1887

Abstract

The human immunodeficiency virus type 1 (HIV-1) epidemic in India is predominantly caused by genetic subtype C, though other minor subtypes have also been reported. One of the major accessory proteins of HIV-1, namely Vpr, is known to influence key steps in viral replication, cell cycle progression, promoter activation, apoptosis and pathogenesis. Therefore, we carried out a genetic and functional analysis of the Vpr variants from eight HIV-1-infected individuals from north India. The sequence analyses revealed that six of eight samples clustered with ancestral subtype C. Remarkably, five of these showed a conserved and region-specific L64P mutation, located in the predicted third -helix. This change adversely affected their ability to activate the HIV-1 long terminal repeat promoter without compromising their ability to cause apoptosis. Bootscan, phylogenetic and SimPlot analysis of the remaining two samples (VprS2 and A6) revealed very interesting mosaic genomes derived from B, C and D subtypes. The N-terminal half of the VprS2 gene consisted of genomic segments derived from subtypes B/D, C and D but the C-terminal half was derived predominantly from subtype C. Interestingly the N-terminal half of sample A6 also showed similar B/D, C and D inter-subtype recombinant structure but the C-terminal half was entirely derived from the consensus B subtype. Multiple breakpoints in a short stretch of 291 nt encoding the Vpr gene strongly suggest that this region is a potential hot-spot for the formation of inter-subtype recombinants and also highlight the importance of the rapidly evolving HIV-1 epidemic in the north Indian region due to multiple genetic subtypes.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.011080-0
2009-11-01
2019-11-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/11/2768.html?itemId=/content/journal/jgv/10.1099/vir.0.011080-0&mimeType=html&fmt=ahah

