Simian immunodeficiency virus disease course is predicted by the extent of virus replication during primary infection

Abstract

To elucidate the relationship between early viral infection events and immunodeficiency virus disease progression, quantitative-competitive and branched-DNA methods of simian immunodeficiency virus (SIV) RNA quantitation were cross-validated and used to measure viremia following infection of rhesus macaques with the pathogenic SIVmac251 virus isolate. Excellent correlation between the methods suggests that both accurately approximate SIV copy number. Plasma viremia was evident 4 days postinfection, and rapid viral expansion led to peak viremia levels of 10(7) to 10(9) SIV RNA copies/ml by days 8 to 17. Limited resolution of primary viremia was accompanied by relatively short, though variable, times to the development of AIDS (81 to 630 days). The persistent high-level viremia observed following intravenous inoculation of SIVmac251 explains the aggressive disease course in this model. Survival analyses demonstrated that the disease course is established 8 to 17 days postinfection, when peak viremia is observed. The most significant predictor of disease progression was the extent of viral decline following peak viremia; larger decrements in viremia were associated with both lower steady-state viremia (P = 0.0005) and a reduced hazard of AIDS (P = 0.004). The data also unexpectedly suggested that following SIVmac251 infection, animals with the highest peak viremia were better able to control virus replication rather than more rapidly developing disease. Analysis of early viral replication dynamics should help define host responses that protect from disease progression and should provide quantitative measures to assess the extent to which protective responses may be induced by prophylactic vaccination.

FIG. 1

Comparison of QC-PCR and bDNA assays for SIV (n = 41). Eq, equivalents.

FIG. 2

Plasma SIV RNA copy numbers during the first 100 days following primary infection of rhesus macaques inoculated with SIVmac251. For clarity, animals manifesting the slowest courses of disease (26852 and 21332; slow progressors) are compared to the most rapid progressors within each group (26494 and 27141). Animals manifesting intermediate survival times are plotted separately as intermediate progressors. Only SIV copy numbers above 3 to 5 log units of SIV RNA/ml are shown in order to adequately represent different patterns of peak viremia and viral decline observed during early infection. The survival time for each animal is indicated as the day (d) post-SIV infection when euthanasia was performed. (A and B) Rhesus macaques from group 1. Animal 26494 did not seroconvert to SIV antigens and was terminated with fulminant SIV infection 99 days postinoculation. The remaining five animals seroconverted and were euthanized between 148 and 630 days postinfection. For animal 26852, the plasma virus load after day 100 decreased to approximately 5 × 10⁵ SIV RNA copies/ml and remained fairly steady until termination at day 630. (C and D) Rhesus macaques from group 2. Animals 27141, 21350, and 23810 did not seroconvert and were euthanized with progressive disease at 81, 167, and 178 days, respectively, postinfection. The remaining three animals seroconverted and were euthanized between 183 and 312 days postinfection. Animal 21332 was terminated with a plasma virus load of 8.7 × 10⁵ SIV RNA copies/ml.