Initiation of antiretroviral therapy 48 hours after infection with simian immunodeficiency virus potently suppresses acute-phase viremia and blocks the massive loss of memory CD4+ T cells but fails to prevent disease.
We investigated whether a 28-day course of potent antiretroviral therapy, initiated at a time point (48 h postinoculation) following simian immunodeficiency virus (SIV) inoculation when the acquisition of a viral infection was virtually assured, would sufficiently sensitize the immune system and result in controlled virus replication when treatment was stopped. The administration of tenofovir 48 h after SIV inoculation to six Mamu-A*01-negative rhesus macaques did, in fact, potently suppress virus replication in all of the treated rhesus macaques, but plasma viral RNA rapidly became detectable in all six animals following its cessation. Unexpectedly, the viral set points in the treated monkeys became established at two distinct levels. Three controller macaques had chronic phase virus loads in the range of 1 x 10(3) RNA copies/ml, whereas three noncontroller animals had set points of 2 x 10(5) to 8 x 10(5) RNA copies/ml. All of the noncontroller monkeys died with symptoms of immunodeficiency by week 60 postinfection, whereas two of the three controller animals were alive at week 80. Interestingly, the three controller macaques each carried major histocompatibility complex class I alleles that previously were reported to confer protection against SIV, and two of these animals generated cytotoxic T-lymphocyte escape viral variants during the course of their infections.
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 2089-0460, USA.
Makoto
M
Kubo
Yoshiaki
Y
Nishimura
Masashi
M
Shingai
Wendy
W
Lee
Jason
J
Brenchley
Bernard
B
Lafont
Alicia
A
Buckler-White
Tatsuhiko
T
Igarashi
Malcolm A
MA
Martin
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007267:Injections; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D063065:Organophosphonates / Q000008:administration & dosage; D016415:Sequence Alignment; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000068698:Tenofovir; D013997:Time Factors; D014766:Viremia / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D015483:HIV Antibodies; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine