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AIDS:
doi: 10.1097/QAD.0b013e328010beb5
Opinion

AIDS vaccine development and challenge viruses: getting real

Vlasak, Josefa,b; Ruprecht, Ruth Mb,c

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From the aFaculty of Biological Sciences, University of South Bohemia, Ceske Budejovice, Czech Republic

bDana-Farber Cancer Institute, USA

cHarvard Medical School, Boston, Massachusetts, USA.

Correspondence to Dr R.M. Ruprecht, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA. E-mail: ruth_ruprecht@dfci.harvard.edu

There is consensus that effective AIDS vaccines should induce both cellular and humoral immunity. Challenge of macaques with SIV or constructs of SIV and HIV (SHIV) has been invaluable to test vaccine efficacy; however, the biological relevance of some results is uncertain. Ideally, biologically meaningful challenges should mimic human HIV-1 transmission as closely as possible and will, therefore, involve (a) R5 viruses, (b) mucosal challenge routes, (c) viruses with neutralization profiles resembling those of recently transmitted HIV-1 isolates (for testing neutralizing antibody-based vaccines), and (d) heterologous challenge viruses.

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Challenge virus: route of transmission, tropism, and target cell distribution

Because approximately 90% of newly acquired human HIV-1 infections involves mucosal transmission of R5 strains, R5 viruses are preferred for primate experiments. Early-stage infections with R5 versus X4 strains differ: R5 strains preferentially infect and destroy memory CD4 T cells [1–7], because CCR5 expression is restricted to this subset. In contrast, CXCR4 is preferentially expressed on naive CD4 T cells, thus rendering these cells susceptible to elimination by X4 strains [5]. Because tissue distribution of naive and memory CD4 T cells differs, X4 strains replicate predominantly in peripheral blood and lymph nodes, whereas R5 viruses replicate mostly within mucosal tissues [2–4,6–10]. Consequently, X4 and R5 strains interact with the immune system differently, which may affect vaccine efficacy. For instance, R5 virus-mediated destruction of vaccine-induced memory CD4 T cells may render vaccination less likely to succeed against R5 than against X4 virus challenge; the latter may, therefore, yield unrealistically favorable outcomes [11].

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Mucosal challenges in primates: dose matters

As most human HIV-1 infections occur mucosally, developing vaccine protection against this dominant transmission mode will have the highest impact on the epidemic. Recent studies have focused on challenge virus doses. In standard protocols, high inocula ensure systemic infection in all control monkeys, permitting efficacy studies with relatively few animals. Systemic HIV-1 infection among sexually exposed humans, however, requires many exposures [12–15]; one transmission between discordant couples occurred per 122, 1429, or 357 sexual exposures, depending on the HIV-positive partner's stage of disease (acute infection, chronic stable disease, or 0.5–2 years before death, respectively) [15]. Risk factors, such as the presence of other sexually transmitted diseases, could increase transmission rates [16]. Nevertheless, challenge virus doses used in primates far exceed the infectious inoculum during human sexual intercourse.

Several groups have explored multiple low-dose challenges [17–21]; challenge doses were adjusted to permit infection of all control monkeys after approximately five weekly inoculations [18–21]. This infection rate still exceeds estimates obtained from HIV-1-discordant couples, although it is a step in the right direction and reflects the constraints of using costly primates. Obviously, one cannot conduct experiments where > 100 exposures are needed to ensure transmission or where low transmission rates demand large monkey groups to obtain statistical power.

Vaccine efficacy itself may be a function of the challenge virus dose: host immune defenses could be overwhelmed by unphysiologically high inocula, although lower virus doses might be withstood. For instance, vaccination completely protected three of five monkeys against low-dose challenge but none against a 10-fold higher dose, although viremia was reduced compared with controls [22].

A caveat of multiple ‘low-dose’ virus challenges is that subthreshold exposures may stimulate antiviral cellular immunity and protect against subsequent mucosal rechallenge [23,24]. These finding are strikingly similar to the HIV-1 resistance observed among African sex workers [25]. Cellular immunity induced by low-dose virus exposure may complicate the interpretation of the correlates of protection in vaccinated monkeys. Additionally, repeated exposures to host-cell components contained in challenge stock virions could theoretically induce innate and/or adaptive immunity and render the animals increasingly resistant to mucosal infection. This risk could be minimized by producing virus stocks in peripheral blood mononuclear cells of the same species as that used in vaccine studies.

