Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques

SIV/HIV-1 (SHIV) chimeric clones, constructed by substituting portions of t he pathogenic molecular clone SIVmac239 with counterpart portions from HIV- 1 clones, provide a means to analyze functions of selected HIV-1 genes in v ivo in nonhuman primates. Our studies focused on SHIVSF33, which contains t he vpu, tat, rev, and env genes of the cytopathic, T-cell line tropic clone HIV-1SF33 (subtype-B); this clone has a premature stop codon in the vpu ge ne. In three juvenile macaques inoculated intravenously with SHIVSF33, low- level persistent infection was established; no disease was observed for a p eriod of >2 years. However, at similar to 16 months p.i., one of four SHIVS F33-infected juvenile macaques exhibited an increase in virus load, depleti on of CD4(+) T cells in peripheral blood and lymph nodes, and other symptom s of simian AIDS (SAIDS). Virus recovered from this animal in the symptomat ic stage was designated SHIVSF33A (A, adapted); this virus displayed multip le amino acid sequence changes throughout the HIV-1 env gene compared with the input SHIVSF33 clone. Additionally, a mutation in all clones from SHIVS F33A restored the open reading frame for the vpu gene, in vitro evaluations in tissue-culture systems revealed that SHIVSF33A replicated to higher lev els and exhibited greater cytopathicity than SHIVSF33. Furthermore cloned e nv genes for SHIVSF33A were more fusogenic in a cell;fusion assay compared with the env gene of the SHIVSF33. Intravenous inoculation of SHIVSF33A int o juvenile and newborn macaques resulted in a rapid decline in CD4(+) T cel ls to very low levels and development of a fatal AIDS-like disease. A cell- free preparation of this pathogenic chimeric virus also established persist ent infection when applied to oral mucosal membranes of juvenile macaques a nd produced a fatal AIDS-like disease. These studies on pathogenic SHIVSF33 A establish the basis for further investigations on the role of the HIV-1 e nv gene in virus adaptation and in mechanism(s) of immunodeficiency in prim ates; moreover, the chimeric virus SHIVSF33A can play a role in elucidating mucosal membrane transmission and development of antiviral vaccines in new borns as well as juvenile and adult macaques. (C) 1999 Academic Press.