GMHC Treatment Issues, Volume 10, Number 6/7 - June/July 1996
Gregg Gonslaves

The symposium gathered together about 75 scientists from academia and industry, with a high concentration of investigators affiliated with the AIDS Clinical Trials Group. Many of the researchers in attendance were people with a long history of presumptuous optimism about the power of antiretroviral therapy. There was scant representation of researchers and clinicians who have strong concerns about defining optimal use of the new generation of anti-HIV drugs, development of resistance and compliance with dosage schedules.

At its worst, the proceedings took place in an idealized world full of antiretroviral-naive patients who could reap the benefits of a "hit early and hit hard" strategy employing fresh triple combination regimens to which their HIV had not had the opportunity to develop resistance. Such patients were also assumed to all respond to therapy and stay on their drugs through whatever side effects and drug-drug interactions they encountered. At its best, the meeting triggered a thoughtful discussion concerning exactly what is happening in patients on the potent new combinations, of exactly how far the new therapies can take us and how much farther we have to go.

A lot of the conference consisted of a recapitulation of the results of studies presented in other forums, broad theoretical musings or a recitation of studies planned by NIH-sponsored trial networks or industry. But several key lectures marked considerable advances in the viral suppression debate.

The conference began with a presentation by Guiseppe Panteleo, of the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases. Dr. Panteleo discussed the changes in distribution of virus during the acute and chronic phases of HIV infection and the implications for therapy. Using macaques acutely infected with Simian Immunodeficiency Virus, Dr. Panteleo described how SIV infiltrates the lymph nodes during the first week after transmission but by the second week is either cleared by the immune response or exhausts the initial supply of the activated CD4 cells it targets. By the end of the first month of infection, most of the SIV in the lymph nodes is composed of virions caught in the network of follicular dendritic cells (FDCs), where they remain highly concentrated and infectious.

The story is largely the same in humans. There are many individual cells expressing HIV in the lymph nodes during early infection, but after three months the viral population there consists mainly of FDC-associated virions. Dr. Panteleo then asked if peripheral control of HIV infection by antiretroviral therapy in the blood also indicated control of viral replication in the lymph nodes. Answering his own question, Dr. Panteleo said that even with complete suppression of virus in plasma there was still a large pool of virus trapped in the lymph nodes. Additionally, the decline in blood-borne free virus did not affect levels of proviral DNA (HIV genetic material integrated into the cell's chromosomes), from which he surmised the existence of a large pool of latently infected cells. Dr. Panteleo thought that it might be possible to achieve full or almost full clearance of virus in very early acute infection, but once the chronic phase of the disease has begun, eliminating HIV is not possible.

The next speaker at the meeting was John Coffin from the Tufts University School of Medicine, one of the grand old men of retrovirology. Building on work by David Ho, George Shaw and others, Dr. Coffin's presentation focused on viral population dynamics. After describing the steady-state achieved by HIV infection following primary infection, Dr. Coffin reminded those present of the astounding reproductive capacity of the virus: within a year HIV has gone through approximately 180 generations; within five to six years, it has gone through 1,000 generations. While the new potent therapies have stirred up a lot of hope, the evolutionary potential of the virus may just outrun our ability to control it. Indeed, in the HIV steady-state, Dr. Coffin calculates that there are already 1,000 cells with viral mutants resistant to any given triple combination regimen. Most of these mutants may have impaired function, but if one of them has a selective advantage over other HIV in the presence of therapy, it will be the basis for creating a new multi-drug resistant viral population.

Dr. Coffin outlined some of the additional barriers to eradicating the virus from infected individuals. In what would become one of the central themes of the meeting, Dr. Coffin expressed concerns about the population of latently infected or long-lived productively infected cells, which could easily reseed the body with HIV should therapy wipe out the active virus-producing cells and then be discontinued. Probably the most remarkable presentation of the meeting was by Alan Perelson of the Los Alamos National Laboratory. Using data from a triple combination study of AZT/3TC and Agouron Pharmaceutical's protease inhibitor nelfinavir, Dr. Perelson has developed a complex mathematical model of two-phased viral decline under antiretroviral therapy. In the first phase, after initiation of three-drug therapy, there is a one- to two- log (90 to 99 percent) reduction in virus, which represents the clearance of activated HIV-producing CD4 T- cells and free virus. The second phase is much more drawn out (ten- to twenty-fold slower decay) and represents the clearance of either latently infected cells, in which HIV is not reproducing, or long-lived infected cells chronically emitting a low stream of new HIV (these latter cells probably are macrophages).

Dr. Perelson tried fitting the patient data to a mathematical model based on either latently infected or long-lived productively infected cells. He concluded that viral production by long-lived HIV-producing cells infected before initiation of therapy better explained the second phase of viral decline. Dr. Perelson then calculated the length of treatment required to eradicate HIV from long-lived infected cells. For patients in the AZT/3TC/nelfinavir study, the clearance of long-lived cells would take anywhere from a few months to approximately five years. Barring the appearance of drug resistance in the trial participants, the model brazenly implied that something close to eradication will be achieved after long-lived cells are cleared.

In one of the meeting's last lectures, Anthony Kelleher, M.D., from Center for Immunology at St. Vincent's Hospital in Syndey, Australia, discussed whether or not even the most suppressive antiretroviral therapy can rebuild immune function. Dr. Kelleher has observed that protease inhibitor therapy increases CD4 and CD8 T-cell numbers and restores immune cells' proliferative responses to various mitogens and recall antigens. But it cannot mend the holes in immune system response that open up as entire cell subsets disappear. According to Dr. Kelleher, the increase in CD4 and CD8 T-cell numbers during protease inhibitor therapy represents a peripheral expansion of pre-existing memory T- cells with no generation of the new naòve T-cells needed to fight infections to which an individual has no previous exposure. Based on these findings, Dr. Kelleher recommended early and potent antiretroviral therapy in order to preserve the diversity of the immune response.

He also posed a warning to individuals with symptomatic disease or very low T-cell counts who have seen their CD4 counts bound upward on the new triple combination therapies. Any gaps in these people's immune repertoire are likely to remain despite the higher CD4 count, and withdrawal of prophylactic therapy for opportunistic infections is not a good idea.

The use of the new protease-containing triple combination regimens is in its infancy. Only time will tell if the dramatic reductions in viral load are buying people with HIV/AIDS simply a few months or years or are turning HIV disease into a chronic, manageable illness. "Can HIV Be Eradicated From An Infected Individual?" Maybe yes and maybe no. That was the answer from the two-day gathering.

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