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SHIV challenges: closer to the real thing

SHIV constructs that encode HIV-1 env are unique in that they allow direct testing of HIV-1 env-based vaccines and neutralizing antibodies isolated from HIV-1-infected individuals. Consequently, primate-tested active/passive immunization could be directly entered into clinical trials, thus accelerating development.

There are other advantages of SHIV strains compared with SIV: (a) new anti-HIV-1 neutralizing antibodies could potentially be isolated from infected animals, (b) non-clade B SHIV strains can be generated to reflect clades prevalent in different parts of the world (Table 1), and (c) HIV-1 env evolution can be studied in infected primates. If the latter follows a similar path as that in infected humans, as suggested for HIVIIIB env [26,27], primate models will be further validated.

Table 1
Table 1
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HIV-1 clade C is the most prevalent subtype worldwide, affecting > 50% of all individuals with HIV/AIDS. Development of anti-HIV-1 clade C vaccines should, therefore, be a top priority. To date, however, most primate challenge studies have involved clade B SHIV strains. Recently, we have constructed a highly replication-competent clade C SHIV, SHIV-1157ipd3N4 [28], that fulfills the criteria for biological relevance: (a) R5 tropism, (b) mucosal transmissibility, and (c) susceptibility to neutralizing antibodies. Efficacy testing of anti-HIV-1 clade C vaccine candidates in primates is now feasible (Rasmussen et al., unpublished data).

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Neutralization sensitivity: avoid stealth envelopes

Late-stage viruses that have undergone multiple rounds of neutralizing antibody selection followed by repeated escapes develop hard-to-neutralize envelopes. Using viruses encoding such impenetrable envelopes in primates may set the bar for achieving vaccine protection unrealistically high. Neutralization resistance has been an issue for some SIV challenge stocks, particularly SIVmac239 and primary SIVmac251 grown in rhesus monkey peripheral blood mononuclear cells. Essentially, neutralizing antibody-based vaccines cannot be evaluated for efficacy with these strains.

According to an intriguing study, recently transmitted HIV-1 clade C isolates were surprisingly neutralization sensitive [29]. Among discordant couples, recipients harbored more neutralization-sensitive viruses compared with the strains predominant in their infected partners, suggesting that a bottleneck during or shortly after sexual transmission favored neutralization-sensitive quasispecies. In contrast, vertically transmitted pediatric HIV-1 isolates were less neutralization sensitive than maternal isolates [30]. Therefore, the route of transmission may exert a dominant influence on the neutralization sensitivity of transmitted viruses.

To model sexual transmission in primates, SHIV constructs carrying env of recently transmitted HIV-1 isolates will be preferable over SHIV strains with env genes of late-stage viruses. However, the need to adapt new SHIV constructs to monkeys poses a dilemma: adaptation itself causes env mutations, which could be partly a result of neutralizing antibody selection. Rapid animal-to-animal passage during peak viremia before neutralizing antibodies are elicited can avoid selecting neutralizing antibody-escape variants, as we recently demonstrated [28].

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Heterologous virus challenge: reflecting viral complexity in real life

Given the multitude of viral quasispecies and increasing divergence of HIV-1 sequences with time, there is no likelihood of human recipients of an AIDS vaccine encountering viruses exactly matched to their vaccines. Therefore, vaccine efficacy testing in primates should reflect this reality. Success with homologous virus challenges may stimulate the development of vaccine strategies inducing narrowly focused immune responses that fail to protect against divergent viruses. Clear differences in outcome of homologous versus heterologous SHIV challenge have recently been demonstrated [22].

Several groups have evaluated vaccine efficacy by heterologous virus challenge [31–37]. In most SHIV challenge studies, vaccine and challenge virus were only partially mismatched, usually in env, probably because all currently used SHIV constructs were built from SIVmac239 backbones. Often, vaccines designed to induce cytotoxic T lymphocyte responses incorporate Gag sequences that match those of the challenge virus. It will be important either to generate immunogens based upon SIV Gag sequences that differ from those of SIVmac239 or, to construct SHIV strains with backbones that differ from SIVmac239.

Another issue to consider is the diversity of viral inocula. In animal models, challenge inocula consisting of biological isolates with swarms of viral quasispecies and challenge inocula that are homogeneous and consist of molecularly cloned virus have different advantages. While biological isolates better reflect the inoculum involved in human HIV-1 transmission, molecularly cloned virus is well defined and is, therefore, well suited as a standard virus to evaluate different vaccine regimens. In some cases, HIV-1 transmission has been associated with substantial reductions in viral diversity [29,38,39], suggesting that only a small portion of viral quasispecies was transmitted. If a diverse virus population is reduced during the bottleneck of mucosal transmission to a founder virus in the recipient, inoculation with an already narrow, well-defined population could have the same results and consequently the diversity of viral inocula may not be as critical an aspect in animal models.

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Summary

We believe that AIDS vaccine efficacy studies in primate models should involve mucosal challenge with R5 strains, preferably SHIV constructs because of the added advantage of directly testing anti-HIV-1 Env responses. To reflect the heterogeneity of the many HIV-1 quasispecies circulating in human populations, vaccine and challenge virus should not be exact matches in primate studies; ideally, AIDS vaccine efficacy studies should employ a fully heterologous challenge virus, rather than one differing only in Env. This may require the construction of SHIV strains based upon SIV backbones that differ from SIVmac239. Lastly, replacing standard single high-dose viral challenges with repeated low-dose mucosal exposures has shown promise. Ultimately, efficacy data generated in primate models through this new approach need to be compared directly with phase III clinical vaccine trials for validation.

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Acknowledgements

We thank Dr Shiu-Lok Hu (University of Washington, Seattle) for critical review of this manuscript.

Sponsorship: This work was supported in part by NIH grants P01 AI48240 and R37 AI34266 to R.M.R.

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References

1. Schnittman SM, Lane HC, Greenhouse J, Justement JS, Baseler M, Fauci AS. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci USA 1990; 87:6058–6062.

2. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998; 280:427–431.

3. Veazey RS, Tham IC, Mansfield KG, DeMaria M, Forand AE, Shvetz DE, et al. Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vitro. J Virol 2000; 74:57–64.

4. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200:749–759.

5. Nishimura Y, Igarashi T, Donau OK, Buckler-White A, Buckler C, Lafont BA, et al. Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses. Proc Natl Acad Sci USA 2004; 101:12324–12329.

6. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 2005; 434:1148–1152.

7. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434:1093–1097.

8. Smit-McBride Z, Mattapallil JJ, McChesney M, Ferrick D, Dandekar S. Gastrointestinal T lymphocytes retain high potential for cytokine responses but have severe CD4(+) T-cell depletion at all stages of simian immunodeficiency virus infection compared to peripheral lymphocytes. J Virol 1998; 72:6646–6656.

9. Harouse JM, Gettie A, Tan RC, Blanchard J, Cheng-Mayer C. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science 1999; 284:816–819.

10. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 2004; 200:761–770.

11. Feinberg MB, Moore JP. AIDS vaccine models: challenging challenge viruses. Nat Med 2002; 8:207–210.

12. Chakraborty H, Sen PK, Helms RW, Vernazza PL, Fiscus SA, Eron JJ, et al. Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model. AIDS 2001; 15:621–627.

13. Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, Wabwire-Mangen F, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357:1149–1153.

14. Pilcher CD, Tien HC, Eron JJ Jr, Vernazza PL, Leu SY, Stewart PW, et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 2004; 189:1785–1792.

15. Wawer MJ, Gray RH, Sewankambo NK, Serwadda D, Li X, Laeyendecker O, Kiwanuka N, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai. Uganda J Infect Dis 2005; 191:1403–1409.

16. Galvin SR, Cohen MS. The role of sexually transmitted diseases in HIV transmission. Nat Rev Microbiol 2004; 2:33–42.

17. van Rompay KK, Schmidt KA, Lawson JR, Singh R, Bischofberger N, Marthas ML. Topical administration of low-dose tenofovir disoproxil fumarate to protect infant macaques against multiple oral exposures of low doses of simian immunodeficiency virus. J Infect Dis 2002; 186:1508–1513.

18. Ma ZM, Abel K, Rourke T, Wang Y, Miller CJ. A period of transient viremia and occult infection precedes persistent viremia and antiviral immune responses during multiple low-dose intravaginal simian immunodeficiency virus inoculations. J Virol 2004; 78:14048–14052.

19. McDermott AB, Mitchen J, Piaskowski S, De Souza I, Yant LJ, Stephany J, et al. Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates. J Virol 2004; 78:3140–3144.

20. Otten RA, Adams DR, Kim CN, Jackson E, Pullium JK, Lee K, et al. Multiple vaginal exposures to low doses of R5 simian–human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates. J Infect Dis 2005; 191:164–173.

21. Wilson NA, Reed J, Napoe GS, Piaskowski S, Szymanski A, Furlott J, et al. Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J Virol 2006; 80:5875–5885.

22. Someya K, Cecilia D, Ami Y, Nakasone T, Matsuo K, Burda S, et al. Vaccination of rhesus macaques with recombinant Mycobacterium bovis bacillus Calmette-Guerin Env V3 elicits neutralizing antibody-mediated protection against simian–human immunodeficiency virus with a homologous but not a heterologous V3 motif. J Virol 2005; 79:1452–1462.

23. Clerici M, Clark EA, Polacino P, Axberg I, Kuller L, Casey NI, et al. T-cell proliferation to subinfectious SIV correlates with lack of infection after challenge of macaques. AIDS 1994; 8:1391–1395.

24. Salvato MS, Emau P, Malkovsky M, Schultz KT, Johnson E, Pauza CD. Cellular immune responses in rhesus macaques infected rectally with low dose simian immunodeficiency virus. J Med Primatol 1994; 23:125–130.

25. Rowland-Jones S, Sutton J, Ariyoshi K, Dong T, Gotch F, McAdam S, et al. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat Med 1995; 1:59–64.

26. Beaumont T, van Nuenen A, Broersen S, Blattner WA, Lukashov VV, Schuitemaker H. Reversal of human immunodeficiency virus type 1 IIIB to a neutralization-resistant phenotype in an accidentally infected laboratory worker with a progressive clinical course. J Virol 2001; 75:2246–2252.

27. Hofmann-Lehmann R, Vlasak J, Chenine AL, Li PL, Baba TW, Montefiori DC, et al. Molecular evolution of human immunodeficiency virus env in humans and monkeys: similar patterns occur during natural disease progression or rapid virus passage. J Virol 2002; 76:5278–5284.

28. Song RJ, Chenine AL, Rasmussen RA, Goins LM, Ruprecht CR, Mirshahidi S, et al. Molecularly cloned SHIV-1157ipd3N4: a highly replication competent, mucosally transmissible R5 simian–human immunodeficiency virus encoding HIV clade C env. J Virol 2006; 80:8729–8738.

29. Derdeyn CA, Decker JM, Bibollet-Ruche F, Mokili JL, Muldoon M, Denham SA, et al. Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science 2004; 303:2019–2022.

30. Wu X, Parast AB, Richardson BA, Nduati R, John-Stewart G, Mbori-Ngacha D, et al. Neutralization escape variants of human immunodeficiency virus type 1 are transmitted from mother to infant. J Virol 2006; 80:835–844.

31. Letvin NL, Huang Y, Chakrabarti BK, Xu L, Seaman MS, Beaudry K, et al. Heterologous envelope immunogens contribute to AIDS vaccine protection in rhesus monkeys. J Virol 2004; 78:7490–7497.

32. Singh DK, Liu Z, Sheffer D, Mackay GA, Smith M, Dhillon S, Hegde R, et al. A noninfectious simian/human immunodeficiency virus DNA vaccine that protects macaques against AIDS. J Virol 2005; 79:3419–3428.

33. Zhan X, Martin LN, Slobod KS, Coleclough C, Lockey TD, Brown SA, et al. Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV. Vaccine 2005; 23:5306–5320.

34. Ellenberger D, Otten RA, Li B, Aidoo M, Rodriguez IV, Sariol CA, et al. HIV-1 DNA/MVA vaccination reduces the per exposure probability of infection during repeated mucosal SHIV challenges. Virology 2006; 352:216–225.

35. Horiuchi R, Akahata W, Kuwata T, Enose Y, Ido E, Suzuki H, et al. DNA vaccination of macaques by a full-genome SHIV plasmid that has an IL-2 gene and produces non-infectious virus particles. Vaccine 2006; 24:3677–3685.

36. Liu Z, Singh DK, Sheffer D, Smith MS, Dhillon S, Chebloune Y, et al. Immunoprophylaxis against AIDS in macaques with a lentiviral DNA vaccine. Virology 2006; 351:444–454.

