High Specific Infectivity of Plasma Virus from the Pre-Ramp-Up and Ramp-Up Stages of Acute Simian Immunodeficiency Virus Infection

Abstract

To define the ratio of simian immunodeficiency virus (SIV) RNA molecules to infectious virions in plasma, a ramp-up-stage plasma pool was made from the earliest viral RNA (vRNA)-positive plasma samples (collected approximately 7 days after inoculation) from seven macaques, and a set-point-stage plasma pool was made from plasma samples collected 10 to 16 weeks after peak viremia from seven macaques; vRNA levels in these plasma pools were determined, and serial 10-fold dilutions containing 1 to 1,500 vRNA copies/ml were made. Intravenous (i.v.) inoculation of a 1-ml aliquot of diluted ramp-up-stage plasma containing 20 vRNA copies infected 2 of 2 rhesus macaques, while for the set-point-stage plasma, i.v. inoculation with 1,500 vRNA copies was needed to transmit infection. Further, when the heat-inactivated set-point-stage plasma pool was mixed with ramp-up-stage virions, infection of inoculated macaques was blocked. Notably, 2 of 2 animals inoculated with 85 ml of a pre-ramp-up plasma pool containing <3 SIV RNA copies/ml developed SIV infections characterized by high levels of viral replication, demonstrating that "vRNA-negative" plasma collected from macaques in the pre-ramp-up stage is infectious. Furthermore, there is a high ratio of infectious virions to total virions in ramp-up-stage plasma (between 1:1 and 1:10) and a lower ratio in set-point-stage plasma (between 1:75 and 1:750). Heat-inactivated chronic-stage plasma can "neutralize" the highly infectious ramp-up-stage virions. These findings have implications for the understanding of the natural history of SIV and human immunodeficiency virus infection and transmission.

Viral Dynamics during Primary Simian Immunodeficiency Virus Infection: Effect of Time-Dependent Virus Infectivity

“…The average initial and setpoint viral infection rates were estimated to be ␤ 0 ϭ 5.3 (95% CI ϭ 3.3 to 7.2; median, 4.5) ϫ 10 Ϫ8 ml RNA Ϫ1 day Ϫ1 and ␤ ϱ ϭ 1.1 (95% CI ϭ 0.53 to 1.6; median, 0.81) ϫ 10 Ϫ8 ml RNA Ϫ1 day Ϫ1 , respectively. This shows that set-point plasma virus is less infectious than ramp-up plasma virus, supporting the experimental finding in Ma et al (26). Calculating the ratio of ␤ 0 to ␤ ϱ , we found that the ramp-up plasma virus has an infection rate that is 7.7 (95% CI ϭ 5.1 to 10.3; median, 7.8) times greater than the set-point plasma virus.…”

“…A recent experiment indicates that the infectivity of SIV changes over time during primary infection (26). Ma et al (26) infected macaques with SIV isolated either during ramp-up or at set-point.…”

“…The parameters ␦, p, and c are the rate constants of infected cell loss, virus production by infected cells, and virus clearance, respectively. Based on the experimental data in Ma et al (26), we assume that the rate of virus infection ␤(t) decays over time. The data are not sufficient to determine the exact form of ␤(t).…”

“…They then used those two pools of plasma from different stages of infection to titrate the amount needed for subsequent intravenous infection of naive rhesus macaques (for further details, see reference 26). We model the kinetics of acute infection in these eight donor animals (25479, 25948, 29459, 29271, 27361, 29029, 26811, and 25908) and in six recipient animals (35036, 33815, 34373, 33952, 34846, and 36068) from (26). Three of the latter (35036, 33815, and 36068) were infected by intravenous inoculation of ramp-up plasma, while the other three (34373, 33952, and 34846) were infected by intravenous inoculation of set-point plasma.…”

“…In the experiment by Ma et al (26), 20 vRNA copies of ramp-up plasma were injected i.v. into recipient animals.…”