title: Antiretroviral therapy during primary immunodeficiency virus infection can induce persistent suppression of virus load and protection from heterologous challenge in rhesus macaques.
abstract: A limited period of chemotherapy during primary immunodeficiency virus infection might provide a long-term clinical benefit even if treatment is initiated at a time point when virus is already detectable in plasma. To evaluate this strategy, we infected rhesus macaques with the pathogenic simian/human immunodeficiency virus RT-SHIV and treated them with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for 8 weeks starting 7 or 14 days postinfection. PMPA treatment suppressed viral replication efficiently in all of the monkeys. After chemotherapy ended, virus replication rebounded and viral RNA in plasma reached levels comparable to that of the controls in four of the six monkeys. However, in the other two animals, virus loads peaked only moderately after withdrawal of the drug and then declined to low or even undetectable levels. These low levels of viremia remained stable for at least 31 weeks after cessation of therapy. At this time point, these two monkeys were challenged with SIV(8980) to evaluate whether the host responses which were able to keep RT-SHIV replication under control were also sufficient to protect against infection with a highly pathogenic heterologous virus. Both monkeys proved to be protected against the heterologous virus. In one of the two animals, low levels of SIV(8980) replication were detected. Thus, by chemotherapy during the acute phase of pathogenic virus replication, we could achieve not only persistent virus load suppression in two out of six monkeys but also protection from subsequent heterologous challenge. By this chemotherapeutic attenuation, the replication kinetics of attenuated viruses could be mimicked and a vaccination effect similar to that induced by live attenuated simian immunodeficiency virus vaccines was achieved.
authors.affiliation: Departments of Virology and Animal Science, Biomedical Primate Research Center, 2288 GJ Rijswijk, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Rosenwirth
authors.forename: P
authors.initials: P
authors.lastname: ten Haaft
authors.forename: W M
authors.initials: WM
authors.lastname: Bogers
authors.forename: I G
authors.initials: IG
authors.lastname: Nieuwenhuis
authors.forename: H
authors.initials: H
authors.lastname: Niphuis
authors.forename: E M
authors.initials: EM
authors.lastname: Kuhn
authors.forename: N
authors.initials: N
authors.lastname: Bischofberger
authors.forename: J L
authors.initials: JL
authors.lastname: Heeney
authors.forename: K
authors.initials: K
authors.lastname: Uberla
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D006801:Humans; D016131:Lymphocyte Subsets; D008253:Macaca mulatta; D008562:Membrane Glycoproteins; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011995:Recombination, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D000068698:Tenofovir; D014759:Viral Envelope Proteins; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine