Generation of the Pathogenic R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 by Serial Passaging in Rhesus Macaques

Abstract

A new pathogenic R5-tropic simian/human immunodeficiency virus (SHIV) was generated following serial passaging in rhesus macaques. All 13 animals inoculated with SHIV _AD8 passaged lineages experienced marked depletions of CD4 ⁺ T cells. Ten of these infected monkeys became normal progressors (NPs) and had gradual losses of both memory and naïve CD4 ⁺ T lymphocytes, generated antiviral CD4 ⁺ and CD8 ⁺ T cell responses, and sustained chronic immune activation while maintaining variable levels of plasma viremia (10 ² to 10 ⁵ RNA copies/ml for up to 3 years postinfection [p.i.]). To date, five NPs developed AIDS associated with opportunistic infections caused by Pneumocystis carinii , Mycobacterium avium , and Campylobacter coli that required euthanasia between weeks 100 and 199 p.i. Three other NPs have experienced marked depletions of circulating CD4 ⁺ T lymphocytes (92 to 154 cells/μl) following 1 to 2 years of infection. When tested for coreceptor usage, the viruses isolated from four NPs at the time of their euthanasia remained R5 tropic. Three of the 13 SHIV _AD8 -inoculated macaques experienced a rapid-progressor syndrome characterized by sustained plasma viremia of >1 × 10 ⁷ RNA copies/ml and rapid irreversible loss of memory CD4 ⁺ T cells that required euthanasia between weeks 19 and 23 postinfection. The sustained viremia, associated depletion of CD4 ⁺ T lymphocytes, and induction of AIDS make the SHIV _AD8 lineage of viruses a potentially valuable reagent for vaccine studies.