Abstract
To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency viruses (SHIVs). These viruses were composed of simian immunodeficiency virus SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rep. Virus replication was assessed during primary infection of rhesus monkeys by measuring plasma SIVmac p27 levels and by quantifying virus replication in lymph nodes using in situ hybridization. SHIV-HXBc2, which expresses the HIV-1 env of a T-cell-tropic, laboratory-adapted strain of HIV-1 (HXBc2), replicated well in rhesus monkey peripheral blood leukocytes (PBL) in vitro but replicated only to low levels when inoculated in rhesus monkeys. In contrast, SHIV-89.6 was constructed with the HIV-1 env gene of a T-cell- and macrophage-tropic clone of a patient isolate of HIV-1 (89.6). This virus replicated to a lower level in monkey PBL in vitro but replicated to a higher degree in monkeys during primary infection. Moreover, monkeys infected with SHIV-89.6 developed an inversion in the PBL CD4/CD8 ratio coincident with the clearance of primary viremia. The differences in the in vivo consequences of infection by these two SHIVs could not be explained by differences in the immune responses elicited by these viruses, since infected animals had comparable type-specific neutralizing antibody titers, proliferative responses to recombinant HIV-1 gp120, and virus-specific cytolytic effector T-cell responses. With the demonstration that a chimeric SHIV can replicate to high levels during primary infection in rhesus monkeys, this model can now be used to define genetic determinants of HIV-1 pathogenicity.
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- Borrow P., Lewicki H., Hahn B. H., Shaw G. M., Oldstone M. B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994 Sep;68(9):6103–6110. doi: 10.1128/jvi.68.9.6103-6110.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark S. J., Saag M. S., Decker W. D., Campbell-Hill S., Roberson J. L., Veldkamp P. J., Kappes J. C., Hahn B. H., Shaw G. M. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med. 1991 Apr 4;324(14):954–960. doi: 10.1056/NEJM199104043241404. [DOI] [PubMed] [Google Scholar]
- Collman R., Balliet J. W., Gregory S. A., Friedman H., Kolson D. L., Nathanson N., Srinivasan A. An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1. J Virol. 1992 Dec;66(12):7517–7521. doi: 10.1128/jvi.66.12.7517-7521.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- D'Souza M. P., Durda P., Hanson C. V., Milman G. Evaluation of monoclonal antibodies to HIV-1 by neutralization and serological assays: an international collaboration. Collaborating Investigators. AIDS. 1991 Sep;5(9):1061–1070. doi: 10.1097/00002030-199109000-00001. [DOI] [PubMed] [Google Scholar]
- Daar E. S., Moudgil T., Meyer R. D., Ho D. D. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med. 1991 Apr 4;324(14):961–964. doi: 10.1056/NEJM199104043241405. [DOI] [PubMed] [Google Scholar]
- Fisher A. G., Collalti E., Ratner L., Gallo R. C., Wong-Staal F. A molecular clone of HTLV-III with biological activity. Nature. 1985 Jul 18;316(6025):262–265. doi: 10.1038/316262a0. [DOI] [PubMed] [Google Scholar]
- Fox C. H., Tenner-Rácz K., Rácz P., Firpo A., Pizzo P. A., Fauci A. S. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. doi: 10.1093/infdis/164.6.1051. [DOI] [PubMed] [Google Scholar]
- Fultz P. N. Nonhuman primate models for AIDS. Clin Infect Dis. 1993 Aug;17 (Suppl 1):S230–S235. doi: 10.1093/clinids/17.supplement_1.s230. [DOI] [PubMed] [Google Scholar]
