GENEVA (AP) _ Dr. Jonathan Mann, the American expert who has led the World Health Organization's battle against AIDS, announced Friday that he is resigning because of major differences with WHO's director-general.

The announcement surprised Mann's co-workers in WHO's AIDS program. One British AIDS specialist called the resignation a ''major disaster.''

The organization's director-general, Dr. Hiroshi Nakajima of Japan, issued a statement saying he regretted the announcement ''which happened, without previous consultation, at a time when the organization is confronted with new challenges concerning the fight against AIDS.'' He declined further comment.

Mann's letter of resignation indicated there had been disagreements between the two men ever since Nakajima took office in 1988. Nakajima succeeded Dr. Halfdan Mahler of Denmark.

''On the basis of my experiences during the last two years, I have now come to the conclusion that there is a great variance between our positions on a series of issues which I consider critical for the Global AIDS Strategy and the WHO Global Program on Aids,'' he said.

The program seeks to control an epidemic that has spread to more than 150 countries since it was first identified in 1981. More than 220,000 cases were registered worldwide by the WHO last month. Mann estimates there will be 6 million cases by the year 2000.

His letter of resignation and a memorandum he sent to his staff, both released to the media, did not explain the differences he had with Nakajima.

However, the departure follows persistent rumors of low morale among the 4,500-staff of WHO. Many blamed the director-general's management style for the problem. Critics reportedly complained of autocratic methods and of sudden transfers without prior notice.

The Netherland's mission to the United Nations, in a confidential letter quoted by Dutch newspapers this year, said work at the agency was deteriorating.

Mann said his resignation was effective at the end of his term in June.

Nakajima, 61, took office in 1988. Before that, he was in charge of WHO's Manila-based regional office for the Western Pacific. He held that job nine years.

When his candidacy for the top executive post became known, there were reports critically assessing his work on his previous assignments.

Mann, a public health official who grew up in Boston and attended Harvard, joined WHO in June 1986. The AIDS program then consisted of Mann and a secretary, with funds coming from the regular WHO budget.

The program now has a staff of close to 200 and a special budget that has tripled in the past three years to $109 million.

Mann, 42, has been traveling throughout the world to push a worldwide campaign to inform people of the dangers of AIDS and the methods of protection.

WHO spokeswoman Therese Gastaut said that following the announcement of Mann's resignation, he and Nakajima had a ''cordial'' meeting and agreed there are ''no differences on the fundamental problems'' of the Global AIDS Strategy.

It was not immediately possible to reconcile that statement with Mann's letter and memorandum. Gastaut said Nakajima could not be interviewed because he was leaving for Afghanistan on Friday night. Mann left word with his office that he was not prepared to talk to the media.

In London, Dr. Tony Pinching, who works at one of Britain's leading AIDS treatment centers, said: ''The loss of Dr. Mann is a major disaster, but it goes beyond that, and I view this with very grave concern indeed.

''There are few people of his caliber around. He has directed the program with great vision and ability and will be very difficult to replace.''

The resignation symbolized a ''very serious breakdown within the WHO'' which must be resolved for the sake of the program, he said.

The British government's chief medical officer, Sir Donald Acheson, said: ''I have a very high personal regard for Dr. Mann who has worked tirelessly with all countries to develop a global strategy to reduce the spread of HIV, (the AIDS virus), to provide appropriate care, and protect the rights and dignity of those affected.''