Increased mucosal transmission but not enhanced pathogenicity of the CCR5-tropic, simian AIDS-inducing simian/human immunodeficiency virus SHIV(SF162P3) maps to envelope gp120.
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.
Hsu
Mayla
M
Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York 10016, USA.
Harouse
Janet M
JM
Gettie
Agegnehu
A
Buckner
Clarisa
C
Blanchard
James
J
Cheng-Mayer
Cecilia
C
D000595:Amino Acid Sequence; D000818:Animals; D002678:Chimera; D003001:Cloning, Molecular; D006678:HIV / Q000472:pathogenicity / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000821:virology*; D019713:Receptors, CCR5 / Q000502:physiology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity / Q000502:physiology*; D014407:Tumor Cells, Cultured
D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5