SCIENCE/TECHNOLOGY
AAAS Symposium Emphasizes Progress Made in AIDS Research How AIDS virus disrupts immune system is becoming clearer; approaches to treating infections the virus causes have advanced significantly Rudy M. Baum, C&EN San Francisco
Slow but significant progress is being made in understanding the h u m a n immunodeficiency virus (HIV)—the cause of acquired immune deficiency syndrome (AIDS)— and in developing methods for treating HIV infections, according to speakers at a symposium at the recent American Association for the Advancement of Science annual meeting in New Orleans. One prominent AIDS researcher at the AAAS meeting, William A. Haseltine of Dana-Farber Cancer Institute in Boston, even predicted that a "cure for AIDS" will be developed. Haseltine, speaking to a press conference, said that it has now become probable that combination therapies involving a number of drugs will allow people infected with HIV to live normal lives and not transmit the virus to others. In fact, treatments already available to AIDS patients are blurring the distinction between AIDS, which has a clinically based definition, and HIV infection, according to Sten Vermund of the National Institute of Allergy & Infectious Diseases (NIAID). This is especially true for treatments such as zidovudine (AZT), which retards HIV replication, and aerosolized pentamidine, which is effective in treating and preventing an opportunistic infection called Pneumocystis carinii pneumonia. Vermund, an epidemiologist, provided the symposium with the run24
March 12, 1990 C&EN
down of AIDS statistics that have come to characterize any such gathering. Among them: The proportion of AIDS patients who are male homosexuals (61%) is shrinking relative to those who are intravenous drug users (20%) and heterosexuals (5%). Vermund points out that most intravenous drug users are heterosexuals, and says, "It disturbs me when people ask, 'Why haven't we seen an explosion [of AIDS cases] in the heterosexual population? 7 " Epidemiologists who are tracking the AIDS epidemic think that is "exactly what we are seeing," he says. Figures cited by Vermund, however, suggest that male homosexuals will continue for some time to bear the brunt of the AIDS epidemic. Surveys indicate that a staggering percentage of gay men in major metropolitan areas are infected with HIV—for example, in San Francisco, 52%; in Los Angeles, 48%; in Denver, 40%; and in Madison /Milwaukee, 28%. Surveillance data do suggest
Hazeltine: cure for AIDS possible
that since 1987 the number of newcases of AIDS among gay men, while continuing to rise, has leveled off significantly from the exponential increase observed through the first several years of the epidemic. Vermund attributes this trend to changes in sexual behavior among many gay men and to the availability of zidovudine. The now proven effectiveness of zidovudine in delaying the onset of AIDS in HIV-infected individuals, coupled with the promise of new anti-HIV agents, has "completely changed" the question of screening for HIV infection in the U.S., Vermund says. People at risk for HIV infection now have a compelling reason to know whether, in fact, they are infected with the virus and, if they are, their immune system status so that appropriate treatment can be initiated. Vermund was echoed on this point by another speaker at the symposium, Ann Collier of the University of Washington, Seattle. It now appears that there is no true HIV latency period, and that a low level of virus replication occurs throughout an infection, Collier says. This low level of HIV replication places continuous pressure on the immune system, especially on the T4 lymphocytes that are one of the primary targets of the virus. Depletion of T4 lymphocytes eventually leads to the immune system's collapse that characterizes AIDS. All people who are infected with HIV and whose T4 lymphocytes have been depleted to below 500 per mL (normal T4 levels are between 900 and 1200 per mL) should be offered zidovudine, Collier told the symposium. Such a policy raises a number of issues, however. There may be as many as 600,000 such individuals in the U.S., and existing
