HIV/AIDS research after HAART.

The success in therapy against HIV with HAART has been more than most of us could have hoped for, even allowing for the tact that one group claimed the possibility of eradication of the virus in 1995. However, most scientists knew such therapy would be needed for life, and that some toxicity and drug resistance were predictable. Nonetheless, the overall success of HAART has made HIV/AIDS the "flagship" among viruses and viral disease for antiviral therapy, proving for the first time that if we know sufficient detail of the molecular mechanism of viral replication, then effective antiviral therapy is achievable. I make this point because pharmaceutical companies (and academic scientists) in the mainstream had abandoned antiviral research in the 1970s, because of the prior lack of success and the knowledge that unlike bacteria and other unicellular microbial parasites, viruses have no metabolism of their own and are highly dependent upon the cell's machinery for their replication. In short, therapy had to be more specific and in general more sophisticated.

HAART therapy was born Dora a sophisticated understanding of HIV replication. It had its origins in the 1970s with elucidation of the replication cycle of animal retroviruses, especially the discovery of reverse transcriptase (RT), and by the findings that drugs that inhibit replication of animal retroviruses even prevented disease in animals (mice) by blocking transmission of a mouse retrovirus from a pregnant mouse to its offspring. But going from mouse to man was tar from simple or obvious because of the thinking that drug toxicity and drug resistance would be too problematic. Indeed, no one had ever shown efficacy of antiretrovirals in animals infected with retroviruses over a protracted period. Thus, the historic contribution of the development of AZT in the mid-1980s by Burroughs-Wellcome and The National Cancer Institute cannot be overstated. This set the stage for many groups, especially many pharmaceutical companies, to develop other RT inhibitors.

RT, of course, is an enzyme necessary for HIV replication and carried by the virus. Consequently, it was natural also to try to find inhibitors of other enzymes--more or less specific to HIV and essential to its replication. The protease of HIV was an obvious target. Proteases of animal retroviruses and their biological function had been characterized years earlier in animal retroviruses and in the first human retrovirus to be discovered, the leukemia-causing retrovirus called HTLV-1. This was subsequently done with the HIV protease. Its structure was elucidated by scientists, and they began to test inhibitors of this enzyme. This led to the introduction of protease inhibitors in the clinic. Combination with RT inhibitors was a "no brainer" and was instituted rapidly by many clinicians in the US and Europe, collaborating with drug companies in what would soon emerge as the major advance we call HAART. This is the origin of HAART, although only in the broadest conceptual context.

What has occurred over the past 10 years since the development of HAART has been less exciting but more fundamental in our uuderstanding of HIV. Because of drug resistance and toxicity, we knew we would need to continue basic research on HIV and attempt to develop additional approaches to therapy. In this regard, substantial advances, with practical implications in my view, have emerged from 3 general areas: 1) more details of HIV replication and of cellular factors that work against HIV, 2) greater understanding of HIV pathogenesis, including people who resist HIV infection, and 3) a realization that we can target not only viral but also cellular factors needed by the virus.

As to the future, basic studies of HIV replication will continue to be needed because we will continue to need new therapies, but I believe we should not and will not be limited to approaches that target steps in HIV replication. New therapies will also come from studies of pathogenesis and of the immune response to infection. Some therapies will target cellular factors (required by HIV, but to some extent dispensable by our cells, or at least factors which the cell is less dependent upon than the virus). The advantage of targeting cellular factors is that they are far less mutable than HIV proteins and therefore less likely to have escape mutations. Though it is still possible that HIV "strains" could emerge that avoid utilization of the particular cellular factor, this should present more of a challenge for the virus.

The details of HIV replication that now have the most pregnant implications are related to early steps of HIV infection. With a far greater understanding of the HIV cell entry process, we can now envisage HIV entry inhibitors as whole new classes of drugs for the future. Each of the now-known several steps in the entry process can be targeted, but I am most excited by the possibility of antagonists of the key portal of entry of most HIV infections, CCR5. This cellular protein is present on the surface of some cells. It is particularly abundant on activated T cells, and its normal function is to receive signals from some of the human molecules called chemokines. It so happens that the HIV envelope protein uses this molecule to initiate most HIV infections. It is important to recall that some people are born without CCR5 and are healthy, ie, CCR5 does not seem to be needed by modern humans. It may be dispensable for us, but usually not for HIV. This presents a new and exciting target for HIV therapy, and we should see this emerge in the near fixture. However, as stated above, CCR5 antagonists are not the limit. There are several steps to HIV entry into the cell, and several of these can, have been, and will continue to be targeted.

