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1.
JBMR Plus ; 8(5): ziae034, 2024 May.
Article in English | MEDLINE | ID: mdl-38586475

ABSTRACT

Mutations in PLEKHM1 cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of Plekhm1 gene in mice lead to defective osteoclast bone resorption and increased trabecular bone mass without overt abnormalities in other organs. As an adaptor protein, pleckstrin homology and RUN domain containing M1 (PLEKHM1) interacts with the key lysosome regulator small GTPase RAB7 via its C-terminal RUBICON homologous (RH) domain. In this study, we have conducted a structural-functional study of the PLEKHM1 RH domain and RAB7 interaction in osteoclasts in vitro. The single mutations of the key residues in the Plekhm1 RH predicted from the crystal structure of the RUBICON RH domain and RAB7 interface failed to disrupt the Plekhm1-Rab7 binding, lysosome trafficking, and bone resorption. The compound alanine mutations at Y949-R954 and L1011-I1018 regions decreased Plekhm1 protein stability and Rab7-binding, respectively, thereby attenuated lysosome trafficking and bone resorption in osteoclasts. In contrast, the compound alanine mutations at R1060-Q1068 region were dispensable for Rab7-binding and Plekhm1 function in osteoclasts. These results indicate that the regions spanning Y949-R954 and L1011-I1018 of Plekhm1 RH domain are functionally important for Plekhm1 in osteoclasts and offer the therapeutic targets for blocking bone resorption in treatment of osteoporosis and other metabolic bone diseases.

2.
Cell Rep Med ; 4(7): 101101, 2023 07 18.
Article in English | MEDLINE | ID: mdl-37421947

ABSTRACT

Merkel cell carcinoma (MCC), a rare but aggressive skin cancer, remains a challenge in the era of precision medicine. Immune checkpoint inhibitors (ICIs), the only approved therapy for advanced MCC, are impeded by high primary and acquired resistance. Hence, we dissect transcriptomic heterogeneity at single-cell resolution in a panel of patient tumors, revealing phenotypic plasticity in a subset of treatment-naive MCC. The tumor cells in a "mesenchymal-like" state are endowed with an inflamed phenotype that portends a better ICI response. This observation is also validated in the largest whole transcriptomic dataset available from MCC patient tumors. In contrast, ICI-resistant tumors predominantly express neuroepithelial markers in a well-differentiated state with "immune-cold" landscape. Importantly, a subtle shift to "mesenchymal-like" state reverts copanlisib resistance in primary MCC cells, highlighting potential strategies in patient stratification for therapeutics to harness tumor cell plasticity, augment treatment efficacy, and avert resistance.


Subject(s)
Carcinoma, Merkel Cell , Skin Neoplasms , Humans , Carcinoma, Merkel Cell/drug therapy , Carcinoma, Merkel Cell/genetics , Carcinoma, Merkel Cell/pathology , Transcriptome/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Immunotherapy , Gene Expression Profiling
3.
Elife ; 112022 06 27.
Article in English | MEDLINE | ID: mdl-35758636

ABSTRACT

Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin, and its expression increases during osteoclast differentiation. Nonetheless, the precise functions of Tfr1 and Tfr1-mediated iron uptake in osteoclast biology and skeletal homeostasis remain incompletely understood. To investigate the role of Tfr1 in osteoclast lineage cells in vivo and in vitro, we crossed Tfrc (encoding Tfr1)-floxed mice with Lyz2 (LysM)-Cre and Cathepsin K (Ctsk)-Cre mice to generate Tfrc conditional knockout mice in myeloid osteoclast precursors (Tfr1ΔLysM) or differentiated osteoclasts (Tfr1ΔCtsk), respectively. Skeletal phenotyping by µCT and histology unveiled a significant increase in trabecular bone mass with normal osteoclast number in long bones of 10-week-old young and 6-month-old adult female but not male Tfr1ΔLysM mice. Although high trabecular bone volume in long bones was observed in both male and female Tfr1ΔCtsk mice, this phenotype was more pronounced in female knockout mice. Consistent with this gender-dependent phenomena, estrogen deficiency induced by ovariectomy decreased trabecular bone mass in Tfr1ΔLysM mice. Mechanistically, disruption of Tfr1 expression attenuated mitochondrial metabolism and cytoskeletal organization in mature osteoclasts in vitro by attenuating mitochondrial respiration and activation of the Src-Rac1-WAVE regulatory complex axis, respectively, leading to decreased bone resorption with little impact on osteoclast differentiation. These results indicate that Tfr1-mediated iron uptake is specifically required for osteoclast function and is indispensable for bone remodeling in a gender-dependent manner.


