1887

Chapter 9 : Host-Driven Plasticity of the Human Immunodeficiency Virus Genome

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817213/9781555817084_Chap09-1.gif /docserver/preview/fulltext/10.1128/9781555817213/9781555817084_Chap09-2.gif

Abstract:

This chapter describes the scale and driving force behind the profound genomic plasticity of human immunodeficiency virus (HIV). It discusses the intense interplay between the virus and the immune system of the host. It also speculates on the impact of this variability on the prospects for the development of effective vaccines and novel therapies. The evolution of HIV is, as with all organisms, driven predominantly by Darwinian natural selection that comprises two fully independent but essential components. The first is the production of random mutations that form a pool of organisms differing slightly in pheno-type. Second, is selective pressure that drives the rapid and spectacular evolution of HIV. Neutralizing antibodies produced are relatively type specific and targeted to one or two regions of the envelope glycoprotein that are relatively free to mutate without the virus taking a significant fitness hit. The options open to the virus for escaping cytotoxic T lymphocyte (CTL) recognition are numerous. First, it may alter one of the amino acids in the epitope necessary for recognition by the corresponding CTL T-cell receptor. In addition to the extreme selection pressure exerted on HIV by the immune system, there is an additional "artificial" pressure driving HIV evolution, particularly in industrialized countries.

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9

Key Concept Ranking

Equine infectious anemia virus
0.5141509
Highly Active Antiretroviral Therapy
0.40958166
0.5141509
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Mechanisms of genomic variation. Three main mechanisms contribute to the extensive genomic variation within the HIV genome. (A) In the absence of a proofreading function, transcription errors made by the viral reverse transcriptase enzyme during the synthesis of a DNA copy of the RNA genome result in (nearly) random mutations that accumulate if beneficial. (B) Template switching of reverse transcriptase from one RNA template to another. Distinct mutations in regions either side of the switching event can then become incorporated into a single genome. (C) Template switching between distinct viral subtypes. In the rare cases of simultaneous infection with two viral subtypes, switching can occur yielding a radically new virus with a mosaic genome. Adapted from .

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Phylogenetic relationships between strains of SIV infecting diverse species of African primates. Shown is the degree of heterogeneity within a portion of the gene, with the bar representing 0.1 replacement per site. Adapted from . doi:10.1128/9781555817213.ch09f02

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Mosaic genome of SIVcpz (and therefore HIV-1). Sequence analyses reveal that the LTRs and the , and genes are derived from the SIVrcm lineage whereas the gene and the 3′ exons of and originate from the SIVgsn/mus/mon lineage. The origin of the 5′ exons of and is unclear. Adapted from . doi:10.1128/9781555817213.ch09f03

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

Comparison of genomic variability. The degree of variation within the HIV envelope glycoprotein in a long-term singly infected individual is comparable to the global variation of the influenza A H3 hemagglutinin protein in 1 year. Variation of the envelope gene within one African nation (Democratic Republic of Congo) is dramatically higher. Adapted from . doi:10.1128/9781555817213.ch09f04

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5
FIGURE 5

Rapid and extensive variation within a CTL epitope. Ultradeep pyrosequencing of the SIVmac gene after infection of cynomolgus macaques reveals the appearance of variants within only 17 days. Such variants, particularly those with mutations within the RM9 CTL epitope, come to dominate the viral population during the ensuing weeks. Adapted from . doi:10.1128/9781555817213.ch09f05

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6
FIGURE 6

Escape from virus-specific CTL recognition. A CTL epitope (blue) within a viral protein is normally processed, bound to an MHC-I molecule, and presented via the endoplasmic reticulum (ER)/Golgi complex on the surface of the cell to be recognized by the corresponding T-cell receptor (TCR) expressed by a CTL. Mutations resulting in the substitution (red) of an amino acid normally recognized by the TCR may result in suboptimal or even no recognition. Mutations resulting in changes of an “anchor” residue can inhibit formation of the MHC-I/β2-microglobulin/epitope complex, preventing expression at the cell surface. Finally, changes in amino acids flanking the epitope may prevent even the wild-type sequence from being processed and expressed. Adapted from . doi:10.1128/9781555817213.ch09f06

