scholarly journals Addition of E138K to R263K in HIV integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity

2014 ◽  
Vol 69 (10) ◽  
pp. 2733-2740 ◽  
Author(s):  
T. Mesplede ◽  
N. Osman ◽  
M. Wares ◽  
P. K. Quashie ◽  
S. Hassounah ◽  
...  
Keyword(s):  
Viral Replication ◽  
Replication Capacity ◽  
Hiv Integrase ◽  
Viral Replication Capacity

scholarly journals Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor

2010 ◽  
Vol 84 (18) ◽  
pp. 9210-9216 ◽  
Author(s):  
Tamara Bar-Magen ◽  
Richard D. Sloan ◽  
Daniel A. Donahue ◽  
Björn D. Kuhl ◽  
Alexandra Zabeida ◽  
...  
Keyword(s):  
Viral Replication ◽  
First Generation ◽  
Second Generation ◽  
Integrase Inhibitor ◽  
Replication Capacity ◽  
Strand Transfer ◽  
Viral Replication Capacity ◽  
Transfer Inhibitor ◽  
Potential Basis

ABSTRACT MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer “off” rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg2+ binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.

scholarly journals HLA-B57/B*5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition

2008 ◽  
Vol 83 (6) ◽  
pp. 2743-2755 ◽  
Author(s):  
Toshiyuki Miura ◽  
Mark A. Brockman ◽  
Arne Schneidewind ◽  
Michael Lobritz ◽  
Florencia Pereyra ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Fitness ◽  
Replication Capacity ◽  
Elite Controllers ◽  
Immunodeficiency Virus ◽  
Viral Replication Capacity

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag240-249 TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.

scholarly journals An Intact U5-Leader Stem Is Important for Efficient Replication of Simian Immunodeficiency Virus

2001 ◽  
Vol 75 (23) ◽  
pp. 11924-11929 ◽  
Author(s):  
Yongjun Guan ◽  
Karidia Diallo ◽  
James B. Whitney ◽  
Chen Liang ◽  
Mark A. Wainberg
Keyword(s):  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Point Mutations ◽  
Large Deletion ◽  
Primer Binding Site ◽  
Replication Capacity ◽  
Biologically Relevant ◽  
Immunodeficiency Virus ◽  
Efficient Replication ◽  
Viral Replication Capacity

ABSTRACT Previous work has shown that four deletions in simian immunodeficiency virus (SIV), termed SD1a, SD1b, SD1c, and SD6, which eliminated sequences at nucleotide positions 322 to 362, 322 to 370, 322 to 379, and 371 to 379, respectively, located downstream of the primer binding site, impaired viral replication capacity to different extents. Long-term culturing of viruses containing the SD1a, SD1b, and SD6 deletions led to revertants that possessed wild-type replication kinetics. We now show that these revertants retained the original deletions in each case but that novel additional mutations were also present. These included a large deletion termed D1 (nt +216 to +237) within the U5 region that was shown to be biologically relevant to reversion of both the SD1a and SD1b constructs. In the case of SD6, two compensatory point mutations, i.e., A+369G, termed M1, located immediately upstream of the SD6 deletion, and C+201T, termed M2, within U5, were identified and could act either singly or in combination to restore viral replication. Secondary structure suggests that an intact U5-leader stem is important in SIV for infectiousness and that the additional mutants described played important roles in restoration of this motif.

scholarly journals Impairment of viral replication capacity by nef alleles from HIV elite controllers

Retrovirology ◽  
2011 ◽  
Vol 8 (S2) ◽  
Author(s):  
Philip Mwimanzi ◽  
Tristan Markle ◽  
Hirohito Otsuka ◽  
Yoko Ogata ◽  
Michiyo Tokunaga ◽  
...  
Keyword(s):  
Viral Replication ◽  
Replication Capacity ◽  
Elite Controllers ◽  
Viral Replication Capacity

scholarly journals Impact of HLA-B*81-Associated Mutations in HIV-1 Gag on Viral Replication Capacity

2012 ◽  
Vol 86 (6) ◽  
pp. 3193-3199 ◽  
Author(s):  
J. K. Wright ◽  
V. L. Naidoo ◽  
Z. L. Brumme ◽  
J. L. Prince ◽  
D. T. Claiborne ◽  
...  
Keyword(s):  
Viral Replication ◽  
Replication Capacity ◽  
Viral Replication Capacity ◽  
Hiv 1

scholarly journals Glioma Virotherapy: Effects of Innate Immune Suppression and Increased Viral Replication Capacity

2006 ◽  
Vol 66 (4) ◽  
pp. 2314-2319 ◽  
Author(s):  
Avner Friedman ◽  
Jianjun Paul Tian ◽  
Giulia Fulci ◽  
E. Antonio Chiocca ◽  
Jin Wang
Keyword(s):  
Viral Replication ◽  
Immune Suppression ◽  
Innate Immune ◽  
Replication Capacity ◽  
Viral Replication Capacity

scholarly journals Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

2012 ◽  
Vol 87 (3) ◽  
pp. 1465-1476 ◽  
Author(s):  
Shigeru Nomura ◽  
Noriaki Hosoya ◽  
Zabrina L. Brumme ◽  
Mark A. Brockman ◽  
Tadashi Kikuchi ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Fluorescent Protein ◽  
Asymptomatic Infection ◽  
Replication Capacity ◽  
Subtype B ◽  
Geographical Regions ◽  
Viral Replication Capacity ◽  
Green Fluorescent ◽  
Hiv 1

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasma-derivedgag-protease. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4+T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wild-type NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.

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