The hypoxic response is an important component of the body’s reaction to impaired tissue oxygenation associated with the anemia and vasoocclusive episodes of sickle cell disease (SCD). It has been reported that HIV infection progresses relatively slowly in patients with SCD (

Am J Hematol 1998;59:199–207
). HIV-1 Tat protein promotes transcription of HIV-1 genes by inducing CDK9/cyclin T1 to phosphorylate the C-terminal domain of RNA polymerase-II. Our previous studies indicate that protein phosphatase-1 (PP1) promotes Tat-induced HIV-1 transcription (
J Biol Chem 2003;278:32189–941
), apparently by interacting with HIV-1 Tat, for disruption of this interaction prevents induction of transcription (
J Biol Chem 2005;280:36364–71
). Recently PP1 activity was shown to be decreased in hypoxia in part through increased association of PP1 with NIPP1 (J Cell Physiol 2006 Jul 6; Epub ahead of print). We hypothesized that decreased PP1 activity during hypoxia would reduce HIV-1 transcription and viral replication, and we have obtained experimental results consistent with this hypothesis.

  1. Increased expression of nuclear inhibitor of PP1 (NIPP1) was associated with inhibition of HIV-1 transcription and viral replication.

  2. Low oxygen tension (3%–6% O2) was associated with transient inhibition of HIV-1 transcription in transfected 293T and HeLa cells.

  3. Low oxygen tension was associated with inhibition of HIV-1 transcription in CEM T cells infected with pseudotyped HIV-1 virus.

We are now planning to examine the possible role of altered PP1 activity in the observed inhibition of HIV-1 transcription during hypoxia. Thus, a clinical insight from patients with SCD has pointed the way to investigating the influence of hypoxia on HIV transcription. An improved understanding of how oxygen status influences viral activation versus inactivation might open new possibilities for treatment of hidden HIV-1 reservoirs that harbor non-replicating HIV-1 virus.

Topics:
hiv-1, hypoxia, arterial oxygen tension, anemia, cyclins, hiv infections, oxygen, protein phosphatase, rna, sickle cell anemia

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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