MACACA FASCICULARIS SUSCEPTIBILITY TO RT-SHIV FOLLOWING INTRAVAGINAL INOCULATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background The reverse transcriptase (RT) of the human immunodeficiency virus (HIV-1) is a major target for controlling HIV infection and/or acquired immunodeficiency syndrome (AIDS) in humans. Suitable macaque model is urgently needed for the evaluation of HIV preventive and therapeutic strategies specifically targeting HIV-1 RT. We have characterized a CCR5-trpoic SIV/HIV-RT chimeric virus (RT-SHIVtc) which exhibited high in vitro sensitivity to nonnucleoside RT inhibitors and is highly pathogenic to mucosal transmission in pigtail macaques. This virus was used to carry out an infectious dose determining study by vaginal transmission in cynomolgus macaques (Macaca fascicularis) which are relatively less expensive and more readily available than other macaques. Methods Fifteen healthy cynomolgus macaques were randomly divided into three groups (n = 5) and intravaginally inoculated with 4,800, 1,200 or 300 TCID50 of RT-SHIVtc. Systemic infections of RT-SHIVtc exposed macaques were monitored by determining both virological findings and immunologic responses during 24 weeks post challenge. Results Within two weeks post inoculation (PI), all five macaques inoculated with the highest dose and four of five macaques inoculated with either medium or the lowest dose, were systemically infected as determined by the isolation of infectious virus and presence of proviral DNA in PBMC and the high level of persistent plasma viremia. All the infected macaques exhibited antiviral antibody response and most of the viremic macaques showed declined CD4+T cells in their blood. Conclusions Our results serve to validate the pathogenicity of RT-SHIVtc mucosal transmission in M. fascicularis. This new macaque model will be very useful for the preclinical evaluation of candidate HIV-1 nonnucleoside RT inhibitors (NNRTI).