association with Vaccine Efficacy in the RV144 HIV-1 Vaccine Trial
    American Society for Microbiology ; 2014
    In:  Journal of Virology Vol. 88, No. 15 ( 2014-08), p. 8242-8255
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 88, No. 15 ( 2014-08), p. 8242-8255
    Abstract: The RV144 HIV-1 vaccine trial demonstrated partial efficacy of 31% against HIV-1 infection. Studies into possible correlates of protection found that antibodies specific to the V1 and V2 (V1/V2) region of envelope correlated inversely with infection risk and that viruses isolated from trial participants contained genetic signatures of vaccine-induced pressure in the V1/V2 region. We explored the hypothesis that the genetic signatures in V1 and V2 could be partly attributed to selection by vaccine-primed T cells. We performed a T-cell-based sieve analysis of breakthrough viruses in the RV144 trial and found evidence of predicted HLA binding escape that was greater in vaccine versus placebo recipients. The predicted escape depended on class I HLA A*02- and A*11-restricted epitopes in the MN strain rgp120 vaccine immunogen. Though we hypothesized that this was indicative of postacquisition selection pressure, we also found that vaccine efficacy (VE) was greater in A*02-positive (A*02 + ) participants than in A*02 − participants (VE = 54% versus 3%, P = 0.05). Vaccine efficacy against viruses with a lysine residue at site 169, important to antibody binding and implicated in vaccine-induced immune pressure, was also greater in A*02 + participants (VE = 74% versus 15%, P = 0.02). Additionally, a reanalysis of vaccine-induced immune responses that focused on those that were shown to correlate with infection risk suggested that the humoral responses may have differed in A*02 + participants. These exploratory and hypothesis-generating analyses indicate there may be an association between a class I HLA allele and vaccine efficacy, highlighting the importance of considering HLA alleles and host immune genetics in HIV vaccine trials. IMPORTANCE The RV144 trial was the first to show efficacy against HIV-1 infection. Subsequently, much effort has been directed toward understanding the mechanisms of protection. Here, we conducted a T-cell-based sieve analysis, which compared the genetic sequences of viruses isolated from infected vaccine and placebo recipients. Though we hypothesized that the observed sieve effect indicated postacquisition T-cell selection, we also found that vaccine efficacy was greater for participants who expressed HLA A*02, an allele implicated in the sieve analysis. Though HLA alleles have been associated with disease progression and viral load in HIV-1 infection, these data are the first to suggest the association of a class I HLA allele and vaccine efficacy. While these statistical analyses do not provide mechanistic evidence of protection in RV144, they generate testable hypotheses for the HIV vaccine community and they highlight the importance of assessing the impact of host immune genetics in vaccine-induced immunity and protection. (This study has been registered at ClinicalTrials.gov under registration no. NCT00223080.)
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01164-14
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
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  • 3
    Online Resource
    Online Resource
    Evolutionary Indicators of Human Immunodeficiency Virus Type 1 Reservoirs and Compartments
    American Society for Microbiology ; 2003
    In:  Journal of Virology Vol. 77, No. 9 ( 2003-05), p. 5540-5546
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 77, No. 9 ( 2003-05), p. 5540-5546
    Abstract: In vivo virologic compartments are cell types or tissues between which there is a restriction of virus flow, while virologic reservoirs are cell types or tissues in which there is a relative restriction of replication. The distinction between reservoirs and compartments is important because therapies that would be effective against a reservoir may not be effective against viruses produced by a given compartment, and vice versa. For example, the use of cytokines to “flush out” long-lived infected cells in patients on highly active antiretroviral therapy (T. W. Chun, D. Engel, M. M. Berrey, T. Shea, L. Corey, and A. S. Fauci, Proc. Natl. Acad. Sci. USA 95:8869-8873, 1998) may be successful for a latent reservoir but may not impact a compartment in which virus continues to replicate because of poor drug penetration. Here, we suggest phylogenetic criteria to illustrate, define, and differentiate between reservoirs and compartments. We then apply these criteria to the analysis of simulated and actual human immunodeficiency virus type 1 sequence data sets. We report that existing statistical methods work quite well at detecting viral compartments, and we learn from simulations that viral divergence from a calculated most recent common ancestor is a strong predictor of viral reservoirs.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.77.9.5540-5546.2003
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2003
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  • 4
    Online Resource
    Online Resource
    Improved Coreceptor Usage Prediction and GenotypicMonitoring of R5-to-X4 Transition by Motif Analysis of HumanImmunodeficiency Virus Type 1 env V3 LoopSequences
    American Society for Microbiology ; 2003
    In:  Journal of Virology Vol. 77, No. 24 ( 2003-12-15), p. 13376-13388
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 77, No. 24 ( 2003-12-15), p. 13376-13388
    Abstract: Early in infection, human immunodeficiency virus type 1 (HIV-1) generally uses the CCR5 chemokine receptor (along with CD4) for cellular entry. In many HIV-1-infected individuals, viral genotypic changes arise that allow the virus to use CXCR4 (either in addition to CCR5 or alone) as an entry coreceptor. This switch has been associated with an acceleration of both CD3 + T-cell decline and progression to AIDS. While it is well known that the V3 loop of gp120 largely determines coreceptor usage and that positively charged residues in V3 play an important role, the process of genetic change in V3 leading to altered coreceptor usage is not well understood. Further, the methods for biological phenotyping of virus for research or clinical purposes are laborious, depend on sample availability, and present biosafety concerns, so reliable methods for sequence-based“ virtual phenotyping” are desirable. We introduce a simple bioinformatic method of scoring V3 amino acid sequences that reliably predicts CXCR4 usage (sensitivity, 84%; specificity, 96%). This score (as determined on the basis of position-specific scoring matrices [PSSM]) can be interpreted as revealing a propensity to use CXCR4 as follows: known R5 viruses had low scores, R5X4 viruses had intermediate scores, and X4 viruses had high scores. Application of the PSSM scoring method to reconstructed virus phylogenies of 11 longitudinally sampled individuals revealed that the development of X4 viruses was generally gradual and involved the accumulation of multiple amino acid changes in V3. We found that X4 viruses were lost in two ways: by the dying off of an established X4 lineage or by mutation back to low-scoring V3 loops.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.77.24.13376-13388.2003
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2003
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  • 5
    Online Resource
    Online Resource
    Selection for Human Immunodeficiency Virus Type 1 Recombinants in a Patient with Rapid Progression to AIDS
    American Society for Microbiology ; 2002
    In:  Journal of Virology Vol. 76, No. 21 ( 2002-11), p. 10674-10684
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 76, No. 21 ( 2002-11), p. 10674-10684
    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.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.76.21.10674-10684.2002
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2002
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  • 6
    Online Resource
    Online Resource
    Virus-Specific CD8 + T-Cell Responses Better Define HIV Disease Progression than HLA Genotype
    American Society for Microbiology ; 2010
    In:  Journal of Virology Vol. 84, No. 9 ( 2010-05), p. 4461-4468
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 84, No. 9 ( 2010-05), p. 4461-4468
    Abstract: HLA alleles B57/58, B27, and B35 have the strongest genetic associations with HIV-1 disease progression. The mechanisms of these relationships may be host control of HIV-1 infection via CD8 + T-cell responses. We examined these immune responses in subjects from the Seattle Primary Infection Cohort with these alleles. CD8 + T-cell responses to conserved HIV epitopes within B57/58 alleles (TW10 and KF11) and B27 alleles (KK10 and FY10) delayed declines in CD4 + T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58 + and B27 + subjects lacking the conserved B57/58- and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8 + T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8 + T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8 + T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8 + T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.02438-09
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2010
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