Subject(s)
Bone Resorption , Iron , Osteoclasts , Receptors, Transferrin , Animals , Bone Resorption/pathology , Cytoskeleton/metabolism , Female , Iron/metabolism , Mice , Mice, Knockout , Mitochondria/metabolism , Osteoclasts/metabolism , Receptors, Transferrin/genetics
6.
Cancers (Basel) ; 13(15)2021 Jul 23.
Article in English | MEDLINE | ID: mdl-34359608

ABSTRACT

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

7.
Cells ; 11(1)2021 12 22.
Article in English | MEDLINE | ID: mdl-35011575

ABSTRACT

Cytoskeleton organization and lysosome secretion play an essential role in osteoclastogenesis and bone resorption. The cytoplasmic dynein is a molecular motor complex that regulates microtubule dynamics and transportation of cargos/organelles, including lysosomes along the microtubules. LIS1, NDE1, and NDEL1 belong to an evolutionary conserved pathway that regulates dynein functions. Disruption of the cytoplasmic dynein complex and deletion of LIS1 in osteoclast precursors arrest osteoclastogenesis. Nonetheless, the role of NDE1 and NDEL1 in osteoclast biology remains elusive. In this study, we found that knocking-down Nde1 expression by lentiviral transduction of specific shRNAs markedly inhibited osteoclastogenesis in vitro by attenuating the proliferation, survival, and differentiation of osteoclast precursor cells via suppression of signaling pathways downstream of M-CSF and RANKL as well as osteoclast differentiation transcription factor NFATc1. To dissect how NDEL1 regulates osteoclasts and bone homeostasis, we generated Ndel1 conditional knockout mice in myeloid osteoclast precursors (Ndel1ΔlysM) by crossing Ndel1-floxed mice with LysM-Cre mice on C57BL/6J background. The Ndel1ΔlysM mice developed normally. The µCT analysis of distal femurs and in vitro osteoclast differentiation and functional assays in cultures unveiled the similar bone mass in both trabecular and cortical bone compartments as well as intact osteoclastogenesis, cytoskeleton organization, and bone resorption in Ndel1ΔlysM mice and cultures. Therefore, our results reveal a novel role of NDE1 in regulation of osteoclastogenesis and demonstrate that NDEL1 is dispensable for osteoclast differentiation and function.


Subject(s)
Cytoplasmic Dyneins/metabolism , Macrophage Colony-Stimulating Factor/metabolism , Microtubule-Associated Proteins/metabolism , Osteogenesis , RANK Ligand/metabolism , Signal Transduction , Actin Cytoskeleton/metabolism , Animals , Bone Marrow/pathology , Bone Resorption/pathology , Bone and Bones/pathology , Cell Differentiation , Cell Proliferation , Cell Survival , Homeostasis , Mice, Inbred C57BL , Mice, Knockout , Microtubules/metabolism , Monocytes/metabolism , Osteoclasts/metabolism , Osteoclasts/pathology
8.
Sci Rep ; 10(1): 8867, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32483262

ABSTRACT

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-ß/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy.


Subject(s)
Carcinoma, Merkel Cell/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Quinazolines/therapeutic use , Animals , Apoptosis/drug effects , Carcinoma, Merkel Cell/metabolism , Carcinoma, Merkel Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Phosphatidylinositol 3-Kinases/chemistry , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/pharmacology , Quinazolines/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Transplantation, Heterologous
9.
Int J Biol Sci ; 14(10): 1221-1231, 2018.
Article in English | MEDLINE | ID: mdl-30123071

ABSTRACT

Purpose: Small cell lung cancer (SCLC) is highly lethal with no effective therapy. Wee1 kinase inhibitor AZD1775 (MK-1775) and mTOR kinase inhibitor MLN0128 (TAK228) are in clinical trials for relapsed SCLC and recurrent lung cancer, respectively. However, there is no preclinical data combining these two drugs in human cancers. Methods: In this study, we set to investigate the combinatorial anti-tumor effects of AZD1775 and MLN0128 on two human SCLC cell lines H69 and H82 in vitro and in vivo. Results: We have found that AZD1775 or MLN0128 treatment results in remarkably suppressed cell proliferation and increased cell death in vitro, what's more, the salient finding here is the potent anti-tumor effect observed in combinatorial treatment in H82 xenograft tumor. Importantly, we have first observed marked induction of ER stress and CHOP-dependent SCLC cell apoptosis in MLN0128 and AZD1775-primed cells. Conclusion: Our study has first provided preclinical evidence that combination of AZD1775 and MLN0128 could be a novel effective therapy for advanced SCLC patients.


Subject(s)
Apoptosis/drug effects , DNA Damage/drug effects , Endoplasmic Reticulum Stress/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Apoptosis/genetics , Benzoxazoles/pharmacology , Cell Line, Tumor , DNA Damage/genetics , Endoplasmic Reticulum Stress/drug effects , Humans , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Pyrimidinones/pharmacology , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
10.
J Clin Diagn Res ; 10(11): ED10-ED11, 2016 Nov.
Article in English | MEDLINE | ID: mdl-28050381

ABSTRACT

Cold antibodies are mostly immunoglobulin M, which interact with red cell antigens at lower temperatures (<37°C). The analysis of samples from subjects with cold antibodies in automated haematology analysers may show abnormal Red Blood Corpuscles (RBC) indices and changes in histogram. High Mean Corpuscular Haemoglobin (MCH) and Mean Haemoglobin Concentration (MCHC) along with plateau effect beyond 110fl at Upper Discriminator (RU) end of RBC histogram are good indicators of presence of cold antibodies in plasma. Cold antibodies in plasma must be considered while reporting the peripheral smear in presence of plateau effect beyond 110fl at RU end of RBC histogram.

11.
Oncotarget ; 7(6): 6576-92, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26536665

ABSTRACT

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.


Subject(s)
Apoptosis/drug effects , Benzoxazoles/pharmacology , Carcinoma, Merkel Cell/pathology , Cell Proliferation/drug effects , Pyrimidines/pharmacology , Skin Neoplasms/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Azepines/pharmacology , Blotting, Western , Carcinoma, Merkel Cell/drug therapy , Carcinoma, Merkel Cell/metabolism , Cellular Senescence , Drug Synergism , Drug Therapy, Combination , Female , Humans , Immunoenzyme Techniques , Mice , Mice, Inbred NOD , Mice, SCID , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/drug therapy , Skin Neoplasms/metabolism , Triazoles/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
12.
Epigenetics ; 10(6): 460-6, 2015.
Article in English | MEDLINE | ID: mdl-25941994

