Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1

• Published in: The Journal of experimental medicine Vol. 206; no. 5; pp. 1117 - 1134
• Main Authors: Keele, Brandon F, Li, Hui, Learn, Gerald H, Hraber, Peter, Giorgi, Elena E, Grayson, Truman, Sun, Chuanxi, Chen, Yalu, Yeh, Wendy W, Letvin, Norman L, Mascola, John R, Nabel, Gary J, Haynes, Barton F, Bhattacharya, Tanmoy, Perelson, Alan S, Korber, Bette T, Hahn, Beatrice H, Shaw, George M
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 11.05.2009
• Subjects: Acquired Immunodeficiency Syndrome - genetics; Acquired Immunodeficiency Syndrome - immunology; Acquired Immunodeficiency Syndrome - transmission; AIDS Vaccines; Animals; Antibodies, Viral - blood; Antibodies, Viral - genetics; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Disease Models, Animal; Evolution, Molecular; Genes, env; Genes, Viral; HIV-1 - genetics; HIV-1 - pathogenicity; Humans; Intestinal Mucosa - virology; Macaca mulatta - genetics; Macaca mulatta - immunology; Mutation; SAIDS Vaccines; Simian Acquired Immunodeficiency Syndrome - genetics; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - transmission; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - immunology; Viremia - genetics
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20082831

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1-5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1-5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV-macaque mucosal infection model for HIV-1 vaccine and microbicide research.