Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy.
BACKGROUND
Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs.


RESULTS
Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 production from long-living virus-infected macrophages. These PI3K/Akt inhibitors hyper-sensitize infected macrophages to extracellular stresses that they are normally exposed to, and eventually lead to cell death of infected macrophages without harming uninfected cells. Based on the data from these Akt inhibitors, we were able to further investigate how HIV-1 infection utilizes the PI3K/Akt pathway to establish the cytoprotective effect of HIV-1 infection, which extends the lifespan of infected macrophages, a key viral reservoir. First, we found that HIV-1 infection activates the well characterized pro-survival PI3K/Akt pathway in primary human macrophages, as reflected by decreased PTEN protein expression and increased Akt kinase activity. Interestingly, the expression of HIV-1 or SIV Tat is sufficient to mediate this cytoprotective effect, which is dependent on the basic domain of Tat - a region that has previously been shown to bind p53. Next, we observed that this interaction appears to contribute to the downregulation of PTEN expression, since HIV-1 Tat was found to compete with PTEN for p53 binding; this is known to result in p53 destabilization, with a consequent reduction in PTEN protein production.


CONCLUSIONS
Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs.
Chugh
Pauline
P
Department of Microbiology and Immunology, School of Medicine, University of Rochester Medical Center 601 Elmwood Avenue Box 672 Rochester, New York 14742 USA. Pauline_Chugh@urmc.rochester.edu
Bradel-Tretheway
Birgit
B
Monteiro-Filho
Carlos M R
CM
Planelles
Vicente
V
Maggirwar
Sanjay B
SB
Dewhurst
Stephen
S
Kim
Baek
B
D002478:Cells, Cultured; D015536:Down-Regulation; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008264:Macrophages; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C039128:miltefosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase