VIRAL FACTORS DETERMINE PROGRESSION TO AIDS IN SIMIAN IMMUNODEFICIENCY VIRUS-INFECTED NEWBORN RHESUS MACAQUES

To evaluate how viral variants may affect disease progression in human pediatric AIDS, we studied the potential of three simian immunodefici ency virus (SIV) isolates to induce simian AIDS in newborn rhesus maca ques. The three virus isolates were previously shown to range from pat hogenic (SIVmac251 and SIVmac239) to nonpathogenic (SIVmac1A11) when i noculated intravenously into juvenile and adult rhesus macaques. Six n ewborn macaques inoculated with pathogenic, uncloned SIVmac251 develop ed persistent, high levels of cell-associated and cell-free viremia, h ad no detectable antiviral antibodies, and had poor weight gain; these animals all exhibited severe clinical disease and pathologic lesions diagnostic for simian AIDS and were euthanatized 10 to 26 weeks after inoculation. Two newborns inoculated with pathogenic, molecularly clon ed SIVmac239 developed persistent high virus load in peripheral blood, but both animals had normal weight gain and developed antiviral antib odies. One of the SIVmac239-infected neonates exhibited pathologic les ions diagnostic for SAIDS and was euthanatized at 34 weeks after inocu lation; the other SIVmac239-infected neonate remained alive and exhibi ted no significant clinical disease for more than 1 year after inocula tion. In contrast, three newborn rhesus macaques inoculated with the n onpathogenic molecular clone, SIVmac1A11, had transient, low-level vir emia, seroconverted by 10 weeks after inoculation, had normal weight g ain, and remained healthy for over 1 year. These results indicate that (i) newborn rhesus macaques infected with an uncloned, virulent SIVma c isolate have a more rapid, fulminant disease course than do adults i noculated with the same virus, (ii) the most rapid disease progression is associated with lack of a detectable humoral immune response in SI V-infected infant macaques, (iii) a molecularly cloned, attenuated SIV isolate is nonpathogenic in neonatal macaques, and (iv) SIV-infected neonatal macaques exhibit patterns of infection, virus load, and disea se progression similar to those observed in human immunodeficiency vir us-infected children. This SIV/neonatal rhesus model of pediatric AIDS provides a rapid, sensitive model with which to compare the virulence of SIV isolates and to study the mechanisms underlying the difference s In disease progression in human immunodeficiency virus-infected infa nts.