Comparative Genetic Variability in HIV-1 Subtype C vpu Gene in Early Age Groups of Infants

Author(s): Uma Sharma, Poonam Gupta, Sunil Gupta, S. Venkatesh, Mohammad Husain*.

Journal Name: Current HIV Research

Volume 16 , Issue 1 , 2018

Become EABM
Become Reviewer

Graphical Abstract:


Objective: Identifying the genetic variability in vertically transmitted viruses in early infancy is important to understand the disease progression. Being important in HIV-1 disease pathogenesis, vpu gene, isolated from young infants was investigated to understand the viral characteristics.

Method: Blood samples were obtained from 80 HIV-1 positive infants, categorized in two age groups; acute (<6 months) and early (>6-18 months). A total of 77 PCR positive samples, amplified for vpu gene, were sequenced and analyzed.

Results: 73 isolates belonged to subtype C. Analysis of heterogeneity of amino acid sequences in infant groups showed that in the sequences of acute age group both insertions and deletions were present while in the early age group only deletions were present. In the acute age group, a deletion of 3 residues (RAE) in the first alfa helix in one sequence and insertions of 1-2 residues (DM, GH, G and H) in the second alfa helix in 4 sequences were observed. In the early age group, deletion of 2 residues (VN) in the cytoplasmic tail region in 2 sequences was observed. Length of the amino terminal was observed to be gradually increasing with the increasing age of the infants. Protein Variation Effect Analyzer software showed that deleterious mutations were more in the acute than the early age group. Entropy analysis revealed that heterogeneity of the residues was comparatively higher in the sequences of acute than the early age group.

Conclusion: Mutations observed in the helixes may affect the conformation and lose the ability to degrade CD4 receptors. Heterogeneity was decreasing with the increasing ages of the infants, indicating positive selection for robust virion survival.

Keywords: HIV-1, pediatric AIDS, vpu, amino acid motifs, genetic heterogeneity, MTCT.