37. Xu R, Srivastava IK, Kuller L, Zarkikh I, Kraft Z, Fagrouch Z, et al. Immunization with HIV-1 SF162-derived envelope gp140 proteins does not protect macaques from heterologous simian–human immunodeficiency virus SHIV89.6P infection. Virology 2006; 349:276–289.

38. Long EM, Martin HL Jr, Kreiss JK, Rainwater SM, Lavreys L, Jackson DJ, et al. Gender differences in HIV-1 diversity at time of infection. Nat Med 2000; 6:71–75.

39. Sagar M, Kirkegaard E, Long EM, Celum C, Buchbinder S, Daar ES, et al. Human immunodeficiency virus type 1 (HIV-1) diversity at time of infection is not restricted to certain risk groups or specific HIV-1 subtypes. J Virol 2004; 78:7279–7283.

40. Shibata R, Kawamura M, Sakai H, Hayami M, Ishimoto A, Adachi A. Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. J Virol 1991; 65:3514–3520.

41. Kuwata T, Igarashi T, Ido E, Jin M, Mizuno A, Chen J, et al. Construction of human immunodeficiency virus 1/simian immunodeficiency virus strain mac chimeric viruses having vpr and/or nef of different parental origins and their in vitro and in vitro replication. J Gen Virol 1995; 76:2181–2191.

42. Li J, Lord CI, Haseltine W, Letvin NL, Sodroski J. Infection of cynomolgus monkeys with a chimeric HIV-1/SIVmac virus that expresses the HIV-1 envelope glycoproteins. J Acquir Immune Defic Syndr 1992; 5:639–646.

43. Li JT, Halloran M, Lord CI, Watson A, Ranchalis J, Fung M, et al. Persistent infection of macaques with simian–human immunodeficiency viruses. J Virol 1995; 69:7061–7067.

44. Raghavan R, Stephens EB, Joag SV, Adany I, Pinson DM, Li Z, et al. Neuropathogenesis of chimeric simian/human immunodeficiency virus infection in pig-tailed and rhesus macaques. Brain Pathol 1997; 7:851–861.

45. Stephens EB, Mukherjee S, Sahni M, Zhuge W, Raghavan R, Singh DK, et al. A cell-free stock of simian–human immunodeficiency virus that causes AIDS in pig-tailed macaques has a limited number of amino acid substitutions in both SIVmac and HIV-1 regions of the genome and has offered cytotropism. Virology 1997; 231:313–321.

46. Narayan SV, Mukherjee S, Jia F, Li Z, Wang C, Foresman L, et al. Characterization of a neutralization-escape variant of SHIVKU-1, a virus that causes acquired immune deficiency syndrome in pig-tailed macaques. Virology 1999; 256:54–63.

47. Luciw PA, Pratt-Lowe E, Shaw KE, Levy JA, Cheng-Mayer C. Persistent infection of rhesus macaques with T-cell-line-tropic and macrophage-tropic clones of simian/human immunodeficiency viruses (SHIV). Proc Natl Acad Sci USA 1995; 92:7490–7494.

48. Luciw PA, Mandell CP, Himathongkham S, Li J, Low TA, Schmidt KA, et al. Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques. Virology 1999; 263:112–127.

49. Dunn CS, Beyer C, Kieny MP, Gloeckler L, Schmitt D, Gut JP, et al. High viral load and CD4 lymphopenia in rhesus and cynomolgus macaques infected by a chimeric primate lentivirus constructed using the env, rev, tat, and vpu genes from HIV-1Lai. Virology 1996; 223:351–361.

50. Himathongkham S, Halpin NS, Li J, Stout MW, Miller CJ, Luciw PA. Simian-human immunodeficiency virus containing a human immunodeficiency virus type 1 subtype-E envelope gene: persistent infection, CD4(+) T-cell depletion, and mucosal membrane transmission in macaques. J Virol 2000; 74:7851–7860.

51. Kuwata T, Takemura T, Takehisa J, Miura T, Hayami M. Infection of macaques with chimeric simian and human immunodeficiency viruses containing Env from subtype F. Arch Virol 2002; 147:1121–1132.

52. Kuwata T, Shioda T, Igarashi T, Ido E, Ibuki K, Enose Y, et al. Chimeric viruses between SIVmac and various HIV-1 isolates have biological properties that are similar to those of the parental HIV-1. AIDS 1996; 10:1331–1337.

