Envelope-modified single-cycle simian immunodeficiency virus selectively enhances antibody responses and partially protects against repeated, low-dose vaginal challenge.
Immunization of rhesus macaques with strains of simian immunodeficiency virus (SIV) that are limited to a single cycle of infection elicits T-cell responses to multiple viral gene products and antibodies capable of neutralizing lab-adapted SIV, but not neutralization-resistant primary isolates of SIV. In an effort to improve upon the antibody responses, we immunized rhesus macaques with three strains of single-cycle SIV (scSIV) that express envelope glycoproteins modified to lack structural features thought to interfere with the development of neutralizing antibodies. These envelope-modified strains of scSIV lacked either five potential N-linked glycosylation sites in gp120, three potential N-linked glycosylation sites in gp41, or 100 amino acids in the V1V2 region of gp120. Three doses consisting of a mixture of the three envelope-modified strains of scSIV were administered on weeks 0, 6, and 12, followed by two booster inoculations with vesicular stomatitis virus (VSV) G trans-complemented scSIV on weeks 18 and 24. Although this immunization regimen did not elicit antibodies capable of detectably neutralizing SIV(mac)239 or SIV(mac)251(UCD), neutralizing antibody titers to the envelope-modified strains were selectively enhanced. Virus-specific antibodies and T cells were observed in the vaginal mucosa. After 20 weeks of repeated, low-dose vaginal challenge with SIV(mac)251(UCD), six of eight immunized animals versus six of six naïve controls became infected. Although immunization did not significantly reduce the likelihood of acquiring immunodeficiency virus infection, statistically significant reductions in peak and set point viral loads were observed in the immunized animals relative to the naïve control animals.
Alpert
Michael D
MD
Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA 01772-9102, USA.
Rahmberg
Andrew R
AR
Neidermyer
William
W
Ng
Sharon K
SK
Carville
Angela
A
Camp
Jeremy V
JV
Wilson
Robert L
RL
Piatak
Michael
M
Mansfield
Keith G
KG
Li
Wenjun
W
Miller
Christopher J
CJ
Lifson
Jeffrey D
JD
Kozlowski
Pamela A
PA
Evans
David T
DT
D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis; D000914:Antibodies, Viral / Q000096:biosynthesis*; D005260:Female; D005814:Genes, Viral; D007117:Immunization, Secondary; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology*; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014621:Vagina / Q000276:immunology / Q000821:virology; D018116:Vesiculovirus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D019562:Viral Load
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D008562:Membrane Glycoproteins; D012191:Retroviridae Proteins; D018449:SAIDS Vaccines; C082614:SIV envelope protein gp41; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus