Pigtail Macaque Model of Human-Simian Immunodeficiency Virus Infection

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Abstract/Summary: Commonly used animal models of HIV-1 include infection of macaques with Simian Immunodeficiency Virus (SIV) or Simian-Human Immunodeficiency Virus (SHIV) containing HIV envelope (Env) or reverse transcriptase. These animal models have been extremely useful in understanding HIV pathogenesis and disease progression, as well as understanding the efficacy of vaccines and drugs. However, the genetic difference between HIV-1 and SIV, and the absence of other HIV-1 genes such as gag, pol, vif, vpr, and nef in SHIV limits the utility of these models in vaccine studies. Ideally, good animal model of HIV-1 infection/AIDS would be infection of macaques with HIV-1. However, HIV-1 does not replicate in macaque cells due to the presence of retroviral restriction factors. HIV-1 can be made to replicate by substituting its accessory genes with SIV genes such as vif, vpx, vpr, and nef, which can counteract interferon-induced restriction factors in macaque cells. Indeed, we have previously reported that Human-Simian Immunodeficiency Virus generated by substitution of HIV-1NL4-3 vif with SIV substitution (named HSIV-vifNL4-3) can replicate persistently in pigtail macaques (PTMs). However, infection did not result in high peak viremia and setpoint viral loads as observed during SIV or Simian-Human Immunodeficiency virus (SHIV) infection of macaques. To further adapt HSIV, we performed serial in vivo passaging to enhance infectivity or replicative capacity. We conducted animal-to-animal transfer of infected blood in 3 immunocompetent PTMs with starting initial inoculum containing a mixture of CXCR4- (HSIV-vifNL4-3 recovered from previously infected macaque) and CCR5-tropic HSIV (HSIV-vif derivative based on pNL-AD8 and Bru-Yu2). Interestingly, all the macaques showed peak viremia close to or above 105 copies/ml and virus replication persisted for more than 20 weeks. We have recovered three CXCR4-tropic infectious molecular clones (IMCs) from passage 3 macaque (HSIV-P3 IMCs) with interesting mutations throughout the genome, perhaps suggesting adaptation to PTMs. We hypothesize that further in vivo passaging of HSIV-P3 IMCs will generate pathogenic variants with enhanced replication capacity. We propose to conduct serial in vivo passaging in older PTMs, which may support better virus replication compared to juvenile/younger macaques. Since we recovered only CXCR4-tropic HSIV, we also propose to use HSIV-P3 IMCs as backbones to develop CCR5-tropic HSIV. The results from this study will provide valuable insights into development of biologically relevant animal model of HIV-1 infection for preclinical evaluation of vaccine prevention of HIV transmission.