Modeling HIV Transmission: New SHIV Recapitulates Differences in Risk by Mucosal Route

An important goal of animal model studies is to recapitulate HIV infection in humans as closely as possible. For researchers working on strategies to prevent transmission, the priority is to mimic the efficiency of virus transfer across different mucosal surfaces. A study just published in the Journal of Infectious Diseases reports that in macaques, an HIV-SIV hybrid called SHIV‐1157ipd3N4 (comprising a backbone of SIVmac239 with the envelope of an R5-using primary clade C HIV isolate) shows differing transmission efficiencies via oral, vaginal and rectal routes that are within the same range reported for HIV in humans. The researchers also show that the induction of inflammation increased the efficiency of transmission, as is also the case in humans, although this was demonstrated only via the oral route in this first study. The paper concludes with the suggestion that SHIV‐1157ipd3N4 “could be a biologically relevant tool to assess mechanisms of mucosal transmission, including the role played by local inflammation and coinfection with other pathogens, and it could also be used to assess the protective potential of microbicides or vaccines in macaques of either Indian or Chinese origin against mucosal challenge.”

The Journal of Infectious Diseases 2010;201:1155–1163

DOI: 10.1086/651274

MAJOR ARTICLE

Relative Transmissibility of an R5 Clade C Simian‐Human Immunodeficiency Virus Across Different Mucosae in Macaques Parallels the Relative Risks of Sexual HIV‐1 Transmission in Humans via Different Routes

Agnès L. Chenine,2,3,a Nagadenahalli B. Siddappa,2,3 Victor G. Kramer,2 Gaia Sciaranghella,2,3 Robert A. Rasmussen,2,3 Sandra J. Lee,1 Michael Santosuosso,3,4 Mark C. Poznansky,3,4 Vijayakumar Velu,6 Rama R. Amara,6 Chris Souder,6 Daniel C. Anderson,6 François Villinger,6 James G. Else,6 Francis J. Novembre,6 Elizabeth Strobert,6 Shawn P. O’Neil,3,5 W. Evan Secor,7 and Ruth M. Ruprecht2,3

1Department of Biostatistics and Computational Biology, 2Dana‐Farber Cancer Institute, 3Harvard Medical School, 4Partners AIDS Research Center and Infectious Diseases Medicine, Massachusetts General Hospital, Boston, 5New England Primate Research Center, Southborough, Massachusetts; 6Yerkes National Primate Research Center, Emory University, and 7Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

Background. Worldwide, 90% of all human immunodeficiency virus (HIV) transmissions occur mucosally; almost all involve R5 strains. Risks of sexual HIV acquisition are highest for rectal, then vaginal, and finally oral exposures.

Methods. Mucosal lacerations may affect the rank order of susceptibility to HIV but cannot be assessed in humans. We measured relative virus transmissibility across intact mucosae in macaques using a single stock of SHIV‐1157ipd3N4, a simian‐human immunodeficiency virus encoding a primary R5 HIV clade C env (SHIV‐C).

Results. The penetrability of rhesus macaque mucosae differed significantly, with rectal challenge requiring the least virus, followed by vaginal and then oral routes ( , oral vs vaginal;  rectal vs vaginal). These findings imply that intrinsic mucosal properties are responsible for the differential mucosal permeability. The latter paralleled the rank order reported for humans, with relative risk estimates within the range of epidemiological human studies. To test whether inflammation facilitates virus transmission—as predicted from human studies—we established a macaque model of localized buccal inflammation. Systemic infection occurred across inflamed but not normal buccal mucosa.

Conclusion. Our primate data recapitulate virus transmission risks observed in humans, thus establishing R5 SHIV‐1157ipd3N4 in macaques as a robust model system to study cofactors involved in human mucosal HIV transmission and its prevention.