THE NEW YEAR sees a welcome boost for scientists engaged in the battle against HIV and AIDS. American researchers have determined the three-dimensional structure of the enzyme HIV integrase, which the virus needs if it is to multiply inside human cells. The discovery opens up the possibility of designing new drugs to combat the disease.

Before HIV can reproduce inside an infected cell its genes must be incorporated into the cell鈥檚 own DNA. This process is controlled by HIV integrase, which cuts the human DNA and splices in the viral genes. 杏吧原创s have seen the enzyme as an ideal target for drugs. Human cells do not seem to contain any similar enzymes, so it should be possible to design a drug which inactivates HIV integrase but is not toxic to human cells.

But before designing a drug which targets a specific enzyme, researchers must know the enzyme鈥檚 structure. Until now, efforts to determine the precise shape of HIV integrase have been thwarted because the enzyme is highly insoluble in water. Biologists can work out the structure of molecules by studying the diffraction of X-rays shone through pure crystals of the substance. But these crystals can only be obtained from a concentrated solution of the substance in question.

This problem of producing a concentrated solution of HIV integrase has now been solved by a group led by Robert Craigie of the US National Institute of Dfabetes and Digestive and Kidney Diseases in Bethesda, Maryland. Craigie鈥檚 team altered the enzyme to make it more soluble. The researchers looked at a region of the molecule which seems to be important for the enzyme鈥檚 activity, and systematically produced 鈥渕utant鈥� forms of this region.

HIV integrase, like all proteins, is made up of building blocks called amino acids. The researchers replaced water-repelling amino acids in this region with other, water-attracting amino acids. 鈥淲e struck lucky,鈥� says Tim Jenkins, who works in Craigie鈥檚 laboratory. One of the mutant forms of the enzyme was soluble, yet was still able to act as an integrase.

To work out this mutant鈥檚 structure, Craigie teamed up with an X-ray crystallography group at the same institute, headed by David Davies. They discovered that its shape resembled those of several molecules from a group of enzymes called polynucleotidyl transferases, which manipulate DNA inside cells. By comparing the shape of the mutant HIV integrase with other enzymes from this group the researchers were able to pinpoint the precise region responsible for its activity (Science, vol 266, p 1981).

Now that the active site of HIV integrase is known, the scene is set for researchers to design drugs which bind to it and block the enzyme鈥檚 activity.

Two other key HIV enzymes 鈥� HIV protease and reverse transcriptase 鈥� are also required for the virus to reproduce inside human cells, and pharmaceuticals companies have already found drugs which inhibit them. The most widely used anti-HIV drug, Wellcome鈥檚 AZT, blocks reverse transcriptase. And several companies, including Wellcome and Roche, are developing drugs which inhibit the protease enzyme.

Craigie and Davies point out that HIV mutates rapidly to escape the effects of a drug targeted at only one enzyme. They say a more effective weapon against AIDS may be a cocktail of drugs against each of the three enzymes. 鈥淭he chance that the virus could simultaneously develop resistance to drugs against three different targets is likely to be extremely low,鈥� says Craigie.

Back in the 1950s my own introduction at Oxford to overnight accommodation
accompanied the trauma of entrance examinations and interviews. A mere grammar-school
boy, I lacked the hardening of a residential public-school training. A sleepless
night in a cold, unheated bedroom left me ill prepared for the early-morning
intrusion of my staircase 鈥榮cout鈥� who delivered me one small jug of warm(ish)
water (shaving?), a large jug of ice-cold water (washing?) and an enormous
floral earthenware bowl (for standing in while shaving and washing).

Yet my interest in attending that noble institution persisted and it
was as an undergraduate there that I came to appreciate the sagacity of
that apocryphal college Master who, on being shown plans for college refurbishment,
demanded to know what several new small rooms were to be used for. On being
told these were to be bathrooms for the undergraduates, he retorted: 鈥楪ood
God, they鈥檙e only here for eight weeks at a time!鈥� Plus ca change, I thought,
when I recently stayed overnight for a pre-Christmas scientific conference
at a Midlands university.

A room on the 16th floor sounded impressive 鈥� shades of a penthouse
suite 鈥� and, at a first glance, looked reasonable for the 鈥榤odest鈥� price
charged. There was the bed, the half-wardrobe vacated by the term-time student
occupant, a washbasin, the now statutory assembly of tea/coffee/sugar/milk
sachets and the obligatory needle-and-thread repair kit to tackle loose
buttons, torn shirts, holed socks or any of the 101 hazards that can afflict
the unwary conference-goer. Toilet and bathing facilities were, I was assured,
available along the corridor. But then first appearances can be deceptive.

Only when I returned to go to bed did I discover that the taps on the
washbasin were not of the conventional turn-on-and-off type, but rather
of the push-down-and-hold variety. I presume that these had been installed
to accommodate the forgetfulness, recklessness or just plain latent vandalism
of students who might be tempted to turn taps on but not off. They do little,
however, for the more mature ablutioner and certainly prevent any sort of
washing in clean running water. They must also be a nightmare for the incapacitated
or one-armed user.

I thought I鈥檇 cheer myself up by reading a while in bed. There was a
reading lamp on the distant desk and the cable stretched just far enough
to enable me to balance the lamp on a chair placed near the bed. But there
was clearly no way in which I would be able to turn out the light from the
bed 鈥� no switch on the lamp, power point beyond reach. I鈥檇 have to get out
again to do this.

Students may put their beds to a variety of uses, but can鈥檛 we assume
that, just occasionally, reading is one of them? I abandoned my book, extinguished
the light and tripped my way into bed. I was instantly transported back
to the 1950s 鈥� a freezing bed and a room which became progressively colder
the more I wrestled to fall asleep. In desperation, I toyed with the idea
of opening a window to let in some heat from the December night outside,
but couldn鈥檛 face the dark journey to the light switch past unremembered
obstacles.

Morning mercifully arrived. Swathed in overcoat, scarf and gloves, and
carrying the necessary accessories for bathing and dressing, I set off for
the bathroom, hoping to defrost in a hot bath. The bath cubicle was furnished
with a single hook 鈥� no shelf, stool or any surface to put things down.
Perhaps one is meant to enter and exit in the nude. A container of bath
cleaner was the only other facility provided, though no brush or cloth to
apply it.

Back in my room I sought solace in a shave. In the absence of an electric
shaver point, I battled again with the push-and-hold water supply. But early
December mornings are dark. The electric light was situated so as to offer
no illumination of my face in front of the mirror, so I tried to rig up
the desk lamp to shine from the side. I shaved that side. The lamp cable
didn鈥檛 stretch to the other side. I shaved in the shade, cut myself and
emerged smooth but bloodied, making a mental note to sit in profile during
the day鈥檚 symposium.

鈥楺uality鈥� is a term increasingly creeping into the vocabulary of higher-education
institutions. If providing rooms for conferences is to be a significant
(and profitable) part of their business, they鈥檒l have to rethink the quality
of such provision. Universities have long got away with poor standards because
conference participants cannot generally afford inflated hotel prices and
because it鈥檚 convenient to sleep on the same site as the meetings are held.

Sadly, my host university was not atypical. I presume that students
tolerate such ill-designed accommodation only because, like conference folk,
they are strapped for cash and need to be on site. Yet better and more thoughtful
design and provision need represent little additional burden to the university;
the extra cost would be recouped from more customers coming to appreciate
a better service. Who knows, we might then even be in a position to share
our expertise with institutions overseas!

Dr David Weitzman writes from the warmth and comfort of his own bedroom
and shower in Cardiff.