Faculty Bibliography

Now that all states are reporting newly identified H.I.V. infections in addition to AIDS cases, the picture of this country's AIDS epidemic could change significantly. On Jan. 1, Georgia became the last state to start reporting H.I.V. infections. ''In New York City, we have a very old, continuously evolving epidemic and a brand new H.I.V. surveillance system'' that ''allows us to understand not only who is acquiring H.I.V. but who is transmitting it,'' said Dr. Lucia V. Torian, who directs the city's H.I.V. monitoring. A New York law required H.I.V. reporting to begin on June 1, 2000. At the 11th annual Conference on Retroviruses and Opportunistic Infections here, Dr. Denis Nash, formerly of the city health department and now with the New York Academy of Medicine, reported New York City data on new H.I.V. cases for 2001. About two-thirds were men and one-third women. Blacks and Hispanics were 5 and 2.5 times, respectively, as likely to become infected with H.I.V. as non-Hispanic whites in the city. The numbers have been stable since then

Functional roles of the two ABC signature sequences ("LSGGQ") in the N- and C-terminal nucleotide binding domains of P-glycoprotein were studied by mutating the conserved Ser residues to Ala. The two single mutants (S528A; S1173A) each impaired ATPase activity mildly, and showed generally symmetrical effects on function, consistent with equivalent mechanistic roles of the two nucleotide sites. Synergy between the two mutations when combined was remarkable and resulted in strong catalytic impairment. The Ser residues are not involved significantly in MgATP- or MgADP-binding or in interdomain communication between catalytic sites and drug binding sites. Retention of product MgADP is not the cause of reduced turnover. Mutation of Ser to Ala reduced the strength of interaction with the chemical transition state specifically, as shown by vanadate-ADP and beryllium fluoride-ADP trapping experiments. Therefore, the two conserved ABC signature motif Ser residues of P-glycoprotein cooperatively accelerate ATP hydrolysis via chemical transition state interaction. Because the transition state complex is currently believed to form in the dimerized state of the nucleotide binding domains, one may also conclude that both Ser-OH are necessary for correct formation of the dimer state.

The research could have far-reaching implications. Experts knew that HIV could be resistant to nevirapine, but they were surprised by the findings that even a single dose could cause such a reaction. And because nevirapine is one of the three frontline therapies recommended by the World Health Organization to fight the spread of AIDS in developing countries, the results provide a sobering counterweight to its potency in reducing transmission of the virus to infants. A committee of experts said that AZT treatment for the mother from the 28th week of pregnancy, with a single dose of nevirapine at the onset of labor and a single dose of nevirapine plus one week of AZT for her newborn, was the most efficacious regimen for women who do not need chronic antiretroviral therapy. The Thai study found that women whose virus was drug resistant and later required long-term antiretroviral therapy were less likely to achieve maximal reduction of the amount of HIV in their blood if the drug therapy included nevirapine. But if treatment started more than six months after taking nevirapine, the amount of virus in the blood was lower

Her team investigated the outbreak using the new test, which is based on a technique known as P.C.R. (for polymerase chain reaction) and which can detect H.I.V., the AIDS virus, weeks earlier than the standard test. The initial weeks of H.I.V. infection is a period when the virus is easily transmitted because it is present in large amounts in the blood and semen. A Kaiser-Permanente team led by Dr. Michael Horberg analyzed the charts of 641 infected patients and 256 of 395 noninfected patients. A year after surgery, there were seven deaths among the infected patients and two among the noninfected. But the team attributed the deaths in infected patients to pre-existing conditions other than H.I.V. infection. The team undertook the study because doctors had a perception that suppressed immune function from H.I.V. would lead to a worse surgical outcome among infected patients. The team concluded that ''H.I.V. status should not by itself be a criterion for surgical consideration.''