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817213.chap9
1. Abecasis, A. B.,, P. Lemey,, N. Vidal,, T. de Oliveira,, M. Peeters,, R. Camacho,, B. Shapiro,, A. Rambaut,, and A. M. Vandamme. 2007. Recombination confounds the early evolutionary history of human immunodeficiency virus type 1: subtype G is a circulating recombinant form. J. Virol. 81:85438551.
2. Aghokeng, A. F.,, A. Ayouba,, E. Mpoudi-Ngole,, S. Loul,, F. Liegeois,, E. Delaporte,, and M. Peeters. 2010. Extensive survey on the prevalence and genetic diversity of SIVs in primate bushmeat provides insights into risks for potential new cross-species transmissions. Infect. Genet. Evol. 10:386396.
3. Allen, T. M.,, D. H. O'Connor,, P. Jing,, J. L. Dzuris,, B. R. Mothe,, T. U. Vogel,, E. Dunphy,, M. E. Liebl,, C. Emerson,, N. Wilson,, K. J. Kunstman,, X. Wang,, D. B. Allison,, A. L. Hughes,, R. C. Desrosiers,, J. D. Altman,, S. M. Wolinsky,, A. Sette,, and D. I. Watkins. 2000. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407:386390.
4. Bailes, E.,, F. Gao,, F. Bibollet-Ruche,, V. Courgnaud,, M. Peeters,, P. A. Marx,, B. H. Hahn,, and P. M. Sharp. 2003. Hybrid origin of SIV in chimpanzees. Science 300:1713.
5. Bimber, B. N.,, B. J. Burwitz,, S. O'Connor,, A. Detmer,, E. Gostick,, S. M. Lank,, D. A. Price,, A. Hughes,, and D. O'Connor. 2009. Ultradeep pyrosequencing detects complex patterns of CD8+ T-lymphocyte escape in simian immunodeficiency virus-infected macaques. J. Virol. 83:82478253.
6. Borrow, P.,, H. Lewicki,, X. Wei,, M. S. Horwitz,, N. Peffer,, H. Meyers,, J. A. Nelson,, J. E. Gairin,, B. H. Hahn,, M. B. Oldstone,, and G. M. Shaw. 1997. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3:205211.
7. Bradney, A. P.,, S. Scheer,, J. M. Crawford,, S. P. Buchbinder,, and D. C. Montefiori. 1999. Neutralization escape in human immunodeficiency virus type 1-infected long-term nonprogressors. J. Infect. Dis. 179:12641267.
8. Braibant, M.,, H. Agut,, C. Rouzioux,, D. Costagliola,, B. Autran,, and F. Barin. 2008. Characteristics of the env genes of HIV type 1 quasispecies in long-term nonprogressors with broadly neutralizing antibodies. J. Acquir. Immune Defic. Syndr. 47:274284.
9. Bunnik, E. M.,, L. Pisas,, A. C. van Nuenen,, and H. Schuitemaker. 2008. Autologous neutralizing humoral immunity and evolution of the viral envelope in the course of subtype B human immunodeficiency virus type 1 infection. J. Virol. 82:79327941.
10. Cao, Y.,, L. Qin,, L. Zhang,, J. Safrit,, and D. D. Ho. 1995. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N. Engl. J. Med. 332:201208.
11. Carotenuto, P.,, D. Looij,, L. Keldermans,, F. de Wolf,, and J. Goudsmit. 1998. Neutralizing antibodies are positively associated with CD4+ T-cell counts and T-cell function in long-term AIDS-free infection. AIDS 12:15911600.
12. Cecilia, D.,, C. Kleeberger,, A. Munoz,, J. V. Giorgi,, and S. Zolla-Pazner. 1999. A longitudinal study of neutralizing antibodies and disease progression in HIV-1-infected subjects. J. Infect. Dis. 179:13651374.
13. Chase, A. J.,, A. R. Sedaghat,, J. R. German,, L. Gama,, M. C. Zink,, J. E. Clements,, and R. F. Siliciano. 2007. Severe depletion of CD4+ CD25+ regulatory T cells from the intestinal lamina propria but not peripheral blood or lymph nodes during acute simian immunodeficiency virus infection. J. Virol. 81:1274812757.
14. Cheng-Mayer, C.,, D. Seto,, M. Tateno,, and J. A. Levy. 1988. Biologic features of HIV-1 that correlate with virulence in the host. Science 240:8082.
15. Cheynier, R.,, S. Henrichwark,, F. Hadida,, E. Pelletier,, E. Oksenhendler,, B. Autran,, and S. Wain-Hobson. 1995. Clonal expansion of T cells and HIV genotypes in microdissected splenic white pulps indicates viral replication in situ and infiltration of HIV-specific cytotoxic T lymphocytes. Adv. Exp. Med. Biol. 374:173182.