- Hirsch V. M., Dapolito G., Johnson P. R., Elkins W. R., London W. T., Montali R. J., Goldstein S., Brown C. Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J Virol. 1995 Feb;69(2):955–967. doi: 10.1128/jvi.69.2.955-967.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirsch V. M., Martin J. E., Dapolito G., Elkins W. R., London W. T., Goldstein S., Johnson P. R. Spontaneous substitutions in the vicinity of the V3 analog affect cell tropism and pathogenicity of simian immunodeficiency virus. J Virol. 1994 Apr;68(4):2649–2661. doi: 10.1128/jvi.68.4.2649-2661.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Igarashi T., Shibata R., Hasebe F., Ami Y., Shinohara K., Komatsu T., Stahl-Hennig C., Petry H., Hunsmann G., Kuwata T. Persistent infection with SIVmac chimeric virus having tat, rev, vpu, env and nef of HIV type 1 in macaque monkeys. AIDS Res Hum Retroviruses. 1994 Aug;10(8):1021–1029. doi: 10.1089/aid.1994.10.1021. [DOI] [PubMed] [Google Scholar]
- Javaherian K., Langlois A. J., Schmidt S., Kaufmann M., Cates N., Langedijk J. P., Meloen R. H., Desrosiers R. C., Burns D. P., Bolognesi D. P. The principal neutralization determinant of simian immunodeficiency virus differs from that of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1418–1422. doi: 10.1073/pnas.89.4.1418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Joling P., Bakker L. J., Van Strijp J. A., Meerloo T., de Graaf L., Dekker M. E., Goudsmit J., Verhoef J., Schuurman H. J. Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent. J Immunol. 1993 Feb 1;150(3):1065–1073. [PubMed] [Google Scholar]
- Kanki P. J., McLane M. F., King N. W., Jr, Letvin N. L., Hunt R. D., Sehgal P., Daniel M. D., Desrosiers R. C., Essex M. Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLV-III. Science. 1985 Jun 7;228(4704):1199–1201. doi: 10.1126/science.3873705. [DOI] [PubMed] [Google Scholar]
- Koup R. A., Safrit J. T., Cao Y., Andrews C. A., McLeod G., Borkowsky W., Farthing C., Ho D. D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994 Jul;68(7):4650–4655. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Letvin N. L. Animal models for the study of human immunodeficiency virus infections. Curr Opin Immunol. 1992 Aug;4(4):481–485. doi: 10.1016/s0952-7915(06)80043-9. [DOI] [PubMed] [Google Scholar]
- Letvin N. L., Li J., Halloran M., Cranage M. P., Rud E. W., Sodroski J. Prior infection with a nonpathogenic chimeric simian-human immunodeficiency virus does not efficiently protect macaques against challenge with simian immunodeficiency virus. J Virol. 1995 Jul;69(7):4569–4571. doi: 10.1128/jvi.69.7.4569-4571.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li J. T., Halloran M., Lord C. I., Watson A., Ranchalis J., Fung M., Letvin N. L., Sodroski J. G. Persistent infection of macaques with simian-human immunodeficiency viruses. J Virol. 1995 Nov;69(11):7061–7067. doi: 10.1128/jvi.69.11.7061-7067.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li J., Lord C. I., Haseltine W., Letvin N. L., 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(7):639–646. [PubMed] [Google Scholar]
- Luciw P. A., Pratt-Lowe E., Shaw K. E., Levy J. A., 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 U S A. 1995 Aug 1;92(16):7490–7494. doi: 10.1073/pnas.92.16.7490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Montefiori D. C., Graham B. S., Zhou J. Y., Zhou J. T., Ahearn J. M. Binding of human immunodeficiency virus type 1 to the C3b/C4b receptor CR1 (CD35) and red blood cells in the presence of envelope-specific antibodies and complement. National Institutes of Health AIDS Vaccine Clinical Trials Networks. J Infect Dis. 1994 Aug;170(2):429–432. doi: 10.1093/infdis/170.2.429. [DOI] [PubMed] [Google Scholar]