The research could have far-reaching implications. Experts knew that H.I.V., the virus that causes AIDS, could be resistant to nevirapine, but they were surprised by the findings that even a single dose could cause such a reaction. And because nevirapine is one of the three front-line therapies recommended by the World Health Organization to fight the spread of AIDS in developing countries, the results provide a counterweight to its potency in reducing transmission of the virus to infants. Health officials have recommended since 1999 that an infected mother receive a single nevirapine pill during labor and that her newborn receive nevirapine once within the first three days of life. The therapy can reduce the risk of transmission of H.I.V. to 12 percent from 25 percent or more. The other new studies offset the good news. The resistance to nevirapine occurred in about 40 percent of infected women who took just one nevirapine pill during labor. Such resistance can persist for long periods of time, particularly when nevirapine is combined with other drugs for long-term treatment of H.I.V. infection and AIDS

The research could have far-reaching implications. Experts knew that HIV could be resistant to nevirapine, but they were surprised by the findings that even a single dose could cause such a reaction. And because nevirapine is one of the three front-line therapies recommended by the World Health Organization to fight the spread of AIDS in developing countries, the results provide a sobering counterweight to its potency in reducing transmission of the virus to infants. The other new studies offset the good news. The resistance to nevirapine occurred in about 40 percent of infected women who took just one nevirapine pill during labor. Such resistance can persist for long periods of time, particularly when nevirapine is combined with other drugs for long-term treatment of HIV infection and AIDS. Speaking at a news conference in San Francisco, Dr. Mary Glenn Fowler, a perinatal AIDS expert at the Centers for Disease Control and Prevention, said the Thai findings concerning AZT and nevirapine were dramatic. But she said that because the Thai study monitored the women and infants for only six months, and the potentially adverse resistance effects began to be seen only at six months, more studies are needed to determine how important resistance will be long term

The organizations and virologists said that no measure could be ruled out because of the unprecedented nature of the epidemic. It is caused by a strain of the A(H5N1) avian influenza virus that has mutated from one that caused smaller outbreaks in Hong Kong in 1997 and 2003. Experts in favor of large-scale vaccination contend that it will reduce the amount of virus that is spread among birds, and possibly to humans. But a crucial factor is that there is not enough vaccine right now to carry out such a measure, and that it would take months to produce enough to immunize birds in countries that decided to do so. The vaccines contain virus that has been grown in eggs and then killed. But because the avian influenza virus can kill chicken eggs, manufacturers have had to compromise by using a different and weaker strain, A(H5N2), and not A(H5N1), to make the vaccines, [Klaus Stoehr] said

The technique involves substituting harmless influenza genes for the ones that make the strain lethal to birds. In a conference call on Tuesday, two of the laboratories said that they had completed the first step in the reverse genetics technique and expected to begin testing the resulting virus in chickens and ferrets by next week. The scientists must make sure that the manufactured virus is harmless to chickens because it must be grown in live eggs. Any vaccine produced from such research will have to be tested in people before it is marketed

The other two groups are the United Nations Food and Agricultural Organization and the World Organization for Animal Health, which held a meeting in Rome on Tuesday. The organizations and virologists there said that no measure could be ruled out because of the ''unprecedented'' nature of the current epidemic. It is caused by a strain of the A(H5N1) avian influenza virus that mutated from one that caused smaller outbreaks in Hong Kong in 1997 and 2003. The mutant A(H5N1) strain has killed birds in Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand and Vietnam. As of yesterday, the W.H.O. said there were 20 known human cases, 16 of them fatal, in Thailand and Vietnam. The virus is grown in live eggs and then killed before it is used as a vaccine. But because the avian influenza virus can kill chicken eggs, manufacturers have had to compromise by using a different and weaker strain, A(H5N2) and not A(H5N1), to make the vaccines, Dr. [Klaus Stohr] said

Last week, WHO said it hoped to develop a seed virus that the UN agency in Geneva can provide in two months at no cost to drug companies so they can make a human vaccine. With the possible exception of two cases in Vietnam, there has been no person-to- person transmission of the A(H5N1) strain that is now spreading in Asia. The new strain has mutated from one that caused outbreaks in Hong Kong in 1997 and 2003, and experts fear that the new strain could cause a worldwide epidemic if it ever combines with a human influenza virus. The chance that such a recombination will occur is low, but WHO is pushing ahead to develop a human vaccine as a precautionary measure, said Dr. Klaus Stohr, leader of the agency's influenza program. Things are evolving according to schedule, he said Tuesday