16. Das, A. T.,, and B. Berkhout. 2010. HIV-1 evolution: frustrating therapies, but disclosing molecular mechanisms. Philos. Trans. R. Soc. Lond. B 365:19651973.
17. Dean, M.,, M. Carrington,, C. Winkler,, G. A. Huttley,, M. W. Smith,, R. Allikmets,, J. J. Goedert,, S. P. Buchbinder,, E. Vittinghoff,, E. Gomperts,, S. Donfield,, D. Vlahov,, R. Kaslow,, A. Saah,, C. Rinaldo,, R. Detels,, and S. J. O'Brien. 1996. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:18561862.
18. Delassus, S.,, R. Cheynier,, and S. Wain-Hobson. 1992. Nonhomogeneous distribution of human immunodeficiency virus type 1 proviruses in the spleen. J. Virol. 66:56425645.
19. Duda, A.,, L. Lee-Turner,, J. Fox,, N. Robinson,, S. Dustan,, S. Kaye,, H. Fryer,, M. Carrington,, M. McClure,, A. R. McLean,, S. Fidler,, J. Weber,, R. E. Phillips,, and A. J. Frater. 2009. HLA-associated clinical progression correlates with epitope reversion rates in early human immunodeficiency virus infection. J. Virol. 83:12281239.
20. Evans, D. T.,, D. H. O'Connor,, P. Jing,, J. L. Dzuris,, J. Sidney,, J. da Silva,, T. M. Allen,, H. Horton,, J. E. Venham,, R. A. Rudersdorf,, T. Vogel,, C. D. Pauza,, R. E. Bontrop,, R. DeMars,, A. Sette,, A. L. Hughes,, and D. I. Watkins. 1999. Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nat. Med. 5:12701276.
21. Fenyo, E. M.,, L. Morfeldt-Manson,, F. Chiodi,, B. Lind,, A. von Gegerfelt,, J. Albert,, E. Olausson,, and B. Asjo. 1988. Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J. Virol. 62:44144419.
22. Fernandez, C. S.,, I. Stratov,, R. De Rose,, K. Walsh,, C. J. Dale,, M. Z. Smith,, M. B. Agy,, S. L. Hu,, K. Krebs,, D. I. Watkins,, D. H. O'Connor,, M. P. Davenport,, and S. J. Kent. 2005. Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost. J. Virol. 79:57215731.
23. Frater, A. J.,, H. Brown,, A. Oxenius,, H. F. Gunthard,, B. Hirschel,, N. Robinson,, A. J. Leslie,, R. Payne,, H. Crawford,, A. Prendergast,, C. Brander,, P. Kiepiela,, B. D. Walker,, P. J. Goulder,, A. McLean,, and R. E. Phillips. 2007. Effective T-cell responses select human immunodeficiency virus mutants and slow disease progression. J. Virol. 81:67426751.
24. Friedrich, T. C.,, E. J. Dodds,, L. J. Yant,, L. Vojnov,, R. Rudersdorf,, C. Cullen,, D. T. Evans,, R. C. Desrosiers,, B. R. Mothe,, J. Sidney,, A. Sette,, K. Kunstman,, S. Wolinsky,, M. Piatak,, J. Lifson,, A. L. Hughes,, N. Wilson,, D. H. O'Connor,, and D. I. Watkins. 2004. Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nat. Med. 10:275281.
25. Frost, S. D.,, T. Wrin,, D. M. Smith,, S. L. Kosakovsky Pond,, Y. Liu,, E. Paxinos,, C. Chappey,, J. Galovich,, J. Beauchaine,, C. J. Petropoulos,, S. J. Little,, and D. D. Richman. 2005. Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. Proc. Natl. Acad. Sci. USA 102:1851418519.
26. Gao, F.,, E. Bailes,, D. L. Robertson,, Y. Chen,, C. M. Rodenburg,, S. F. Michael,, L. B. Cummins,, L. O. Arthur,, M. Peeters,, G. M. Shaw,, P. M. Sharp,, and B. H. Hahn. 1999. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397:436441.
27. Gao, F.,, L. Yue,, A. T. White,, P. G. Pappas,, J. Barchue,, A. P. Hanson,, B. M. Greene,, P. M. Sharp,, G. M. Shaw,, and B. H. Hahn. 1992. Human infection by genetically diverse SIVSM-related HIV-2 in west Africa. Nature 358:495499.
28. Gilbert, M. T.,, A. Rambaut,, G. Wlasiuk,, T. J. Spira,, A. E. Pitchenik,, and M. Worobey. 2007. The emergence of HIV/AIDS in the Americas and beyond. Proc. Natl. Acad. Sci. USA 104:1856618570.
29. Goulder, P. J.,, C. Brander,, Y. Tang,, C. Tremblay,, R. A. Colbert,, M. M. Addo,, E. S. Rosenberg,, T. Nguyen,, R. Allen,, A. Trocha,, M. Altfeld,, S. He,, M. Bunce,, R. Funkhouser,, S. I. Pelton,, S. K. Burchett,, K. McIntosh,, B. T. Korber,, and B. D. Walker. 2001. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412:334338.