References

  1. Adachi, A., Gendelman, H. E., Koenig, S., Folks, T., Willey, R., Rabson, A. & Martin, M. A. ( 1986; ). Production of acquired immunodeficiency syndrome-associated retrovirus in human and non-human cells transfected with an infectious molecular clone. J Virol 59, 284–291.
    [Google Scholar]
  2. Andersen, J. L., DeHart, J. L., Zimmerman, E. S., Ardon, O., Kim, B. & Jacquot, G. ( 2006; ). HIV-1 Vpr-induced apoptosis is cell cycle dependent and requires Bax but not ANT. PLoS Pathog 2, e127 [CrossRef]
    [Google Scholar]
  3. Bano, A. S., Gupta, N., Sharma, Y., Sood, V. & Banerjea, A. C. ( 2007a; ). HIV-1 VprB and C RNA cleavage by potent 10–23 DNAzymes that also cause reversal of G2 cell cycle arrest mediated by Vpr genes. Oligonucleotides 17, 465–472.[CrossRef]
    [Google Scholar]
  4. Bano, A. S., Gupta, N., Sood, V. & Banerjea, A. C. ( 2007b; ). Vpr from HIV-1 subtypes B and C exhibit significant differences in their ability to transactivate LTR-mediated gene expression and also in their ability to promote apoptotic DNA ladder formation. AIDS 21, 1832–1834.[CrossRef]
    [Google Scholar]
  5. Bhanja, P., Sengupta, S., Banerjee, B., Sarkar, K., Jana, S. & Chakrabarti, S. ( 2007; ). Detection of intersubtype recombinants with respect to env and nef genes of HIV-1 among female sex workers in Calcutta, India. Virus Res 130, 310–314.[CrossRef]
    [Google Scholar]
  6. Carr, J. K., Salminen, M. O., Albert, J., Sanders-Buell, E., Gotte, D. & Birx, D. L. ( 1998; ). Full genome sequences of human immunodeficiency virus type 1 subtypes G and A/G intersubtype recombinants. Virology 247, 22–31.[CrossRef]
    [Google Scholar]
  7. Cassol, S., Weniger, B. G., Babu, P. G., Salminen, M. O., Zheng, X. & Htoon, M. T. ( 1996; ). Detection of HIV type 1 env subtypes A, B, C, and E in Asia using dried blood spots: a new surveillance tool for molecular epidemiology. AIDS Res Hum Retroviruses 12, 1435–1441.[CrossRef]
    [Google Scholar]
  8. Dietrich, U., Grez, M., von Briesen, H., Panhans, B., Geissendorfer, M. & Kuhnel, H. ( 1993; ). HIV-1 strains from India are highly divergent from prototypic African and US/European strains, but are linked to a South African isolate. AIDS 7, 23–27.[CrossRef]
    [Google Scholar]
  9. European Commission, UNAIDS ( 1997; ). HIV-1 subtypes: implications for epidemiology, pathogenicity, vaccines and diagnostics. Workshop report from the European Commission (DG XII, INCO-DC) and the Joint United Nations Program on HIV/AIDS. AIDS 11, 17–36.
    [Google Scholar]
  10. Galai, N., Kalinkovich, A., Burstein, R., Vlahov, D. & Bentwich, Z. ( 1997; ). African HIV-1 subtype C and rate of progression among Ethiopian immigrants in Israel. Lancet 349, 180–181.[CrossRef]
    [Google Scholar]
  11. Galli, A., Lai, A., Corvasce, S., Saladini, F., Riva, C., Dehò, L., Caramma, I., Franzetti, M., Romano, L. & other authors ( 2008; ). Recombination analysis and structure prediction show correlation between breakpoint clusters and RNA hairpins in the pol gene of human immunodeficiency virus type 1 unique recombinant forms. J Gen Virol 89, 3119–3125.[CrossRef]
    [Google Scholar]
  12. Ganeshan, S., Dickover, R. E., Korber, B. T., Bryson, V. J. & Wolinsky, S. M. ( 1997; ). Human immunodeficiency virus type 1 genetic evolution in children with different rates of development of disease. J Virol 71, 663–677.
    [Google Scholar]
  13. Hu, D. J., Dondero, T. J., Rayfield, M. A., George, J. R., Schochetman, G. & Jaffe, H. W. ( 1996; ). The emerging genetic diversity of HIV. The importance of global surveillance for diagnostics, research, and prevention. JAMA 275, 210–216.[CrossRef]
    [Google Scholar]
  14. Husain, S., Goila, R., Shahi, S. & Banerjea, A. C. ( 1998; ). First report of a healthy Indian heterozygous for Δ32 mutant of HIV-1 co-receptor-CCR5 gene. Gene 207, 141–147.[CrossRef]
    [Google Scholar]
  15. Jacotot, E., Ravagnan, L., Loeffler, M., Ferri, K. F., Vieira, H. L. & Zamzami, N. ( 2000; ). The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J Exp Med 191, 33–46.[CrossRef]
    [Google Scholar]
  16. Jere, A., Tripathy, S., Agnihotri, K., Jadhav, S. & Paranjape, R. ( 2004; ). Genetic analysis of Indian HIV-1 nef: subtyping, variability and implications. Microbes Infect 6, 279–289.[CrossRef]
    [Google Scholar]
  17. Jian, H. & Zhao, L. J. ( 2003; ). Pro-apoptotic activity of HIV-1 auxiliary regulatory protein Vpr is subtype-dependent and potently enhanced by nonconservative changes of the leucine residue at position 64*. J Biol Chem 278, 44326–44330.[CrossRef]
    [Google Scholar]
  18. Le Rouzic, E. & Benichou, S. ( 2005; ). The Vpr protein from HIV-1: distinct roles along the viral life cycle. Retrovirology 2, 11 [CrossRef]
    [Google Scholar]
  19. Lole, K. S., Bollinger, R. C., Paranjape, R. S., Gadkari, D., Kulkarni, S. S., Novak, N. G., Ingersoll, R., Sheppard, H. W. & Ray, S. C. ( 1999; ). Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination. J Virol 73, 152–160.
    [Google Scholar]
  20. Lum, J. J., Cohen, O. J., Nie, Z., Weaver, J. G., Gomez, T. J. & Yao, X. J. ( 2003; ). Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis. J Clin Invest 111, 1547–1554.[CrossRef]
    [Google Scholar]
  21. Morellet, N., Bouaziz, S., Petitjean, P. & Roques, B. P. ( 2003; ). NMR structure of the HIV-1 regulatory protein VPR. J Mol Biol 327, 215–227.[CrossRef]
    [Google Scholar]
  22. Nei, M. & Gojobori, T. ( 1986; ). Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3, 418–426.
    [Google Scholar]
  23. Neogi, U., Sood, V., Goel, N., Wanchu, A. & Banerjea, A. C. ( 2008; ). Novel HIV-1 long terminal repeat (LTR) sequences of subtype B and mosaic intersubtype B/C recombinants in north India. Arch Virol 153, 1961–1966.[CrossRef]
    [Google Scholar]
  24. Ota, T. & Nei, M. ( 1994; ). Variance and covariances of the numbers of synonymous and nonsynonymous substitutions per site. Mol Biol Evol 11, 613–619.
    [Google Scholar]
  25. Robertson, D. L., Anderson, J. P., Bradac, J. A., Carr, J. K., Foley, B. & Funkhouser, R. K. ( 1999; ). HIV-1 nomenclature proposal: a reference guide to HIV-1 classification. In Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences, pp. 492–505. Edited by C. L. Kuiken, B. Foley, B. H. Hahn, B. Korber, F. McCutchan and P. A. Marx. Los Alamos, NM: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory.
  26. Rodriguez, M. A., Shen, C., Ratner, D., Paranjape, R. S., Kulkarni, S. S. & Chatterjee, R. ( 2007; ). Genetic and functional characterization of the LTR of HIV-1 subtypes A and C circulating in India. AIDS Res Hum Retroviruses 23, 1428–1433.[CrossRef]
    [Google Scholar]
  27. Salminen, M. O., Carr, J. K., Burke, D. S. & McCutchan, F. E. ( 1995; ). Identification of breakpoints in intergenotypic recombinants of HIV type 1 by bootscanning. AIDS Res Hum Retroviruses 11, 1423–1425.[CrossRef]
    [Google Scholar]
  28. Takebe, Y., Uenishi, R. & Li, X. ( 2008; ). Global molecular epidemiology of HIV: understanding the genesis of AIDS pandemic. Adv Pharmacol 56, 1–25.
    [Google Scholar]
  29. Thotala, D., Schafer, E. A., Majumder, B., Janket, M. L., Wagner, M. & Srinivasan, A. ( 2004; ). Structure–functional analysis of human immunodeficiency virus type 1 (HIV-1) Vpr: role of leucine residues on Vpr-mediated transactivation and virus replication. Virology 328, 89–100.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.011080-0
Loading
/content/journal/jgv/10.1099/vir.0.011080-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error