Newly discovered cellular factors that counter HIV infection have also been identified, and these too offer new approaches for future therapy. One of these is called APOBEC-3G, a cumbersome term, but an important cellular protein that helps disable HIV under some circumstances. It is predictable that some scientists will seek to enhance or mimic its activity in the future. And there are others. In other words, I foresee the future as including many new approaches to treat HIV infection, and these new approaches will increasingly include cellular factors that we may either enhance or inhibit to control HIV.

Over the past 10 years, studies of HIV pathogenesis (other than viral entry into cells) that have both impressed me the most and seem to offer therapeutic possibilities include the observations that 1) abnormal activation of the immune system is a central feature of HIV disease, 2) lasting damage is produced very early in infection, 3) "knock out" of T cells in the gut during acute infection is an early and pathogenetically important aspect of HIV infection, and 4) uninfected T cells are also substantially impaired and may die prematurely, apparently more so in the chronic phase of infection. This leads us to consider 1) the therapeutic use of drugs that diminish lymphocyte activation (cyclosporine being the prototype), 2) treating HIV as early as possible, and 3) finding the mechanisms involved in impairing uninfected T cells and attempting to do something about it. For example, working with Daniel Zagury in Paris, we have come to the conclusion that the HIV Tat protein is importantly involved in the impairment of uninfected T-cells. Therapeutic vaccines targeting the Tat protein are underway with promising preliminary results. I think this and some other rationally designed therapeutic vaccine trials will offer alternative or additional therapeutic approaches. The upside of such an approach (compared to HAART) is a lack of toxicity and probably less resistance by HIV. The downside is less power in reducing HIV replication and viral load as compared to HAART.

So, can we eradicate HIV? It is conceptually possible, but may not be doable in the next decade. Even if so, it would likely he limited to very few. Eradication can be approached by 2 paths: the first (and the one now pursued in some clinics) is to vigorously treat active infection with HIV drugs, the second is to target the remaining latently infected T cells ("the reservoir"). These cells harbor silent HIV genomes, which can later be activated and give rise to new viruses as these cells enter loci that have the capacity to induce T cell activation because of their cytokine milieu. Some clinical scientists seek to use chemicals to activate latently infected cells in advance. In so doing, these cells expose themselves to the therapists' arsenal that "destroys" HIV-producing cells. They will do this while using drugs that prevent new HIV infections, eg, entry inhibitors and RT inhibitors. The alternate, more sophisticated, and more "down the road" approach is to use molecular probes that seek, find, and destroy cells harboring HIV genomes--even those hidden in the cell as silent DNA proviruses. I do not envisage the latter such approach becoming a reality for at least another decade, and I do not believe the former approach will succeed; though it is worth the major effort being invested. Consequently, I am not an optimist about near-term eradication.

As for an HIV preventative vaccine, I believe it is achievable, but in nay view it will take another 7 to 15 years. The current and soon to be tried candidates will likely not be effective. Most, if not all, are vaccines that induce cell-mediated immunity (CMI), but for more than 20 years, I have argued that a vaccine candidate must approach or realize complete blockade of HIV inflection at the site of cell entry. CMI-based vaccines do not achieve this. Rather, they allow infection to occur with the hope that the CMI response will keep HIV levels low enough that disease will not occur. I think such viruses will eventually escape. That is why I think we need to completely prevent infection right at the level of HIV entry. This means obtaining neutralizing antibodies, which in turn means an envelope-based vaccine. These antibodies must be broad enough to inhibit various strains of HIV. This was impossible with the kind of envelope vaccine developed by VaxGen, and therefore, it predictably failed. The antibodies also must be sustained, because HIV, as a retrovirus, integrates its genes into human DNA shortly after infecting a cell. This provides little or really no time for an immune response to be recalled. These are truly unprecedented, high hurdles for us to overcome. However, because of the great increase in our understanding of HIV entry, I think we now have insights as to what approaches may bring success.

Robert C. Gallo, MD, co-discovered HIV as the infectious agent that causes AIDS. He is Director of the Institute of Human Virology at the University of Maryland Biotechnology Institute, as well as a Professor in the Department of Microbiology Immunology and a Professor in the School of Medicine at the University of Maryland, Baltimore.