30. Goulder, P. J.,, R. E. Phillips,, R. A. Colbert,, S. McAdam,, G. Ogg,, M. A. Nowak,, P. Giangrande,, G. Luzzi,, B. Morgan,, A. Edwards,, A. J. McMichael,, and S. Rowland-Jones. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3:212217.
31. Hahn, B. H.,, G. M. Shaw,, K. M. De Cock,, and P. M. Sharp. 2000. AIDS as a zoonosis: scientific and public health implications. Science 287:607614.
32. Hemelaar, J.,, E. Gouws,, P. D. Ghys,, and S. Osmanov. 2006. Global and regional distribution of HIV-genetic subtypes and recombinants in 2004. AIDS 20:W13W23.
33. Jakobsen, M. R.,, M. Tolstrup,, O. S. Sogaard,, L. B. Jorgensen,, P. R. Gorry,, A. Laursen,, and L. Ostergaard. 2010. Transmission of HIV-1 drug-resistant variants: prevalence and effect on treatment outcome. Clin. Infect. Dis. 50:566573.
34. Jung, A.,, R. Maier,, J. P. Vartanian,, G. Bocharov,, V. Jung,, U. Fischer,, E. Meese,, S. Wain-Hobson,, and A. Meyerhans. 2002. Recombination: multiply infected spleen cells in HIV patients. Nature 418:144.
35. Kalia, V.,, S. Sarkar,, P. Gupta,, and R. C. Montelaro. 2005. Antibody neutralization escape mediated by point mutations in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41. J. Virol. 79:20972107.
36. Kawashima, Y.,, K. Pfafferott,, J. Frater,, P. Matthews,, R. Payne,, M. Addo,, H. Gatanaga,, M. Fujiwara,, A. Hachiya,, H. Koizumi,, N. Kuse,, S. Oka,, A. Duda,, A. Prendergast,, H. Crawford,, A. Leslie,, Z. Brumme,, C. Brumme,, T. Allen,, C. Brander,, R. Kaslow,, J. Tang,, E. Hunter,, S. Allen,, J. Mulenga,, S. Branch,, T. Roach,, M. John,, S. Mallal,, A. Ogwu,, R. Shapiro,, J. G. Prado,, S. Fidler,, J. Weber,, O. G. Pybus,, P. Klenerman,, T. Ndung'u,, R. Phillips,, D. Heckerman,, P. R. Harrigan,, B. D. Walker,, M. Takiguchi,, and P. Goulder. 2009. Adaptation of HIV-1 to human leukocyte antigen class I. Nature 458:641645.
37. Keele, B. F.,, E. E. Giorgi,, J. F. Salazar-Gonzalez,, J. M. Decker,, K. T. Pham,, M. G. Salazar,, C. Sun,, T. Grayson,, S. Wang,, H. Li,, X. Wei,, C. Jiang,, J. L. Kirchherr,, F. Gao,, J. A. Anderson,, L. H. Ping,, R. Swanstrom,, G. D. Tomaras,, W. A. Blattner,, P. A. Goepfert,, J. M. Kilby,, M. S. Saag,, E. L. Delwart,, M. P. Busch,, M. S. Cohen,, D. C. Montefiori,, B. F. Haynes,, B. Gaschen,, G. S. Athreya,, H. Y. Lee,, N. Wood,, C. Seoighe,, A. S. Perelson,, T. Bhattacharya,, B. T. Korber,, B. H. Hahn,, and G. M. Shaw. 2008. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl. Acad. Sci. USA 105:75527557.
38. Keele, B. F.,, F. Van Heuverswyn,, Y. Li,, E. Bailes,, J. Takehisa,, M. L. Santiago,, F. Bibollet-Ruche,, Y. Chen,, L. V. Wain,, F. Liegeois,, S. Loul,, E. M. Ngole,, Y. Bienvenue,, E. Delaporte,, J. F. Brookfield,, P. M. Sharp,, G. M. Shaw,, M. Peeters,, and B. H. Hahn. 2006. Chimpanzee reservoirs of pandemic and nonpandemic HIV-1. Science 313:523526.
39. Keulen, W.,, C. Boucher,, and B. Berkhout. 1996. Nucleotide substitution patterns can predict the requirements for drug-resistance of HIV-1 proteins. Antiviral Res. 31:4557.
40. Kiepiela, P.,, A. J. Leslie,, I. Honeyborne,, D. Ramduth,, C. Thobakgale,, S. Chetty,, P. Rathnavalu,, C. Moore,, K. J. Pfafferott,, L. Hilton,, P. Zimbwa,, S. Moore,, T. Allen,, C. Brander,, M. M. Addo,, M. Altfeld,, I. James,, S. Mallal,, M. Bunce,, L. D. Barber,, J. Szinger,, C. Day,, P. Klenerman,, J. Mullins,, B. Korber,, H. M. Coovadia,, B. D. Walker,, and P. J. Goulder. 2004. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432:769775.
41. Kim, E.-Y.,, M. Busch,, K. Abel,, L. Fritts,, P. Bustamante,, J. Stanton,, D. Lu,, S. Wu,, J. Glowczwskie,, T. Rourke,, D. Bogdan,, M. Piatak, Jr.,, J. D. Lifson,, R. C. Desrosiers,, S. Wolinsky,, and C. J. Miller. 2005. Retroviral recombination in vivo: viral replication patterns and genetic structure of simian immunodeficiency virus (SIV) populations in rhesus macaques after simultaneous or sequential intravaginal inoculation with SIVmac239Δvpxvpr and SIVmac239Δnef. J. Virol. 79:48864895.
