PI Perspective #24

April 1998     View PDF

HIV Eradication: Dead or Alive, or Even Necessary?

Because the concept of HIV eradication was new and sounded so exciting when first introduced two years ago, it was treated with great fanfare in the popular and community press. Eradication efforts were aimed only at people who were able to begin aggressive antiviral therapy within days or a few months of initial HIV infection, but the media often glossed over this distinction and made it sound like a cure was at hand. This year, the tables turned, with the popular and community media proclaiming the “end of eradication” and often accusing the researchers involved of “hyping” the concept. Our memory is that it was the media, if anyone, and not the researchers, who hyped the concept. Moreover, many commentators glossed over the fact that these initial efforts were solely raising the prospect of eradication in people who have the opportunity to initiate treatment extremely early in the course of disease, known as the “acute infection syndrome.” In most cases, this means people who start treatment even before they experience seroconversion to HIV positive status, signaled by the development of HIV antibodies. No one has even begun to test the question of eradication for the chronically infected patient population, which makes up the vast majority of all HIV infected people.

Today, HIV eradication has neither been achieved nor has it been ruled out or declared a failure in people in these very early stages of HIV infection. While it is true that eradication efforts, such as those previously described by Dr. David Ho and others, have not yet completely eradicated all traces of HIV, a more honest way to describe the story is that they have come surprisingly close. (For background, see PI Perspective #19, Eradication of HIV - Hope or Hype?.) HIV has, in a number of cases, been driven completely from the blood stream and most tissue reservoirs, while the remaining “hideout” of the virus has now been identified as “latently infected memory T-cells.” It is in this class of cells that the last infectious virus or at least some remnants of the genetic material (DNA) of HIV can still be found—but only after an extraordinary search. By the techniques of just a few years ago, we would have considered HIV eradicated in such people.

Even when the most intense research methods find HIV DNA or tiny amounts of replication competent virus, it is not clear whether these remnants are adequate and sufficient to rekindle a productive HIV infection. Work summarized by Dr. Bruce Walker of Massachusetts General Hospital raised the prospect that people treated in acute infection may be able to sustain effective suppression of virus without continuing treatment simply on the strength of their immune responses. His group reported that people treated in acute infection develop a very strong HIV-specific immune response, apparently identical to that seen in a small percentage of long-term non-progressors who seem capable of containing HIV infection without treatment. If the immune responses of these treated people are now truly the same as those seen in the exceptional long-term non-progressors, it might be possible to sustain control of HIV—without further treatment and without actually eradicating every last remnant of HIV.

In a closely related finding, Dr. Franco Lori (formerly of Dr. Robert Gallo’s Lab in the U.S.) reported on a patient treated with a unique combination of drugs, including hydroxyurea (Hydrea). After initial successful treatment and achievement of “undetectable” viral load in blood and body tissue, the patient removed himself from further therapy. Nearly a year later, no trace of HIV has yet reappeared in the patient using standard methods. It took a new level of amplification of the most sensitive known technique to find a single cell in 60 million that still contained a remnant of HIV. In this case, the patient’s one year holiday from therapy did not result in renewed productive infection. Thus, the meaning and clinical significance of the one cell in 60 million containing HIV DNA is quite uncertain. More information about the study of this particular combination can be found in the Hydroxyurea article.

Considering these findings, it would seem premature to suggest that HIV eradication has proven a failure or to castigate its proponents as makers of hype. On the contrary, it’s rather amazing how close the efforts have come to eradication or something functionally resembling it. Research on all aspects of eradication is continuing and has by no means ground to a halt or been declared a failure. The next step in this work is an effort to activate the few remaining cells that harbor HIV in the hopes of making the HIV in them vulnerable to the antiviral drugs and the immune response (they are protected from both as long as the cell remains latent or inactivated). Another approach calls for simply taking some volunteers, successfully treated since very early infection, off therapy to see whether the rekindled immune response is capable of containing the HIV infection. This entails very little risk to the volunteers since they could resume therapy easily if it fails.

These efforts at eradication should continue as an urgent priority. If it can be accomplished in a few people treated early under the most optimal conditions, researchers will learn a great deal which can perhaps later be applied to the more difficult question of people with chronic infection. Few people believe it will be possible to keep today’s patients on aggressive chemotherapy for the rest of their lives, so sooner or later, better and more lasting solutions will be critically needed (as they are already for people failing current therapy). Instead of faulting researchers for raising and pursuing the prospect of eradication or its functional equivalent, we should be applauding their progress and asking how we can help.

If and when eradication happens, it will first happen in a single person or a very few who have had the most optimal care and treatment from the moment of initial infection onward. Certainly, it would be a mistake to think that this could quickly be applied to people with chronic infection. But it would also be a mistake to declare it impossible. As we learn more about the immune responses that are capable of controlling HIV infection in a small percentage of people, we may also learn what it will take to restore them in all the rest of those infected with this daunting virus. We are only at the very earliest stages of understanding what it means to have “undetectable” levels of virus for years on end, or what possibilities are created when we see the return of missing cells and cell function in both acute and chronic infection. Only fools would pretend to think we know the answers to these questions in advance.