AIDS treatment centers simply can't handle that many patients. Treat ment with 500 mg of zidovudine per day will cost about $3200 per year, she says, and it has yet to be resolved who will pay it. Collier also reviewed the status of a number of anti-HIV therapies under development. The most prom ising is another nucleoside analog, 2 / ,3 / -dideoxyinosine (DDI). Collier noted that DDI is undergoing clinical trials under the Food & Drug Admin istration's new "open label" program that provides for Phase II clinical trials comparing DDI with zidovu dine, while at the same time offer ing DDI to individuals who prefer to receive it instead of zidovudine. About 500 AIDS patients are en rolled in the clinical study, but sev eral thousand have elected to re ceive DDI immediately. The 500 par ticipating in the clinical study is close to the minimum needed to obtain statistically significant infor mation on the performance of DDI as an anti-HIV agent. Collier and others are concerned that the open label program, while well meaning, could undermine the development process for new AIDS drugs. Another once promising nucleo side analog, 2 / ,3'-dideoxycytidine (DDC), probably will not find a role as a single agent in treating HIV infections, Collier says. Clinical trials have shown that the drug causes significant adverse side effects at high and low doses, and interest in the drug now focuses on its use in combination with other agents such as zidovudine. Clinical studies of combinations of DDC and zidovu dine, DDI and zidovudine, and α-interferon and zidovudine are currently in progress, Collier says. Haseltine outlined progress in un derstanding HIV and how it dis rupts the human immune system. For a number of years, the accepted wisdom in AIDS research was that HIV, after infecting an individual, entered a latency period the dura tion of which varied from two to 10 years or longer. It now appears that what was viewed as latency is, in fact, a low-level, chronic infection held in check by the immune sys tem, Haseltine says. HIV infection is not a disease that "gets the im mune system before the immune
Fa uci: probe for imm un orégula tion system gets it," he observes. On the contrary, the immune system effectively controls the virus for quite a long time, and efforts to treat HIV disease must focus on preventing the virus from escaping that control. HIV infects a variety of cell types, including T4 lymphocytes, monocytes and macrophages, and some Β lymphocytes of the immune system, as well as microglial cells, mono cytes, and some epithelial cells in the brain, but it selectively kills only those cells that express a significant amount of a cell-surface antigen called CD4. This selective cytotox icity apparently is a direct conse quence of the interaction of the vi ral envelope glycoprotein, gpl20/ gp41, and CD4, Haseltine says, and is mediated by at least three differ ent processes that kill cells. An early paradox of the AIDS epidemic—that only a few T4 cells appeared to be infected with HIV while many T4 cells died—has dis appeared, Haseltine says. The para dox led some scientists to suggest that HIV could not be the cause of AIDS. At Dana-Farber, more sophis ticated ways of detecting HIV indi cate that as many as one in 20 T4 cells are infected with the virus in later stages of an HIV infection. Haseltine also reviewed the nu merous targets HIV offers for drug development. An intriguing effort in his laboratory has focused on the binding of HIV ribonucleic acid (HIV is a retrovirus in which the
genetic material is RNA rather than DNA) within the virus particle. Binding involves a small, specific region of the nucleic acid that the scientists have deleted, resulting in an HIV particle that contains no genetic material. Haseltine hopes to use this construction as a system to deliver drugs or for gene therapy. Another subject Haseltine focused on is the remarkably complex ge netic regulatory mechanisms em ployed by HIV in the course of an infection. Once viral RNA is pro duced in a cell to begin the produc tion of new virus particles, a "cir cus" of events takes place, Haseltine says. This complex pattern of ge netic regulation was not anticipated by researchers when HIV was first discovered, and Haseltine believes that, as has been the case with pre viously characterized viruses, the mechanisms employed by HIV are pointing the way toward a new un derstanding of normal genetic reg ulation in eukaryotic cells. Understanding genetic regulation is not the only area of molecular biology and biomedicine that HIV has dramatically affected. John J. McGowan, an AIDS researcher at NIAID, pointed out that the viral drug discovery process was "virtu ally dead" by the mid-1970s because most scientists had concluded that the replication mechanisms em ployed by viruses were so similar to those of normal cells that it was hopeless to try to