53. Reimann KA, Li JT, Voss G, Lekutis C, Tenner-Racz K, Racz P, et al. An env gene derived from a primary human immunodeficiency virus type 1 isolate confers high in vitro replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys. J Virol 1996; 70:3198–3206.

54. Reimann KA, Li JT, Veazey R, Halloran M, Park IW, Karlsson GB, et al. A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vitro passage in rhesus monkeys. J Virol 1996; 70:6922–6928.

55. Karlsson GB, Halloran M, Li J, Park IW, Gomila R, Reimann KA, et al. Characterization of molecularly cloned simian–human immunodeficiency viruses causing rapid CD4+ lymphocyte depletion in rhesus monkeys. J Virol 1997; 71:4218–4225.

56. Lu Y, Pauza CD, Lu X, Montefiori DC, Miller CJ. Rhesus macaques that become systemically infected with pathogenic SHIV 896-PD after intravenous, rectal, or vaginal inoculation and fail to make an antiviral antibody response rapidly develop AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19:6–18.

57. Shibata R, Maldarelli F, Siemon C, Matano T, Parta M, Miller G, et al. Infection and pathogenicity of chimeric simian–human immunodeficiency viruses in macaques: determinants of high virus loads and CD4 cell killing. J Infect Dis 1997; 176:362–373.

58. Igarashi T, Endo Y, Englund G, Sadjadpour R, Matano T, Buckler C, et al. Emergence of a highly pathogenic simian/human immunodeficiency virus in a rhesus macaque treated with anti-CD8 mAb during a primary infection with a nonpathogenic virus. Proc Natl Acad Sci USA 1999; 96:14049–14054.

59. Ranjbar S, Jones S, Stott EJ, Almond N. The construction and evaluation of SIV/HIV chimeras that express the envelope of European HIV type 1 isolates. AIDS Res Hum Retroviruses 1997; 13:797–800.

60. Cayabyab M, Rohne D, Pollakis G, Mische C, Messele T, Abebe A, et al. Rapid CD4+ T-lymphocyte depletion in rhesus monkeys infected with a simian–human immunodeficiency virus expressing the envelope glycoproteins of a primary dual-tropic Ethiopian Clade C HIV type 1 isolate. AIDS Res Hum Retroviruses 2004; 20:27–40.

61. Tan RC, Harouse JM, Gettie A, Cheng-Mayer C. In vivo adaptation of SHIV(SF162): chimeric virus expressing a NSI, CCR5-specific envelope protein. J Med Primatol 1999; 28:164–168.

62. Chen Z, Huang Y, Zhao X, Skulsky E, Lin D, Ip J, et al. Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serial passages in pig-tailed macaques (Macaca nemestrina). J Virol 2000; 74:6501–6510.

63. Chen Z, Zhao X, Huang Y, Gettie A, Ba L, Blanchard J, et al. CD4+ lymphocytopenia in acute infection of Asian macaques by a vaginally transmissible subtype-C, CCR5-tropic simian/human immunodeficiency virus (SHIV). J Acquir Immune Defic Syndr 2002; 30:133–145.

64. Ndung'u T, Lu Y, Renjifo B, Touzjian N, Kushner N, Pena-Cruz V, et al. Infectious simian/human immunodeficiency virus with human immunodeficiency virus type 1 subtype C from an African isolate: rhesus macaque model. J Virol 2001; 75:11417–11425.

65. Pal R, Taylor B, Foulke JS, Woodward R, Merges M, Praschunus R, et al. Characterization of a simian human immunodeficiency virus encoding the envelope gene from the CCR5-tropic HIV-1Ba-L. J Acquir Immune Defic Syndr 2003; 33:300–307.

66. Kaizu M, Sato H, Ami Y, Izumi Y, Nakasone T, Tomita Y, et al. Infection of macaques with an R5-tropic SHIV bearing a chimeric envelope carrying subtype E V3 loop among subtype B framework. Arch Virol 2003; 148:973–988.

67. Wu Y, Hong K, Chenine AL, Whitney JB, Chen Q, Geng Y, et al. Molecular cloning and in vitro evaluation of an infectious simian–human immunodeficiency virus containing env of a primary Chinese HIV-1 subtype C isolate. J Med Primatol 2005; 34:101–107.

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