From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: UV Light and HIV
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6171
Organization: unspecified
Date: Sun, 13 Sep 92 09:17:25 PDT

The following excerpts are from SCIENCE, Vol. 257, pages 1211-1212 dated 
August 28, 1992. It is from the RESEARCH NEWS section on Molecular Biology.

I CONSIDER IT A "MUST-READ" ARTICLE. I am only excerpting those sections that, 
in my personal opinion, are the most important.

All of the DNCB Treatment Instructions and Fact Sheets warn of the dangers of 
UV. This was not because of HIV activation but because studies showed, years 
ago, that Langerhans cells migrated from the skin under UV light leaving only 
T4 suppressor cells. This phenomena resulted in a shut-down of the immune 
system.

******************************************************************************
AWAKENINGS...UV LIGHT AND HIV GENE ACTIVATION
by Brigid M. Wallace and Jill S. Laser, science writers based in Richmond, VA.

"Like the 'mole' in a John LeCarre spy novel, the AIDS virus has a disturbing 
ability. After entering a susceptible cell, it can go underground, hiding in a 
latent form, often for many years, before flaring up and either destroying the 
host cell or transforming it into a virus-producing factory. Exactly what 
reawakens the sleeping virus remains a mystery, but recent work in several 
labs suggests that one culprit may be ultraviolet (UV) radiation, a worrisome 
finding given that people are routinely exposed to UV radiation.

"While most UV exposures come from the sun's rays, millions of people are also 
exposed through sun lamps and tanning salons, and between 25,000 and 50,000 
per year in the United States receive PUVA therapy, which is used for treating 
psoriasis and certain other skin diseases. And the evidence implicating UV 
radiation in HIV activation includes a finding by molecular virologist John 
Morrey of Utah State University in Logan that PUVA therapy, which combines UV 
with a light-sensitive drug turns on HIV genes in an animal model, indicating 
that it might also activate the dormant viral 'mole' in humans.

"Does all this mean that HIV-infected people should avoid excessive exposures 
to sunlight and PUVA therapy? The jury is still out, but Janust Beer of the 
Food and Drug Administration's radiation Biology branch in Rockville, 
Maryland, says that researchers investigating UV's effects on HIV feel that 
further studies are certainly warranted. Indeed, the FDA itself is 
sufficiently impressed by the finding that the agency has studies under way 
aimed as assessing the risks of UV exposures for HIV-infected people. And 
should those studies show that the exposures contribute to AIDS virus 
activation, the current work may pay off in another way. Researchers are also 
beginning to uncover the molecular mechanisms by which UV light activates 
latent HIV, information likely to aid in the eventual design of drugs that 
prevent or slow the viral re-awakening.

"Awareness that UV light can activate the AIDS virus dates back to work done 
in 1988 by molecular biologist Martin Rosenberg's group at SmithKline and 
French Laboratories in King of Prussia, Pennsylvania. Rosenberg and postdoc 
Kristoffer Valerie embarked on those experiments at a time when there was a 
strong focus in the AIDS research community on identifying the potential 
reactivating agents of latent HIV. Rosenberg's group chose to look at UV 
radiation, which is known to have DNA-damaging effects, since anything that 
could tweak the DNA might have the potential to trigger HIV activation.

"First the researchers needed a good system for assaying the activity of the 
HIV genome. So they constructed a hybrid gene by fusing an HIV gene sequence 
called the 'LTR' (which contains the 'on/off' switch for the viral genes) to a 
reported gene known as CAT (for chloramphenicol acetyltransferase) that makes 
a readily detectable protein. They then put the hybrid gene into human cells 
growing in culture and exposed them to UVC, the most energetic form of UV 
radiation having wavelengths ranging from 200 to 280 nanometers. The idea was 
that any increase in gene expression in response to the radiation would be 
reflected in increased CAT activity in the cells. And indeed, CAT activity 
went up 50- to 150-fold in the UVC-exposed cells, comparable to the levels 
achieved with other factors that had previously been shown to activate HIV 
gene expression. The Rosenberg team showed in further experiments that direct 
sunlight also activates HIV gene expression, although only about 12-fold.

"Other groups have subsequently confirmed these findings, and Anthony Fauci's 
laboratory at the National Institute of Allergy and Infectious Diseases in 
Bethesda went a step further in l989 by showing that UVB light (wavelengths 
between 280 and 315 nanometers) activates latent HIV itself--not just an HIV 
LTR construct--in chronically infected culture monocytes.

