4.7 Article

Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection

期刊

JOURNAL OF EXPERIMENTAL MEDICINE
卷 198, 期 10, 页码 1551-1562

出版社

ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20031266

关键词

HIV; AIDS; antiretroviral therapy; microbicide; chemokine receptor

资金

  1. NCI NIH HHS [N01-CO-124000] Funding Source: Medline
  2. NCRR NIH HHS [RR00164, P51 RR000164] Funding Source: Medline
  3. NIAID NIH HHS [AI41420, R01 AI041420, AI52048, AI49080, P01 AI052048, R01 AI049080] Funding Source: Medline
  4. NICHD NIH HHS [HD36310] Funding Source: Medline

向作者/读者索取更多资源

Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCK5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian-human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission.

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