42. Korber, B.,, M. Muldoon,, J. Theiler,, F. Gao,, R. Gupta,, A. Lapedes,, B. H. Hahn,, S. Wolinsky,, and T. Bhattacharya. 2000. Timing the ancestor of the HIV-1 pandemic strains. Science 288:17891796.
43. Koup, R. A. 1994. Virus escape from CTL recognition. J. Exp. Med. 180:779782.
44. Kuiken, C.,, B. Foley,, T. Leitner,, C. Apetrei,, B. Hahn,, I. Mizrachi,, J. Mullins,, A. Rambaut,, S. Wolinsky,, and B. Korber (ed). 2010. HIV Sequence Compendium 2010. Los Alamos National Laboratory, Los Alamos, NM.d>
45. Larder, B. A.,, G. Darby,, and D. D. Richman. 1989. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243: 17311734.
46. Larder, B. A.,, and S. D. Kemp. 1989. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 246:11551158.
47. Lay, M. D.,, J. Petravic,, S. N. Gordon,, J. Engram,, G. Silvestri,, and M. P. Davenport. 2009. Is the gut the major source of virus in early simian immunodeficiency virus infection? J. Virol. 83:75177523.
48. Leslie, A. J.,, K. J. Pfafferott,, P. Chetty,, R. Draenert,, M. M. Addo,, M. Feeney,, Y. Tang,, E. C. Holmes,, T. Allen,, J. G. Prado,, M. Altfeld,, C. Brander,, C. Dixon,, D. Ramduth,, P. Jeena,, S. A. Thomas,, A. St John,, T. A. Roach,, B. Kupfer,, G. Luzzi,, A. Edwards,, G. Taylor,, H. Lyall,, G. Tudor-Williams,, V. Novelli,, J. Martinez-Picado,, P. Kiepiela,, B. D. Walker,, and P. J. Goulder. 2004. HIV evolution: CTL escape mutation and reversion after transmission. Nat. Med. 10:282289.
49. Liu, R.,, W. A. Paxton,, S. Choe,, D. Ceradini,, S. R. Martin,, R. Horuk,, M. E. MacDonald,, H. Stuhlmann,, R. A. Koup,, and N. R. Landau. 1996. Homozygous defect in HIV-coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367377.
50. Mahalanabis, M.,, P. Jayaraman,, T. Miura,, F. Pereyra,, E. M. Chester,, B. Richardson,, B. Walker,, and N. L. Haigwood. 2009. Continuous viral escape and selection by autologous neutralizing antibodies in drug-naive human immunodeficiency virus controllers. J. Virol. 83:662672.
51. Martinson, J. J.,, N. H. Chapman,, D. C. Rees,, Y. T. Liu,, and J. B. Clegg. 1997. Global distribution of the CCR5 gene 32-basepair deletion. Nat. Genet. 16:100103.
52. Matthews, P. C.,, A. J. Leslie,, A. Katzourakis,, H. Crawford,, R. Payne,, A. Prendergast,, K. Power,, A. D. Kelleher,, P. Klenerman,, J. Carlson,, D. Heckerman,, T. Ndung'u,, B. D. Walker,, T. M. Allen,, O. G. Pybus,, and P. J. Goulder. 2009. HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering. J. Virol. 83:46054615.
53. McKeating, J. A.,, J. Gow,, J. Goudsmit,, L. H. Pearl,, C. Mulder,, and R. A. Weiss. 1989. Characterization of HIV-1 neutralization escape mutants. AIDS 3:777784.
54. Menendez-Arias, L. 2010. Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res. 85:210231.
55. Monken, C. E.,, B. Wu,, and A. Srinivasan. 1995. High resolution analysis of HIV-1 quasispecies in the brain. AIDS 9:345349.
56. Montelaro, R. C.,, B. Parekh,, A. Orrego,, and C. J. Issel. 1984. Antigenic variation during persistent infection by equine infectious anemia virus, a retrovirus. J Biol Chem. 259:1053910544.
57. Moore, P. L.,, N. Ranchobe,, B. E. Lambson,, E. S. Gray,, E. Cave,, M. R. Abrahams,, G. Bandawe,, K. Mlisana,, S. S. Abdool Karim,, C. Williamson,, and L. Morris. 2009. Limited neutralizing antibody specificities drive neutralization escape in early HIV-subtype C infection. PLoS Pathog. 5:e1000598.
58. Morris, A.,, M. Marsden,, K. Halcrow,, E. S. Hughes,, R. P. Brettle,, J. E. Bell,, and P. Simmonds. 1999. Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations. J. Virol. 73:87208731.
59. Nakowitsch, S.,, H. Quendler,, H. Fekete,, R. Kunert,, H. Katinger,, and G. Stiegler. 2005. HIV-1 mutants escaping neutralization by the human antibodies 2F5, 2G12, and 4E10: in vitro experiments versus clinical studies. AIDS 19:19571966.
60. Neel, C.,, L. Etienne,, Y. Li,, J. Takehisa,, R. S. Rudicell,, I. N. Bass,, J. Moudindo,, A. Mebenga,, A. Esteban,, F. Van Heuverswyn,, F. Liegeois,, P. J. Kranzusch,, P. D. Walsh,, C. M. Sanz,, D. B. Morgan,, J. B. Ndjango,, J. C. Plantier,, S. Locatelli,, M. K. Gonder,, F. H. Leendertz,, C. Boesch,, A. Todd,, E. Delaporte,, E. Mpoudi-Ngole,, B. H. Hahn,, and M. Peeters. 2010. Molecular epidemiology of simian immunodeficiency virus infection in wild-living gorillas. J. Virol. 84:14641476.
61. Nerrienet, E.,, M. L. Santiago,, Y. Foupouapouognigni,, E. Bailes,, N. I. Mundy,, B. Njinku,, A. Kfutwah,, M. C. Muller-Trutwin,, F. Barre-Sinoussi,, G. M. Shaw,, P. M. Sharp,, B. H. Hahn,, and A. Ayouba. 2005. Simian immunodeficiency virus infection in wild-caught chimpanzees from Cameroon. J. Virol. 79:13121319.
62. Novitsky, V.,, R. Wang,, L. Margolin,, J. Baca,, S. Moyo,, R. Musonda,, and M. Essex. 2010. Dynamics and timing of in vivo mutations at Gag residue 242 during primary HIV-1 subtype C infection. Virology 403:3746.
63. O'Brien, S. J.,, X. Gao,, and M. Carrington. 2001. HLA and AIDS: a cautionary tale. Trends Mol. Med. 7:379381.
64. O'Connor, D. H.,, T. M. Allen,, T. U. Vogel,, P. Jing,, I. P. DeSouza,, E. Dodds,, E. J. Dunphy,, C. Melsaether,, B. Mothe,, H. Yamamoto,, H. Horton,, N. Wilson,, A. L. Hughes,, and D. I. Watkins. 2002. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat. Med. 8:493499.
65. Peeters, M.,, C. Honore,, T. Huet,, L. Bedjabaga,, S. Ossari,, P. Bussi,, R. W. Cooper,, and E. Delaporte. 1989. Isolation and partial characterization of an HIV-related virus occurring naturally in chimpanzees in Gabon. AIDS 3:625630.
66. Perelson, A. S.,, A. U. Neumann,, M. Markowitz,, J. M. Leonard,, and D. D. Ho. 1996. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271: 15821586.
67. Peyerl, F. W.,, D. H. Barouch,, W. W. Yeh,, H. S. Bazick,, J. Kunstman,, K. J. Kunstman,, S. M. Wolinsky,, and N. L. Letvin. 2003. Simian-human immunodeficiency virus escape from cytotoxic T-lymphocyte recognition at a structurally constrained epitope. J. Virol. 77:1257212578.
68. Phillips, R. E.,, S. Rowland-Jones,, D. F. Nixon,, F. M. Gotch,, J. P. Edwards,, A. O. Ogunlesi,, J. G. Elvin,, J. A. Rothbard,, C. R. Bangham,, C. R. Rizza, et al. 1991. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354:453459.
69. Pilgrim, A. K.,, G. Pantaleo,, O. J. Cohen,, L. M. Fink,, J. Y. Zhou,, J. T. Zhou,, D. P. Bolognesi,, A. S. Fauci,, and D. C. Montefiori. 1997. Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term-nonprogressive infection. J. Infect. Dis. 176: 924932.
70. Ramirez, B. C.,, E. Simon-Loriere,, R. Galetto,, and M. Negroni. 2008. Implications of recombination for HIV diversity. Virus Res. 134:6473.
71. Recordon-Pinson, P.,, G. Anies,, M. Bruyand,, D. Neau,, P. Morlat,, J. L. Pellegrin,, A. Groppi,, R. Thiebaut,, F. Dabis,, H. Fleury,, and B. Masquelier. 2009. HIV type-1 transmission dynamics in recent seroconverters: relationship with transmission of drug resistance and viral diversity. Antivir. Ther. 14:551556.
72. Richman, D. D.,, T. Wrin,, S. J. Little,, and C. J. Petropoulos. 2003. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl. Acad. Sci. USA 100:41444149.
73. Rong, R.,, B. Li,, R. M. Lynch,, R. E. Haaland,, M. K. Murphy,, J. Mulenga,, S. A. Allen,, A. Pinter,, G. M. Shaw,, E. Hunter,, J. E. Robinson,, S. Gnanakaran,, and C. A. Derdeyn. 2009. Escape from autologous neutralizing antibodies in acute/early subtype C HIV-infection requires multiple pathways. PLoS Pathog. 5:e1000594.
74. Rowland-Jones, S. L.,, R. E. Phillips,, D. F. Nixon,, F. M. Gotch,, J. P. Edwards,, A. O. Ogunlesi,, J. G. Elvin,, J. A. Rothbard,, C. R. Bangham,, C. R. Rizza,, and A. McMichael. 1992. Human immunodeficiency virus variants that escape cytotoxic T-cell recognition. AIDS Res. Hum. Retroviruses 8:13531354.