"All these experiments were performed with cultured cells, but more recent 
work described by Utah State's Morrey at this year's meeting of the American 
Society for Photobiology, shows that UV radiation also induces HIV gene 
activation in a living animal--a much more clinically relevant situation. For 
these experiments, Morrey and his colleagues used genetically altered mice 
they had created by introducing into the animals a gene construct made by 
linking the HIV LTR to a reported gene encoding either betagalactosidase or 
firefly luciferase. Exposure of the transgenic mice, to either UVB radiation 
alone or to UVA light combined with a light-sensitive, DNA-binding psoralen 
compound--the PUVA therapy--produced a marked increase in reporter gene 
activity in the animals' skin cells according to Morrey.

"Morrey cautions that while transgenic mice are convenient models for studying 
UV's effects on latent HIV in skin, even the mice do not completely reflect 
what happens in a natural HIV infection in humans. Nevertheless, the says, 'of 
course, our results are worrisome.' Morrey points out that the scientific 
literature contains several reports documenting the presence of HIV DNA in 
cells of the epidermis. Of particular concern is the isolation of HIV from 
Langerhans cells in the skin of HIV-infected people. Some AIDS researchers, 
including molecular biologist William Haseltine of Harvard University's Dana-
Farber Cancer Institute and his Harvard colleague Erik Langhoff, think that 
Langerhans cells may even by the most significant target of HIV, partially 
because they can be infected more efficiently than the better known targets, 
the CD4 T cells and macrophages of the immune system.

"Haseltine himself concedes that not everyone buys that idea. But even if he's 
wrong, the presence of HIV in Langerhans cells and the possibility that the 
virus might be activated by UV radiation are disturbing, given what's known 
about the function of the cells. Langerhans cells apparently detect and pick 
up foreign invaders or antigens in the skin. They then migrate into the 
circulation, where they mature into dendritic cells, which have the job of 
presenting the foreign antigens to the immune cells responsible for initiating 
a specific immune attack. These include the CD4 T cells--the very cells whose 
destruction results in the immune system collapse of AIDS patients. Work 
conducted in several laboratories in the past years, including Ralph 
Steinman's at Rockefeller University (Science, 17 July, p. 383), suggests that 
dendritic cells harboring HIV are capable of infecting CD4 T cells during 
antigen presentation, and this could contribute to the CD4 T cell decline seen 
in the later stages of AIDS.

"Another reason for concern is that a significant proportion of HIV-infected 
individuals have dermatological conditions that may be candidates for PUVA 
therapy, which could do more harm that good if it really activates latent HIV 
in Langerhans cells of the skin. Indeed, in another talk at the meeting, 
Barbara Zmudzka of the FDA's Radiation Biology branch said the epidemiological 
and clinical date will have to be studies and patients carefully monitored to 
see if HIV-infected people should take precautions, such as protecting 
themselves from UV exposure.

"But while those answers aren't yet in, researchers are moving ahead on 
another front: tackling the question of how UV radiation activates HIV gene 
expression in hopes of uncovering a mechanism that might allow them to prevent 
the effect. And their efforts appear to be yielding some answers, according to 
presentation at the meeting.

"At the photobiology meeting, Kristoffer Valerie, who's now at the Medical 
College of Virginia in Richmond, presented an intriguing hypothesis that may 
explain how the activation gets under way. In order for a cell to repair the 
DNA damage caused by UV, the DNA molecule has to unwind from its highly coiled 
state in the chromosome. This uncoiling exposes stretches of DNA and makes 
them accessible to the repair enzymes that correct the UV-induced lesions. 
What Valerie is suggesting is that the uncoiling also exposes HIV genes, 
thereby rendering them susceptible to transcription factors that might turn on 
the previously inaccessible viral genes. Evidence presented by Herrlich 
suggests that one of those factors might by NF-kappaB, a normal cellular 
transcription factor previously implicated in HIV gene activation by numerous 
research teams. He has found, for example, that UV irradiation increases 
NF-kappaB concentrations in cells carrying the HIV LTR.

"Although Valerie has also found that NF-kappaB levels increase after UV 
irradiation, he says the increase was not big enough to account for the 
magnitude of increase in LTR activity. Valerie suggests, however, that his 
cell culture system more closely mimics the actual environment in human cells 
than Herrlich's. But Valerie adds that his finding don't mean that NF-kappaB 
isn't involved, but they do indicate that additional factors also contribute 
to HIV activation in response to UV irradiation.

"Many more experiments need to be carried out before the question of how UV 
radiation trips HIV's transcriptional machinery is completely answered. But 
whatever the nature of the molecular mechanisms, researcher hope that laying 
them bare will lead to the design of agents that inhibit UV-induced activation 
of latent HIV. As Morrey's experiments with transgenic mice suggest, there is 
a certain urgency to finding the answers. Right now, the moles are winning 
out, and there's no George Smiley in sight."
******************************************************************************
Newsgroups: sci.med.aids