Human Immunodefficiency Virus Research Articles

Inhibition of human immunodeficiency virus type 1 reverse transcriptase by 3′-blocked oligonucleotide primers

Human immunodefficiency virus type 1 (HIV-1) reverse transcriptase (RT) (EC 2.7.7.49) with a high specific activity has been purified from the overexpressing Escherichia coli strain DH5α[pJS3.7]. Steady-state kinetics of DNA synthesis catalysed by RT were analysed on polyribo-adenylate 20-mer of (3′-5′)deoxythymidylate [poly(rA)-(dT) 20] and polyribouridylate 20-mer of (3′-5′)-deoxyadenylate [poly(rU).(dA) 20] homopolymeric template-primers. K m values of 40 and 140 nM (3′-OH ends) and k cat values of 4 and 0.14sec −1 were determined for the two different substrates. Oligonucleotide primers (dA) 20 and (dT) 20 were elongated in a terminal transferase-catalysed reaction (EC 2.7.7.31) with ddATP, 3′-dATP (cordycepin), 2′,3′-epoxy-ATP and arabino-ATP; and ddTTP, 3′-azido-TTP, 3′-dUTP, 3′-F-dTTP and rUTP, respectively. The resulting oligonucleotides were hybridized to their complementary templates and the inhibitory potential of these compounds towards DNA synthesis started from unchanged primers was measured. Oligonucleotides with unextendable 3′-groups were shown to act as strong inhibitors of DNA synthesis catalysed by HIV-1 RT. In particular, poly(rA).(dT) 20-[ddTMP] and poly(rU).(dA) 20-[3′-dAMP] were potent competitive inhibitors, displaying k i values of about 6 and 12 nM, respectively. Also 3′-azido-, and 3′-fluoro-terminated oligonucleotides showed competitive inhibition with inhibition constants in the range of 20–35 nM. In contrast, 2′,3′-epoxy-terminated (dA) 21 displayed a mixed-type inhibition with a if K ivalue of 67 nM. Arabino-terminated (dA) 21 was found to be an uncompetitive inhibitor of HIV-1 RT with an inhibition constant of 318 nM. Arabino-terminated primers did not act as strict chain terminators because they could be elongated by HIV-1 RT. This study provides information on the structure-activity relationship of modified 3′-termini of primer molecules which might be exploited as inhibitors of HIV in the future.

Synergistic inhibition of human immunodefficiency virus type 1 [formula omitted] by coumermycin A1 and human leukocyte interferon

Synergistic inhibition of human immunodefficiency virus type 1 [formula omitted] by coumermycin A1 and human leukocyte interferon

Oenothein B, a dimeric hydrolyzable tannin of cyclic structure.

Oenothein B, isolated from the leaves of Oenothera erythrosepala (Onagraceae), had host-mediated antitumor activity and antiviral effects on human immunodefficiency virus (HIV) and herpes simplex virus (HSV). It is a dimeric hydrolyzable tannin with a cyclic structure 1.

Markov control processes with rare state observation: theory and application to treatment scheduling in HIV–1

Markov Decision Processes (MDP) or Partially Observable MDPs (POMDP) are used for modelling situations in which the evolution of a process is partly random and partly controllable. These MDP theories allow for computing the optimal control policy for processes that can continuously or frequently be observed, even if only partially. However, they cannot be applied if state observation is very costly and therefore rare (in time). We present a novel MDP theory for rare, costly observations and derive the corresponding Bellman equation. In the new theory, state information can be derived for a particular cost after certain, rather long time intervals. The resulting information costs enter into the total cost and thus into the optimization criterion. This approach applies to many real world problems, particularly in the medical context, where the medical condition is examined rather rarely because examination costs are high. At the same time, the approach allows for efficient numerical realization. We demonstrate the usefulness of the novel theory by determining, from the national economic perspective, optimal therapeutic policies for the treatment of the human immunodefficiency virus (HIV) in resource-rich and resource-poor settings. Based on the developed theory and models, we discover that available drugs may not be utilized efficiently in resource-poor settings due to exorbitant diagnostic costs.