Zmudzka B Z, Miller S A, Jacobs M E, Beer J Z
Center for Devices and Radiological Health, Food and Drug Administration, Rockville, MD 20857, USA.
Photochem Photobiol. 1996 Aug;64(2):246-53. doi: 10.1111/j.1751-1097.1996.tb02453.x.
This paper presents the first attempt to evaluate the potential of clinical UV exposures to induce the human immunodeficiency (HIV) promoter and, thus, to upregulate HIV growth in those skin cells that are directly affected by the exposure. Using the data for HIV promoter activation in vitro, we computed UVB and psoralen plus UVA (PUVA) doses that produce 50% of the maximal promoter activation (AD50). Then, using (a) literature data for UV transmittance in the human skin, (b) a composite action spectrum for HIV promoter and pyrimidine dimer induction by UVB and (c) an action spectrum for DNA synthesis inhibition by PUVA, we estimated the distribution of medical UVB and PUVA doses in the skin. This allowed us to estimate how deep into the skin the HIV-activating doses might penetrate in an initial and an advanced stage of UVB or PUVA therapy. Such analysis was done for normal type II skin and for single exposures. The results allow us to predict where in the skin the HIV promoter may be induced by selected small and large therapeutic UVB or PUVA doses. To accommodate changes in skin topography due to disease and UV therapy, our considerations would require further refinements. For UVB we found that, when the incident dose on the surface of the skin is 500 J/m2 (290-320 nm) (initial stage of the therapy), the dose producing 50% of the maximal HIV promoter activation (ADUVB50) is limited to the stratum corneum. However, with an incident dose of 5000 J/m2 (an advanced stage of the therapy), ADUVB50) may be delivered as far as the living cells of the epidermis and even to some parts of the upper dermis. For PUVA we found that, when the incident UVA doses are 25 or 100 kJ/m2 (320-400 nm) (an initial and an advanced stage of therapy, respectively), and the 8-methoxypsoralen concentration in the blood is 0.1 microgram/mL (the desired level), the combined doses to the mid epidermis (and some areas of the upper dermis) are well below the 50% HIV promoter-activating PUVA dose (ADPUVA50). Only under the worst scenario conditions, i.e. an exceptionally high drug concentration in the patient's tissues and localization of HIV in the nearest proximity to the skin surface, would the combined PUVA dose expected during photochemotherapy exceed ADPUVA50. These results suggest that the probability of HIV activation in the epidermis by direct mechanisms is higher for UVB than for PUVA treatment. However, complexities of the UV-inducible HIV activation and immunomodulatory phenomena are such that our results by themselves should not be taken as an indication that UVB therapy carries a higher risk than PUVA therapy when administered to HIV-infected patients.
本文首次尝试评估临床紫外线暴露诱导人类免疫缺陷病毒（HIV）启动子的可能性，从而上调在暴露中直接受影响的皮肤细胞中的HIV生长。利用体外HIV启动子激活的数据，我们计算了产生最大启动子激活50%的中波紫外线（UVB）和补骨脂素加长波紫外线（PUVA）剂量（AD50）。然后，利用（a）人类皮肤中紫外线透过率的文献数据，（b）UVB诱导HIV启动子和嘧啶二聚体的复合作用光谱，以及（c）PUVA抑制DNA合成的作用光谱，我们估计了皮肤中医用UVB和PUVA剂量的分布。这使我们能够估计在UVB或PUVA治疗的初始阶段和晚期，激活HIV的剂量可能渗透到皮肤多深的位置。这种分析是针对正常II型皮肤和单次暴露进行的。结果使我们能够预测在皮肤的哪些部位，选定的小剂量和大剂量治疗性UVB或PUVA可能诱导HIV启动子。为了适应由于疾病和紫外线治疗导致的皮肤地形变化，我们的考虑还需要进一步完善。对于UVB，我们发现，当皮肤表面的入射剂量为500 J/m2（290 - 320 nm）（治疗初始阶段）时，产生最大HIV启动子激活50%的剂量（ADUVB50）仅限于角质层。然而，当入射剂量为5000 J/m2（治疗晚期）时，ADUVB50可能会传递到表皮的活细胞甚至上真皮的某些部位。对于PUVA，我们发现，当入射UVA剂量分别为25或100 kJ/m2（320 - 400 nm）（治疗的初始阶段和晚期），且血液中8 - 甲氧基补骨脂素浓度为0.1微克/毫升（理想水平）时，到达表皮中部（和上真皮的一些区域）的联合剂量远低于50%激活HIV启动子的PUVA剂量（ADPUVA50）。只有在最糟糕的情况下，即患者组织中药物浓度异常高且HIV位于最接近皮肤表面的位置，光化学疗法期间预期的联合PUVA剂量才会超过ADPUVA50。这些结果表明，通过直接机制在表皮中激活HIV的可能性对于UVB治疗高于PUVA治疗。然而，紫外线诱导的HIV激活和免疫调节现象非常复杂，以至于我们的结果本身不应被视为表明在对HIV感染患者进行治疗时，UVB疗法比PUVA疗法具有更高的风险。