75. Salazar-Gonzalez, J. F.,, M. G. Salazar,, B. F. Keele,, G. H. Learn,, E. E. Giorgi,, H. Li,, J. M. Decker,, S. Wang,, J. Baalwa,, M. H. Kraus,, N. F. Parrish,, K. S. Shaw,, M. B. Guffey,, K. J. Bar,, K. L. Davis,, C. Ochsenbauer-Jambor,, J. C. Kappes,, M. S. Saag,, M. S. Cohen,, J. Mulenga,, C. A. Derdeyn,, S. Allen,, E. Hunter,, M. Markowitz,, P. Hraber,, A. S. Perelson,, T. Bhattacharya,, B. F. Haynes,, B. T. Korber,, B. H. Hahn,, and G. M. Shaw. 2009. Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-infection. J. Exp. Med. 206:12731289.
76. Salinovich, O.,, S. L. Payne,, R. C. Montelaro,, K. A. Hussain,, C. J. Issel,, and K. L. Schnorr. 1986. Rapid emergence of novel antigenic and genetic variants of equine infectious anemia virus during persistent infection. J. Virol. 57:7180.
77. Schneidewind, A.,, Z. L. Brumme,, C. J. Brumme,, K. A. Power,, L. L. Reyor,, K. O'Sullivan,, A. Gladden,, U. Hempel,, T. Kuntzen,, Y. E. Wang,, C. Oniangue-Ndza,, H. Jessen,, M. Markowitz,, E. S. Rosenberg,, R. P. Sekaly,, A. D. Kelleher,, B. D. Walker,, and T. M. Allen. 2009a. Transmission and long-term stability of compensated CD8 escape mutations. J. Virol. 83:39933997.
78. Schneidewind, A.,, Y. Tang,, M. A. Brockman,, E. G. Ryland,, J. Dunkley-Thompson,, J. C. Steel-Duncan,, M. A. St John,, J. A. Conrad,, S. A. Kalams,, F. Noel,, T. M. Allen,, C. D. Christie,, and M. E. Feeney. 2009b. Maternal transmission of human immunodeficiency virus escape mutations subverts HLA-B57 immunodominance but facilitates viral control in the haploidentical infant. J. Virol. 83:86168627.
79. Sharp, P. M.,, and B. H. Hahn. 2010. The evolution of HIV-and the origin of AIDS. Philos. Trans. R. Soc. Lond. B 365:24872494.
80. Shen, W.,, L. Gao,, M. Balakrishnan,, and R. A. Bambara. 2009. A recombination hot spot in HIV-1 contains guanosine runs that can form a G-quartet structure and promote strand transfer in vitro. J. Biol. Chem. 284:3388333893.
81. Sheppard, H. W.,, C. Celum,, N. L. Michael,, S. O'Brien,, M. Dean,, M. Carrington,, D. Dondero,, and S. P. Buchbinder. 2002. HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion. J. Acquir. Immune Defic. Syndr. 29:307313.
82. Shibata, J.,, K. Yoshimura,, A. Honda,, A. Koito,, T. Murakami,, and S. Matsushita. 2007. Impact of V2 mutations on escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary human immunodeficiency virus type 1 isolate. J. Virol. 81:37573768.
83. Simon-Loriere, E.,, R. Galetto,, M. Hamoudi,, J. Archer,, P. Lefeuvre,, D. P. Martin,, D. L. Robertson,, and M. Negroni. 2009. Molecular mechanisms of recombination restriction in the envelope gene of the human immunodeficiency virus. PLoS Pathog. 5:e1000418.
84. Takehisa, J.,, M. H. Kraus,, A. Ayouba,, E. Bailes,, F. Van Heuverswyn,, J. M. Decker,, Y. Li,, R. S. Rudicell,, G. H. Learn,, C. Neel,, E. M. Ngole,, G. M. Shaw,, M. Peeters,, P. M. Sharp,, and B. H. Hahn. 2009. Origin and biology of simian immunodeficiency virus in wild-living western gorillas. J. Virol. 83:16351648.
85. Tersmette, M.,, R. E. de Goede,, B. J. Al,, I. N. Winkel,, R. A. Gruters,, H. T. Cuypers,, H. G. Huisman,, and F. Miedema. 1988. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-including isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J. Virol. 62:20262032.
86. UNAIDS. 2009. AIDS Epidemic Update 2009. UNAIDS. Geneva, Switzerland. http://www .unaids.org/en/KnowledgeCentre/HIVData/EpiUpdate/EpiUpdArchive/2009/default.asp..
87. Van Heuverswyn, F.,, and M. Peeters. 2007. The origins of HIV and implications for the global epidemic. Curr. Infect. Dis. Rep. 9:338346.