Little K, Thorne C, Luo C, et al. Disease progression in children with vertically-acquired HIV infection in sub-Saharan Africa: reviewing the need for HIV treatment. Curr HIV Res 2007; 5(2): 139-53.
Ahmad N. The vertical transmission of human immunodeficiency virus type 1: molecular and biological properties of the virus. Crit Rev Clin Lab Sci 2005; 42(1): 1-34.
Ahmad N. Molecular mechanism of HIV-1 vertical transmission and pathogenesis in infants. Adv Pharmacol 2008; 56: 453-508.
Ahmad N. Molecular mechanisms of HIV-1 mother-to-child transmission and infection in neonatal target cells. Life Sci 2011; 88(21-22): 980-6.
Cohen EA, Terwilliger EF, Sodroski JG, Haseltine WA. Identification of a protein encoded by the vpu gene of HIV-1. Nature 1988; 334: 532-4.
Strebel K, Klimkait T, Martin M. A novel gene of HIV-1, vpu, and its 16-kilodalton product. Science 1988; 241(4870): 1221-3.
Maldarelli F, Chen MY, Willey RL, Strebel K. Human immunodeficiency virus type 1 Vpu protein is an oligomeric type I integral membrane protein. J Virol 1993; 67(8): 5056-61.
Tokarev A and, Guatelli J. Misdirection of membrane trafficking by HIV-1 Vpu and Nef. Keys to viral virulence and persistence. Cell Logist 2011; 1(3): 90-102.
Schwartz S, Felber BK, Fenyo EM, Pavlakis GN. Env and vpu proteins of human immunodeficiency virus type 1 are produced from multiple bicistronic mRNAs. J Virol 1990; 64: 5448-56.
Willey RL, Maldarelli F, Martin MA, Strebel K. Human Immunodeficiency Virus Type 1 Vpu Protein Induces Rapid Degradation of CD4. J Virol 1992; 66(12): 7193-200.
Crise B, Buonocore L and, Rose JK. CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor. J Virol 1990; 64(11): 5585-93.
Schubert U, Anton LC, Bacik I, Cox JH, Bour S. CD4 Glycoprotein Degradation Induced by Human Immunodeficiency Virus Type 1 Vpu Protein Requires the Function of Proteasomes and the Ubiquitin-Conjugating Pathway. J Virol 1998; 72: 2280-8.
Terwilliger EF, Cohen EA, Lu YC, Sodroski JG, Haseltine WA. Functional role of human immunodeficiency virus type 1 vpu. Proceedings of the National Academy of Science of the Unites States of America. Proc Natl Acad Sci 1989; 86: 5163-7.
Bour S, Strebel K. The HIV-1 Vpu protein: a multifunctional enhancer of viral particle release. Microbes Infect 2003; 5: 1029-39.
Lee CN, Wang WK, Fan WS, et al. Determination of Human Immunodeficiency Virus Type 1 Subtypes in Taiwan by vpu Gene Analysis. J Clin Microbiol 2000; 38(7): 2468-74.
Tamura K, Peterson D, Peterson N, et al. MEGA 5: Molecular Evolutionary Genetics Analysis using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony Methods. Mol Biol Evol 2011; 28: 2731-9.
Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucle Acids Symp Ser 1999; 41: 95-8.
Korber B. HIV Signature and Sequence Variation Analysis. Computational Analysis of HIV Molecular Sequences. In: Rodrigo AG, Learn GH, Eds. Allen G . Dordrecht, Netherlands: Kluwer Academic Publishers 2000; pp. 55-72.
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 2015; 31(16): 2745-7.
Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLoS ONE 2012; 7(10): e46688.
Choi Y. A Fast Computation of Pairwise Sequence Alignment Scores Between a Protein and a Set of Single-Locus Variants of Another Protein. In: Proceedings of the ACM Conference on Bioinformatics, Computational Biology and Biomedicine (BCB ’12). ACM: New York, NY, USA 2012; pp. 414-17.
Siddappa NB, Dash PK, Mahadevan A, et al. Identification of Subtype C Human Immunodeficiency Virus Type 1 by Subtype-Specific PCR and its Use in the Characterization of Viruses Circulating in the Southern Parts of India. J Clin Microbiol 2004; 42(6): 2742-51.
Sharma U, Gupta P, Singhal M, et al. Comparative Genetic Variability in HIV-1 Subtype C nef Gene in Early Age Groups of Infants. J Med Virol 2017; 89(9): 1606-19.
Geffin R, Wolf D, Muller R, et al. Functional and Structural defects in HIV type 1 nef genes derived from pediatric long-term survivors. AIDS Res Hum Retroviruses 2000; 16: 1855-68.
Gojobori T, Yamaguchi Y, Ikeo K, Mizokami M. Evolution of pathogenic viruses with special reference to the rates of synonymous and nonsynonymous substitutions. Jpn J Genet 1994; 69: 481-8.
Strebel K, Klimkait T, Maldarelli F, Martin MA. Molecular and biochemical analyses of human immunodeficiency virus type 1 vpu protein. J Virol 1989; 63(9): 3784-91.
McCormick-Davis C, Dalton SB, Singh DK, Stephens EB. Comparison of Vpu Sequences from Diverse Geographical Isolates of HIV Type 1 Identifies the Presence of Highly Variable Domains, Additional Invariant Amino Acids, and a Signature Sequence Motif Common to Subtype C Isolates. AIDS Res Hum Retroviruses 2000; 16(11): 1089-95.
Cordes FS, Kukol A, Forrest LR, et al. The structure of the HIV-1 Vpu ion channel: modelling and simulation studies. Biochimica et Biophysica Acta 2001; 1512: 291-8.
Fischer WB. Vpu from HIV-1 on an atomic scale: experiments and computer simulations. FEBS Lett 2003; 552: 39-46.
Mehnert T, Routh A, Judge PJ, Lam YH, Fischer D, et al. Biophysical characterization of Vpu from HIV-1 suggests a channel-pore dualism. Proteins 2008; 70: 1488-97.
Padhi S, Burri RR, Jameel S, Priyakumar UD. Atomistic Detailed Mechanism and Weak Cation-Conducting Activity of HIV-1 Vpu Revealed by Free Energy Calculations. PLoS ONE 2014; 9(11): e112983.
Bonifacino JS, Traub LM. Signals for sorting of transmembrane proteins to endosome and lysosomes. Annu Rev Biochem 2003; 72: 395-447.
Ruiz A, Hill MS, Schmitt K, Guatelli J, Stephens EB. Requirements of the membrane proximal tyrosine and dileucine-based sorting signals for efficient transport of the subtype C Vpu protein to the plasma membrane and in virus release. Virol J 2008; 378(1): 58-68.
Tiganos E, Yao XJ, Friborg J, Daniel N, Cohen EA. Putative α Helical Structures in the Human Immunodeficiency Virus Type 1 Vpu Protein and CD4 Are Involved in Binding and Degradation of the CD4 Molecule. J Virol 1997; 71(6): 4452-60.
Hill MS, Ruiz A, Schmitt K, Stephens EB. Identification of amino acids within the second alpha helical domain of the human immunodeficiency virus type 1 Vpu that are critical for preventing CD4 cell surface expression. Virol J 2010; 397(1): 104-12.
Estrabaud E, Le Rouzic E, Lopez-Verges S, et al. Regulated degradation of the HIV-1 Vpu protein through a bTrCP-independent pathway limits the release of viral particles. PLoS Pathog 2007; 3(7): e104.
Nomaguchi M, Fujita M, Adachi A. Role of HIV-1 Vpu protein for virus spread and pathogenesis. Microbes and Infect 2008; 10: 960-7.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2018
Page: [64 - 76]
Pages: 13
DOI: 10.2174/1570162X16666180219154601

Article Metrics

PDF: 24
PRC: 1