AIDSWEEKLY Plus; Monday, October 12, 1998
Daniel J. DeNoon, Senior Editor

And with some 44,000 new HIV infections expected in the U.S. in the coming year, a major effort should be made to identify and treat such patients, argued Bruce D. Walker of Harvard University and Massachusetts General Hospital, Boston.

"HIV eradication may not be required," Walker said. "Clearly in some individuals the immune system can control the virus."

Walker spoke during the AIDS plenary session that has become traditional for the American Society for Microbiology's 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), this year held September 24-27, 1998, in San Diego, California.

Walker did not call for anyone currently on HAART to stop taking antiretroviral medications. But he said that there may soon be enough data to know whether - and when - such a recommendation can be made.

The eminent AIDS researcher painted a picture of two radically different HIV infected populations: those treated soon after becoming infected, and those who do not receive such early treatment.

For the first group, Walker pointed to strong clinical evidence that HAART can permit establishment of the same kind of immune responses seen in the rare HIV infected individuals who never progress to disease.

The second and much larger group with chronic infection appears already to have sustained too much immune damage to control the virus without antiviral drugs. But Walker held out hope that what is learned from the first group may show researchers how to boost anti- HIV immune responses in chronically infected patients. And such knowledge would be of inestimable value in developing an AIDS vaccine.

Walker noted that HIV suppression in people whose immune systems control HIV - the so-called nonprogressors - relies upon virus- specific cytotoxic T-lymphocyte (CTL) responses and not neutralizing antibodies.

CTLs taken from nonprogressors control HIV in laboratory cultures. But CTLs from individuals at the opposite end of the spectrum - rapid progressors who develop AIDS more quickly than is normal - are virtually incapable of attacking the virus.

The dramatic inhibition of HIV by CTLs from nonprogressors occurs even when the cells are removed from culture. This means that CTLs not only directly kill HIV infected cells, but also release cytokines that inactivate progeny virus.

"The real question is whether CTLs can actually inhibit virus when it is infecting cells in vivo," Walker said.

Using new immunologic measures, it is possible to show that increased anti-HIV CTLs correlate with decreased viral load in patients. But these CD8(+) lymphocytes may not themselves be the issue. To work, they require help from CD4(+) T cells.

Walker suggested that as HIV progressively deletes CD4(+) cells (or at least some clonal lines), the immune system loses its direction and CD8(+) cells are no longer capable of doing their job.

"In nonprogressors HIV can induce not only T-helper cells, but also an extremely vigorous response," he said.

These T helper responses are characterized by recognition of the HIV-1 p24 antigen. CTL responses to HIV Gag proteins correlate with the level of virus-specific helper function.

Walker said that he and other workers have in the last two years studied 20 patients with primary HIV infection. Most of these patients had no detectable HIV specific T-helper-cell activity when first seen. But within two months of beginning HAART, most had strong T-helper responses. After six months of treatment, all had strong T- helper responses. In the four patients followed for as long as one year, all still had very strong p24-specific CD4(+) helper responses: the same responses seen in untreated nonprogressors.

"It may be possible to cease antiretroviral therapy in such patients," Walker said. "There is some supportive evidence from animal models."

He therefore advised aggressive treatment be initiated for individuals diagnosed with primary HIV infection, and urged the development of a system to identify such patients.

"Can patients treated in acute infection control virus without drug treatment? In cohorts of early-treated patients we see the opportunity to answer this question," Walker concluded.

Unfortunately, HAART has not yet been shown to restore vigorous T- helper responses in patients with chronic infection. For patients with established HIV infection but with relatively high T-cell counts and relatively low viral loads, there is not the same urgency to begin treatment.
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