IN VIVO EVALUATION OF PRIMATE LENTIVIRUSES

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

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. When strains of lentiviruses become available, it is important to determine the infectivity, pathogenicity, and minimal infectious dose of each virus in a particular nonhuman primate species before it can be used in vaccine trails or therapeutic testing. This project is designed to allow lentiviruses to be tested in vivo. Simian-Human Immunodeficiency Virus-SF162P4 (SHIV SF162P4) is derived from a molecular clone, SHIV SF162, a chimeric virus that contains the env gene of a CCR-5-using primary isolate of subtype B HIV-1. A macaque-passaged stock, SHIV SF162P3 was found to cause a dramatic loss of CD4+ intestinal T cells followed by a gradual depletion of peripheral CD4+ T cells. Lymph node cells and PBMC from a macaque infected with the SHIV SF162P3 virus two weeks after infection were amplified in human PBMC to generate a P4 stock virus and a challenge stock was prepared. HIV-1 clade C virus accounts for greater than 50% of all infections worldwide. Thus, the opportunity to study this subtype in the context of candidate AIDS vaccines is especially valuable. SHIV-1157ipd3N4 is a chimeric virus derived from a molecular clone composed of SIVmac239 expressing HIV clade C env and the associated auxiliary genes tat, vpu, and rev. This parent virus was adapted by serial passage in rhesus monkeys. Genomic DNA from one of these monkeys was amplified to generate a late proviral clone into which an extra NF-kB binding site was engineered to increase replicative capacity. This virus was exclusively R5 tropic and replicated potently in rhesus PBMC and in vivo in rhesus monkeys inoculated intravenously and intrarectally. The current study was undertaken to measure the infectivity and inductive ability of B- and T-cell immune responses by the intravaginal route so that these SHIVs may serve as challenge viruses in future vaccine studies and microbicide trials in Chinese rhesus macaques utilizing this route of infection.