intervene in one without disrupting the other. "AIDS has revolutionized thinking about antiviral" agents in general, Mc Gowan says. A n o t h e r p r o m i n e n t AIDS re searcher, Anthony S. Fauci, direc tor of NIAID, discussed the immunopathogenic mechanisms of HIV infections in a plenary lecture at the AAAS meeting. Fauci echoed Haseltine's conclusion that the HIV burden of T4 lymphocytes in the peripheral blood is much higher than had been realized until recent ly. In only about one in 1000 to one in 10,000 T4 lymphocytes is active HIV replication occurring, Fauci said, but a test called the polymer ase chain reaction has revealed that about one in 100 T4 cells harbors the virus. In advanced stages of the in fection, NIAID researchers detect as March 12, 1990 C&EN
25
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March 12, 1990 C&EN
many as one in 10 T4 cells harbor ing HIV. HIV kills T4 cells. It infects but does not seem to kill monocytes and macrophages. These immune sys tem cells act as an important reser voir of HIV, and they appear to account for most, if not all, of the serious neuropathological effects seen in some HIV infections, Fauci says. Infected monocytes in the brain may inappropriately secrete a num ber of compounds that act to dis rupt neuronal function, he says. Fauci's group at NIAID has fo cused for some time on how cyto kines are involved in activation of a "latent" or quiescent HIV infec tion. Cytokines are the chemical messengers of the immune system, and it has been clear for some time that the system organizes itself through a highly complex network of cytokine-mediated communica tion among cells. Fauci said that a number of ex periments have established that tu mor necrosis factor-alpha (TNF-a), which is secreted by monocytes and macrophages in response to infec
tions, can directly induce HIV ex pression in T4 lymphocytes. It does this by interacting with control ele ments in the HIV genome that are very similar to a genetic regulatory element called NF-κΒ present in im mune system cells. The NIAID scientists have also shown that another cytokine, interleukin-6 (IL-6), which has a num ber of immunoregulatory functions, directly stimulates HIV expression in chronically infected monocytes and macrophages. IL-6 appears to have no effect on HIV expression in T4 cells. In combination, IL-6 and TNF-α act synergistically to activate HIV expression in an infected indi vidual, Fauci says. Yet other cyto kines are able to suppress the acti vation of HIV expression by IL-6. Fauci noted that HIV is "capturing well-defined mechanisms" used by the normal immune system to regu late itself. Despite the havoc HIV has caused, the virus will turn out also to be an important probe in dissect ing immune function and under standing immune diseases that have nothing to do with HIV, he says. D
Oxidative coupling technology may offer new route to olefins Joseph Haggin, C&EN Chicago
Although oxidative coupling can convert methane to olefins and oth er higher hydrocarbons, research ers have run into problems when attempting to convert methanecontaining mixtures, such as natu ral gas. Solving these problems has been the aim of several develop ment laboratories, including the Institut Français du Pétrole (IFP), which has recently disclosed some of the details of its technology. Charles J. Cameron, research engineer in IFP's department of natural gas upgrading, and his colleagues have demonstrated that oxidative coupling of methane produces ethane and ethylene when reacted over basic oxide catalysts. However, this chemistry is not well suited for converting the mixtures of alkanes typically encountered in natural gas. For example, Cameron's group has
found that, if mixtures of methane, ethane, and oxygen are cofed over oxide catalysts, oxygen is preferentially consumed for the oxidative dehydrogenation of ethane to ethylene, and the methane remains virtually unreacted. But if the ethane is separated from the feed mixture, another reaction occurs. The heat generated from the exothermic, oxidative coupling of methane can be used in the thermal conversion of the separated ethane to ethylene and hydrogen. IFP's experiments indicate that the process suggested by this chemistry has a C2+ selectivity (production of C2 and higher alkanes) of over 80%, with about 16% methane conversion and virtually complete oxygen consumption. The ethane/ethylene ratio in the product can be controlled to some extent by varying the reactor parameters. The tandem operations of meth-