- Montefiori D. C., Robinson W. E., Jr, Schuffman S. S., Mitchell W. M. Evaluation of antiviral drugs and neutralizing antibodies to human immunodeficiency virus by a rapid and sensitive microtiter infection assay. J Clin Microbiol. 1988 Feb;26(2):231–235. doi: 10.1128/jcm.26.2.231-235.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Montefiori D. C., Zhou J., Shaff D. I. CD4-independent binding of HIV-1 to the B lymphocyte receptor CR2 (CD21) in the presence of complement and antibody. Clin Exp Immunol. 1992 Dec;90(3):383–389. doi: 10.1111/j.1365-2249.1992.tb05855.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mori K., Ringler D. J., Kodama T., Desrosiers R. C. Complex determinants of macrophage tropism in env of simian immunodeficiency virus. J Virol. 1992 Apr;66(4):2067–2075. doi: 10.1128/jvi.66.4.2067-2075.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murphey-Corb M., Martin L. N., Rangan S. R., Baskin G. B., Gormus B. J., Wolf R. H., Andes W. A., West M., Montelaro R. C. Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys. Nature. 1986 May 22;321(6068):435–437. doi: 10.1038/321435a0. [DOI] [PubMed] [Google Scholar]
- Nooij F. J., Borst J. G., Van Meurs G. J., Jonker M., Balner H. Differentiation antigens on rhesus monkey lymphocytes. I. Identification of T cells bearing CD3 and CD8, and of a subset of CD8-bearing cells. Eur J Immunol. 1986 Aug;16(8):975–979. doi: 10.1002/eji.1830160817. [DOI] [PubMed] [Google Scholar]
- Reimann K. A., Cate R. L., Wu Y., Palmer L., Olson D., Waite B. C., Letvin N. L., Burkly L. C. In vivo administration of CD4-specific monoclonal antibody: effect on provirus load in rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques. AIDS Res Hum Retroviruses. 1995 Apr;11(4):517–525. doi: 10.1089/aid.1995.11.517. [DOI] [PubMed] [Google Scholar]
- Reimann K. A., Tenner-Racz K., Racz P., Montefiori D. C., Yasutomi Y., Lin W., Ransil B. J., Letvin N. L. Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Virol. 1994 Apr;68(4):2362–2370. doi: 10.1128/jvi.68.4.2362-2370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reimann K. A., Waite B. C., Lee-Parritz D. E., Lin W., Uchanska-Ziegler B., O'Connell M. J., Letvin N. L. Use of human leukocyte-specific monoclonal antibodies for clinically immunophenotyping lymphocytes of rhesus monkeys. Cytometry. 1994 Sep 1;17(1):102–108. doi: 10.1002/cyto.990170113. [DOI] [PubMed] [Google Scholar]
- Rho H. M., Poiesz B., Ruscetti F. W., Gallo R. C. Characterization of the reverse transcriptase from a new retrovirus (HTLV) produced by a human cutaneous T-cell lymphoma cell line. Virology. 1981 Jul 15;112(1):355–360. doi: 10.1016/0042-6822(81)90642-5. [DOI] [PubMed] [Google Scholar]
- Shaw G. M., Hahn B. H., Arya S. K., Groopman J. E., Gallo R. C., Wong-Staal F. Molecular characterization of human T-cell leukemia (lymphotropic) virus type III in the acquired immune deficiency syndrome. Science. 1984 Dec 7;226(4679):1165–1171. doi: 10.1126/science.6095449. [DOI] [PubMed] [Google Scholar]
- Spiegel H., Herbst H., Niedobitek G., Foss H. D., Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992 Jan;140(1):15–22. [PMC free article] [PubMed] [Google Scholar]
- Sullivan N., Sun Y., Li J., Hofmann W., Sodroski J. Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates. J Virol. 1995 Jul;69(7):4413–4422. doi: 10.1128/jvi.69.7.4413-4422.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tenner-Racz K., Racz P., Bofill M., Schulz-Meyer A., Dietrich M., Kern P., Weber J., Pinching A. J., Veronese-Dimarzo F., Popovic M. HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS. Am J Pathol. 1986 Apr;123(1):9–15. [PMC free article] [PubMed] [Google Scholar]
- Voss G., Li J., Manson K., Wyand M., Sodroski J., Letvin N. L. Human immunodeficiency virus type 1 envelope glycoprotein-specific cytotoxic T lymphocytes in simian-human immunodeficiency virus-infected rhesus monkeys. Virology. 1995 Apr 20;208(2):770–775. doi: 10.1006/viro.1995.1209. [DOI] [PubMed] [Google Scholar]
- Watanabe M., Reimann K. A., DeLong P. A., Liu T., Fisher R. A., Letvin N. L. Effect of recombinant soluble CD4 in rhesus monkeys infected with simian immunodeficiency virus of macaques. Nature. 1989 Jan 19;337(6204):267–270. doi: 10.1038/337267a0. [DOI] [PubMed] [Google Scholar]