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.
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.
Mori
K
K
AIDS Research Center, National Institute of Infectious Diseases, Tokyo Japan. mori@nih.go.jp
Yasutomi
Y
Y
Sawada
S
S
Villinger
F
F
Sugama
K
K
Rosenwith
B
B
Heeney
J L
JL
Uberla
K
K
Yamazaki
S
S
Ansari
A A
AA
Rübsamen-Waigmann
H
H
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use*; D019556:COS Cells; D006678:HIV / Q000201:enzymology* / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D011810:Quinoxalines / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D013997:Time Factors; D014766:Viremia
D000914:Antibodies, Viral; D000998:Antiviral Agents; C411722:GW420867; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase