Suppression of acute viremia by short-term postexposure prophylaxis of simian/human immunodeficiency virus SHIV-RT-infected monkeys with a novel reverse transcriptase inhibitor (GW420867) allows for development of potent antiviral immune responses resulting in efficient containment of infection

Abstract

A nonnucleoside reverse transcriptase (RT) inhibitor, GW420867, was tested for postexposure prophylaxis (PEP) in rhesus macaques experimentally infected with 100 50% tissue culture infective doses of a chimeric simian/human immunodeficiency virus (SHIV) containing the RT gene of HIV-1 (SHIV-RT). Animals were either mock treated, or treated for 4 weeks starting at 8 or 24 h postinfection (p.i.) with GW420867. While such therapy led to undetectable plasma viremia in three of six monkeys, a transient plasma viremia was noted in the other three treated animals at 2 to 4 weeks following cessation of therapy. Following this transient viremia all drug-treated animals showed low or undetectable levels of plasma viremia up to the last sample examined at 90 weeks p.i. Despite low and/or undetectable viremia, virus-specific cytotoxic T lymphocyte and viral Env-specific proliferative responses were seen in the peripheral blood mononuclear cells of both mock- and drug-treated animals as early as 3 weeks p.i. Such virus-specific cellular responses, however, were better maintained in the drug-treated animals than the mock-treated animals. In contrast to the virus-specific cellular response, the magnitude and kinetics of virus specific humoral responses appeared to correlate with the detection of viremia. These data support the view that a short-term PEP with GW420867 permits the generation and maintenance of long-lasting virus-specific cell-mediated immune responses while markedly reducing viral loads to undetectable levels for a prolonged period of time (90 weeks) and leads to long-term disease protection. This model provides a unique means to define mechanisms and correlates of disease protection.

FIG. 1

Plasma viral RNA in SHIV-RT-infected animals treated with GW420867 or left untreated. Viral RNA levels in the plasma are expressed as copy number per milliliter.

FIG. 2

Humoral response against SHIV-RT. Shown are results of antibody ELISA analysis of plasma samples from the control animals and GW420867-treated animals. A 1:100 dilution of each plasma sample in phosphate-buffered saline (pH 7.4) containing a blocking reagent was assayed for SIV-specific antibody by using standard ELISA techniques with 96-well plates precoated with SIVmac239 virion lysate (14). The OD₄₉₂ was recorded and used as a relative measure of antibody titer. The duration of drug treatment is indicated by the bar with arrowheads.

FIG. 3

Virus-specific cellular immunity CTL activity in the PBMC samples of control and GW420867-treated animals was determined by using autologous B-LCL target cells previously infected with a VV construct containing SIVmac gag-pol (A) and a VV construct containing SIVmac env (B). In addition, controls used B-LCL infected with VV wild type (NYCBH strain). The percentage of net specific lysis was calculated for each effector-to-target cell combination, and this value was subtracted from the value obtained with the wild-type VV target cell control. Only results of effector/target ratio of 80:1 are shown. pre., preinfection.

FIG. 4

In vitro proliferative response of PBMC against SIVmac env-rVV-infected autologous B-LCL. PBMC used for this assay were aliquots of the same specimen used for the CTL assay. The stimulation index was calculated as the mean counts per minute of PBMC cultured with env-rVV divided by the mean counts per minute of PBMC cultured with control VV. pre., preinfection.