88. van't Wout, A. B.,, N. A. Kootstra,, G. A. Mulder-Kampinga,, N. Albrecht-van Lent,, H. J. Scherpbier,, J. Veenstra,, K. Boer,, R. A. Coutinho,, F. Miedema,, and H. Schuitemaker. 1994. Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J. Clin. Investig. 94: 20602067.
89. Vercauteren, J.,, A. M. Wensing,, D. A. van de Vijver,, J. Albert,, C. Balotta,, O. Hamouda,, C. Kucherer,, D. Struck,, J. C. Schmit,, B. Asjo,, M. Bruckova,, R. J. Camacho,, B. Clotet,, S. Coughlan,, Z. Grossman,, A. Horban,, K. Korn,, L. Kostrikis,, C. Nielsen,, D. Paraskevis,, M. Poljak,, E. Puchhammer-Stockl,, C. Riva,, L. Ruiz,, M. Salminen,, R. Schuurman,, A. Sonnerborg,, D. Stanekova,, M. Stanojevic,, A. M. Vandamme,, and C. A. Boucher. 2009. Transmission of drug-resistant HIV-1 is stabilizing in Europe. J. Infect. Dis. 200:15031508.
90. Walker, B. D. 2007. Elite control of HIV Infection: implications for vaccines and treatment. Top. HIV Med. 15:134136.
91. Watkins, B. A.,, S. Buge,, K. Aldrich,, A. E. Davis,, J. Robinson,, M. S. Reitz, Jr.,, and M. Robert-Guroff. 1996. Resistance of human immunodeficiency virus type 1 to neutralization by natural antisera occurs through single amino acid substitutions that cause changes in antibody binding at multiple sites. J. Virol. 70:84318437.
92. Wei, X.,, J. M. Decker,, S. Wang,, H. Hui,, J. C. Kappes,, X. Wu,, J. F. Salazar-Gonzalez,, M. G. Salazar,, J. M. Kilby,, M. S. Saag,, N. L. Komarova,, M. A. Nowak,, B. H. Hahn,, P. D. Kwong,, and G. M. Shaw. 2003. Antibody neutralization and escape by HIV-1. Nature 422:307312.
93. Wei, X.,, S. K. Ghosh,, M. E. Taylor,, V. A. Johnson,, E. A. Emini,, P. Deutsch,, J. D. Lifson,, S. Bonhoeffer,, M. A. Nowak,, B. H. Hahn,, M. S. Saag,, and G. Shaw. 1995. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373: 117122.
94. Weiss, R. A. 2003. HIV and AIDS in relation to other pandemics. EMBO Rep. 4(Spec. No.):S10S14.
95. Wensing, A. M.,, D. A. van de Vijver,, G. Angarano,, B. Asjo,, C. Balotta,, E. Boeri,, R. Camacho,, M. L. Chaix,, D. Costagliola,, A. De Luca,, I. Derdelinckx,, Z. Grossman,, O. Hamouda,, A. Hatzakis,, R. Hemmer,, A. Hoepelman,, A. Horban,, K. Korn,, C. Kucherer,, T. Leitner,, C. Loveday,, E. MacRae,, I. Maljkovic,, C. de Mendoza,, L. Meyer,, C. Nielsen,, E. L. Op de Coul,, V. Ormaasen,, D. Paraskevis,, L. Perrin,, E. Puchhammer-Stockl,, L. Ruiz,, M. Salminen,, J. C. Schmit,, F. Schneider,, R. Schuurman,, V. Soriano,, G. Stanczak,, M. Stanojevic,, A. M. Vandamme,, K. Van Laethem,, M. Violin,, K. Wilbe,, S. Yerly,, M. Zazzi,, and C. A. Boucher. 2005. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J. Infect. Dis. 192:958966.
96. Wolinsky, S. M.,, B. T. Korber,, A. U. Neumann,, M. Daniels,, K. J. Kunstman,, A. J. Whetsell,, M. R. Furtado,, Y. Cao,, D. D. Ho,, and J. T. Safrit. 1996. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272:537542.
97. Wong, J. K.,, C. C. Ignacio,, F. Torriani,, D. Havlir,, N. J. Fitch,, and D. D. Richman. 1997. In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J. Virol. 71:20592071.
98. Wooley, D. P.,, R. A. Smith,, S. Czajak,, and R. C. Desrosiers. 1997. Direct demonstration of retroviral recombination in a rhesus monkey. J. Virol. 71:96509653.
99. Worobey, M.,, M. Gemmel,, D. E. Teuwen,, T. Haselkorn,, K. Kunstman,, M. Bunce,, J. J. Muyembe,, J. M. Kabongo,, R. M. Kalengayi,, E. Van Marck,, M. T. Gilbert,, and S. M. Wolinsky. 2008. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 455:661664.
100. Zhu, T.,, B. T. Korber,, A. J. Nahmias,, E. Hooper,, P. M. Sharp,, and D. D. Ho. 1998. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 391:594597.
101. Zhuang, J.,, A. E. Jetzt,, G. Sun,, H. Yu,, G. Klarmann,, Y. Ron,, B. D. Preston,, and J. P. Dougherty. 2002. Human immunodeficiency virus type 1 recombination: rate, fidelity, and putative hot spots. J. Virol. 76:1127311282.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error