ABSTRACT

Pathologic c-Myc expression is frequently detected in human cancers, including Merkel cell carcinoma (MCC), an aggressive skin cancer with no cure for metastatic disease. Bromodomain protein 4 (BRD4) regulates gene transcription by binding to acetylated histone H3 lysine 27 (H3K27Ac) on the chromatin. Super-enhancers of transcription are identified by enrichment of H3K27Ac. BET inhibitor JQ1 disrupts BRD4 association with super-enhancers, downregulates proto-oncogenes, such as c-Myc, and displays antitumor activity in preclinical animal models of human cancers. Here we show that an enhancer proximal to the c-Myc promoter is enriched in H3K27Ac and associated with high occupancy of BRD4, and coincides with a putative c-Myc super-enhancer in MCC cells. This observation is mirrored in tumors from MCC patients. Importantly, depleted BRD4 occupancy at the putative c-Myc super-enhancer region by JQ1 correlates with decreased c-Myc expression. Thus, our study provides initial evidence that super-enhancers regulate c-Myc expression in MCC.


Subject(s)
Carcinoma, Merkel Cell/genetics , Epigenesis, Genetic/genetics , Nuclear Proteins/genetics , Proto-Oncogene Proteins c-myb/biosynthesis , Skin Neoplasms/genetics , Transcription Factors/genetics , Acetylation/drug effects , Animals , Apoptosis/drug effects , Azepines/administration & dosage , Carcinoma, Merkel Cell/drug therapy , Carcinoma, Merkel Cell/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatin , Enhancer Elements, Genetic/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Mice , Neoplasm Metastasis , Nuclear Proteins/metabolism , Promoter Regions, Genetic , Protein Binding , Proto-Oncogene Proteins c-myb/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/metabolism , Transcription Factors/metabolism , Triazoles/administration & dosage , Xenograft Model Antitumor Assays
13.
Cancer Res ; 74(23): 7090-102, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25277525

ABSTRACT

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus, we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by using the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathologic c-Myc activation. Moreover, JQ1 potently abrogates c-Myc expression in MCC cells and causes marked G1 cell-cycle arrest. Mechanistically, JQ1-induced cell-cycle arrest coincides with downregulation of cyclin D1 and upregulation of p21, p27, and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27, or p57 by shRNA partially protects cells from JQ1-induced cell-cycle arrest. In addition, c-Myc knockdown by shRNA generates significant cell-cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence, indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc.


Subject(s)
Azepines/pharmacology , Carcinoma, Merkel Cell/drug therapy , Carcinoma, Merkel Cell/genetics , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Proto-Oncogene Proteins c-myc/genetics , Triazoles/pharmacology , Animals , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Down-Regulation/drug effects , Down-Regulation/genetics , Female , G1 Phase Cell Cycle Checkpoints/drug effects , G1 Phase Cell Cycle Checkpoints/genetics , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , HEK293 Cells , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Signal Transduction/drug effects , Signal Transduction/genetics , Xenograft Model Antitumor Assays/methods
14.
Cancer Lett ; 344(2): 272-281, 2014 Mar 28.
Article in English | MEDLINE | ID: mdl-24262658

ABSTRACT

Merkel cell carcinoma (MCC) is an aggressive skin cancer with rising incidence. In this study, we demonstrate that mTOR activation and suppressed autophagy is common in MCCs. mTOR inhibition in two primary human MCC cell lines induces autophagy and cell death that is independent of caspase activation but can be attenuated by autophagy inhibition. This is the first study to evaluate mTOR and autophagy in MCC. Our data suggests a potential role of autophagic cell death upon mTOR inhibition and thus uncovers a previously underappreciated role of mTOR signaling and cell survival, and merits further studies for potential therapeutic targets.


