Increased mucosal transmission but not enhanced pathogenicity of the CCR5-tropic, simian AIDS-inducing simian/human immunodeficiency virus SHIV(SF162P3) maps to envelope gp120 - PubMed (original) (raw)

Increased mucosal transmission but not enhanced pathogenicity of the CCR5-tropic, simian AIDS-inducing simian/human immunodeficiency virus SHIV(SF162P3) maps to envelope gp120

Mayla Hsu et al. J Virol. 2003 Jan.

Abstract

Through rapid serial transfer in vivo, the chimeric CCR5-tropic simian/human immunodeficiency virus SHIV(SF162) evolved from a virus that is nonpathogenic and poorly transmissible across the vaginal mucosa to a variant that still maintains CCR5 usage but which is now pathogenic and establishes intravaginal infection efficiently. To determine whether envelope glycoprotein gp120 is responsible for increased pathogenesis and transmissibility of the variant SHIV(SF162P3), we cloned and sequenced the dominant envelope gene (encoding P3 gp120) and characterized its functions in vitro. Chimeric SHIV(SF162) virus expressing P3 gp120 of the pathogenic variant, designated SHIV(SF162PC), was also constructed and assessed for its pathogenicity and mucosal transmissibility in vivo. We found that, compared to wild-type SHIV(SF162) gp120, P3 gp120 conferred in vitro neutralization resistance and increased entry efficiency of the virus but was compromised in its fusion-inducing capacity. In vivo, SHIV(SF162PC) infected two of two and two of three rhesus macaques by the intravenous and intravaginal routes, respectively. Nevertheless, although peak viremia reached 10(6) to 10(7) RNA copies per ml of plasma in some infected animals and was associated with depletion of gut-associated CD4(+) lymphocytes, none of the animals maintained a viral set point that would be predictive of progression to disease. Together, the data from this study suggest a lack of correlation between entry efficiency and cytopathic properties of envelope glycoproteins with viral pathogenicity. Furthermore, whereas env gp120 contains the determinant for enhanced mucosal transmissibility of SHIV(SF162P3), the determinant(s) of its increased virulence may require additional sequence changes in env gp41 and/or maps to other viral genes.

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Figures

FIG. 1.

FIG. 1.

Amino acid sequence alignment of V1-V5 gp120 of SF162 and serially passaged clone P3. Dashes indicate amino acid identity. Amino acid changes generating new potential sites of N-linked glycosylation are boxed.

FIG. 2.

FIG. 2.

Neutralization of luciferase reporter viruses. (A) Neutralization by MAbs against the CD4 binding site (CD4bs), CD4 induced site (CD4i), and the V3 loop (anti-V3 loop). (B) Neutralization by sera isolated from a macaque infected with SHIVSF162 (serum 26419-32) and SHIVSF162P3 (serum 353-66N). Percent neutralization was determined by luciferase expression by viruses infected in the presence relative to the absence of antibodies. Three independent assays were carried out and representative neutralization curves are shown.

FIG. 3.

FIG. 3.

Relative entry of luciferase reporter viruses expressing SF162 gp120 or P3 gp120. (A) Entry of HOS.CD4.CCR5 cells. (B) Entry of CEMx174 5.25 M7 cells. Data for relative entry of HOS.CD4.CCR5 cells are the means and standard errors of six independent experiments, while those for CEMx174 5.25 M7 cells are the averages of two independent experiments.

FIG. 4.

FIG. 4.

Fusogenic capacity and susceptibility to T-20. (A) Fusion of SF162 and P3 gp120-expressing 293T cells with CEMx174 5.25 M7 cells. Results shown are the means and standard errors from three independent experiments. (B) Inhibition of luciferase reporter virus fusion with HOS.CD4.CCR5 cells by T-20. Viruses and T-20 were incubated for 1 h at 37°C before addition to cells, and inhibition relative to viruses in the absence of drug was calculated. The means and standard errors from three independent experiments are shown.

FIG. 5.

FIG. 5.

i.v. and IVAG infection of macaques. (A) i.v. infection of rhesus macaques with SHIVSF162PC. (B) IVAG infection of rhesus macaques with SHIVSF162PC. Filled symbols indicate viral loads expressed as RNA copies per milliliter, while empty symbols depict CD4/CD8 cell ratios. (C) Percentages of CD4+ lymphocytes from PBMCs, colonic lymph node mononuclear cells (LNMC), and lamina propria (LPL) during acute infection. The percentage of CD4+ lymphocytes in the intestinal tract of uninfected macaques has been shown to be in the range of 34 to 57% (75).

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References

    1. Albert, J., B. Abrahamsson, K. Nagy, E. Aurelius, H. Gaines, G. Nystrom, and E. M. Fenyo. 1990. Rapid development of isolate-specific neutralizing antibodies after primary HIV-1 infection and consequent emergence of virus variants which resist neutralization by autologous sera. AIDS 4:107-112. - PubMed
    1. Arendrup, M., C. Nielsen, J. E. Hansen, C. Pedersen, L. Mathiesen, and J. O. Nielsen. 1992. Autologous HIV-1 neutralizing antibodies: emergence of neutralization-resistant escape virus and subsequent development of escape virus neutralizing antibodies. J. Acquir. Immune Defic. Syndr. 5:303-307. - PubMed
    1. Baba, T. W., V. Liska, R. Hofmann-Lehmann, J. Vlasak, W. Xu, S. Ayehunie, L. A. Cavacini, M. R. Posner, H. Katinger, G. Stiegler, B. J. Bernacky, T. A. Rizvi, R. Schmidt, L. R. Hill, M. E. Keeling, Y. Lu, J. E. Wright, T. C. Chou, and R. M. Ruprecht. 2000. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 6:200-206. - PubMed
    1. Berger, E. A. 1997. HIV entry and tropism: the chemokine receptor connection. AIDS 11:S3-S16. - PubMed
    1. Berkowitz, R. D., A. B. van't Wout, N. A. Kootstra, M. E. Moreno, V. D. Linquist-Stepps, C. Bare, C. A. Stoddart, H. Schuitemaker, and J. M. McCune. 1999. R5 strains of human immunodeficiency virus type 1 from rapid progressors lacking X4 strains do not possess X4-type pathogenicity in human thymus. J. Virol. 73:7817-7822. - PMC - PubMed

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