Subject(s)
Carcinoma, Merkel Cell/enzymology , Carcinoma, Merkel Cell/pathology , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , TOR Serine-Threonine Kinases/metabolism , Amino Acid Chloromethyl Ketones/pharmacology , Carcinoma, Merkel Cell/drug therapy , Caspases/metabolism , Cell Line, Tumor , Cell Survival/physiology , Enzyme Activation , Formaldehyde , Humans , Paraffin Embedding , Phagosomes/enzymology , Phagosomes/metabolism , Protein Kinase Inhibitors/pharmacology , Skin Neoplasms/drug therapy , TOR Serine-Threonine Kinases/antagonists & inhibitors , Tissue Fixation , Up-Regulation
16.
J Proteomics Bioinform ; 6: 275-282, 2013 Nov 25.
Article in English | MEDLINE | ID: mdl-25284964

ABSTRACT

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin. The incidence has been quadrupled with a 5-year mortality rate of 46%, presently there is no cure for metastatic disease. Despite the contribution of Merkel cell polyomavirus, the molecular events of MCC carcinogenesis are poorly defined. To better understand MCC carcinogensis, we have performed the first quantitative proteomic comparison of formalin-fixed, paraffin-embedded (FFPE) MCC tissues using another neuroendocrine tumor (carcinoid tumor of the lung) as controls. Bioinformatic analysis of the proteomic data has revealed that MCCs carry distinct protein expression patterns. Further analysis of significantly over-expressed proteins suggested the involvement of MAPK, PI3K/Akt/mTOR, wnt, and apoptosis signaling pathways. Our previous study and that from others have shown mTOR activation in MCCs. Therefore, we have focused on two downstream molecules of the mTOR pathway, lactate dehydrogenase B (LDHB) and heterogeneous ribonucleoprotein F (hnRNPF). We confirm over-expression of LDHB and hnRNPF in two primary human MCC cell lines, 16 fresh tumors, and in the majority of 80 tissue microarray samples. Moreover, mTOR inhibition suppresses LDHB and hnRNPF expression in MCC cells. The results of the current study provide insight into MCC carcinogenesis and provide rationale for mTOR inhibition in pre-clinical studies.

17.
Virol J ; 5: 99, 2008 Aug 23.
Article in English | MEDLINE | ID: mdl-18721481

ABSTRACT

The enormous genetic variability reported in HIV-1 has posed problems in the treatment of infected individuals. This is evident in the form of HIV-1 resistant to antiviral agents, neutralizing antibodies and cytotoxic T lymphocytes (CTLs) involving multiple viral gene products. Based on this, it has been suggested that a comprehensive analysis of the polymorphisms in HIV proteins is of value for understanding the virus transmission and pathogenesis as well as for the efforts towards developing anti-viral therapeutics and vaccines. This study, for the first time, describes an in-depth analysis of genetic variation in Vpr using information from global HIV-1 isolates involving a total of 976 Vpr sequences. The polymorphisms at the individual amino acid level were analyzed. The residues 9, 33, 39, and 47 showed a single variant amino acid compared to other residues. There are several amino acids which are highly polymorphic. The residues that show ten or more variant amino acids are 15, 16, 28, 36, 37, 48, 55, 58, 59, 77, 84, 86, 89, and 93. Further, the variant amino acids noted at residues 60, 61, 34, 71 and 72 are identical. Interestingly, the frequency of the variant amino acids was found to be low for most residues. Vpr is known to contain multiple CTL epitopes like protease, reverse transcriptase, Env, and Gag proteins of HIV-1. Based on this, we have also extended our analysis of the amino acid polymorphisms to the experimentally defined and predicted CTL epitopes. The results suggest that amino acid polymorphisms may contribute to the immune escape of the virus. The available data on naturally occurring polymorphisms will be useful to assess their potential effect on the structural and functional constraints of Vpr and also on the fitness of HIV-1 for replication.


Subject(s)
Epitopes, T-Lymphocyte/immunology , Gene Products, vpr/chemistry , Genes, vpr , HIV Infections/immunology , HIV-1/genetics , Polymorphism, Genetic , T-Lymphocytes, Cytotoxic/immunology , Amino Acid Sequence , Gene Products, vpr/genetics , Gene Products, vpr/immunology , HIV Infections/virology , HIV-1/immunology , Humans , Molecular Sequence Data , Sequence Alignment
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