Microbicides

Microbicides represent a high-tech replacement of condoms. The idea is to develop a cream that can be used during an intercourse to inactivate HIV, thus protecting the recipient from being infected. The main target population for this treatment is women, in particular prostitutes in places where condom use is not culturally acceptable. Huge amounts of money are now poured into this area of research at the expense of other approaches. As usual, this situation is masterfully used by inventive HIV researchers, who throw in their favorite anti-HIV drug as a microbicide component to get easy funding. Examples are plenty, from reverse transcriptase inhibitors to protease inhibitors to CCR5 inhibitors. It is not surprising that no effective microbicide has been developed yet. But even if such a microbicide is developed, what will be its impact on HIV epidemic? My prediction is that it will be minimal, due to limited population that will use it. I hope funding agencies realize it and find a better use for their money.

Vaccine

Vaccine research is on the rise now and it gets most funding in the HIV field. We now understand (or have good theories which explain most experimental and clinical findings) how HIV out smarts the immune system. What we still do not have is a working immunogen that would induce development of neutralizing antibodies active against multiple strains of HIV. We know how to induce effective T cell response, but such response would be effective only against already infected cells. Therefore, it may alleviate the disease, but cannot prevent infection. Indeed, induction of broadly neutralizing antibodies is the only mechanism that would protect against de novo infection. Multiple clinical trials planned for the near future will test many different antigen delivery systems, but all these trials rely on common HIV genes from various HIV clades, which are known to fail to induce broad neutralizing activity under natural infection conditions. I hope studies in the next decade will identify a vaccine candidate with capacity to induce such broad neutralizing activity.

Drugs

This area of research had its successes during the previous years, and I expect this success story to continue in the next decade. We have effective inhibitors of two HIV enzymes, reverse transcriptase and protease. Inhibitors of the third viral enzyme, integrase, are in the final stages of clinical testing and are expected to complement the list of available anti-HIV drugs. One inhibitor of HIV entry (T20 or Fuzeon) is on the market now, and many others targeting the fusion process or HIV receptors (CD4, CCR5, and CXCR4) are in the pipeline. Scientists at the universities and biotech companies are working on inhibitors of HIV nuclear import and assembly. An interesting target for future drugs is HIV transcription. This is a hard target, given that HIV is transcribed by the cellular transcription machinery. However, if HIV transcription can be specifically blocked by drugs, this would prevent reactivation of virus from latently infected cells and would convert HIV disease into a permanently dormant infection.

Basic research

Our progress in treating HIV infection is due to successes in basic research that happened during the years of AIDS epidemic. The fact that the stream of new findings is not diminishing with years has to be attributed to the complexity of HIV disease, which is really amazing given the relatively simple genetic backbone of this virus. In addition to helping us understand the virus and the disease that it causes, HIV research also reveals new information on the function of human immune defenses. The current rage is a newly discovered arm of immunity named 'intrinsic immunity', as opposed to previously recognized 'innate' and 'adaptive' mechanisms. These intrinsic mechanisms, exemplified by anti-HIV factors APOBEC3 and TRIM5α, protect individual cells from infection by retroviruses. Given that retroviruses accompany humans since the origin of our species, studies of these intrinsic mechanisms may reveal a lot about past and future retroviral infections. It would be interesting to find out whether genomic variations in these intrinsic factors correlate with susceptibility or resistance to retroviruses. I expect that more intrinsic factors will be found. These factors may be stimulated by drugs or other means to increase resistance to HIV infection, which may be another approach to HIV vaccine.

Clinical research

Since the infamous claim that HIV will be cured after introduction of highly active antiretroviral therapy (HAART), HIV clinical research saw its ups and downs. We still do not fully understand pathogenesis of HIV disease, although a recent identification of gut lymphoid tissue as the major site of HIV replication was an important step in that direction. A lot of discussions still go on regarding the role of direct versus indirect cell killing in CD4+ T cell depletion, the role of macrophages as long-term HIV reservoir, the existence of the sacred sites of HIV replication unavailable to drugs, the reason for exclusive prevalence of R5 HIV strains in transmission and the factors responsible for R5 to X4 switch during disease progression, and the role of immune system activation in HIV disease pathogenesis. I hope many of these questions will be resolved during the next 10 years, thus opening new opportunities to treatment and maintenance of HIV-infected patients.

Conclusion

In summary, I believe HIV will be with us for at least another 10 years. During this time, we will see a steady progress in HIV basic research and development of new anti HIV drugs. I hope for good vaccine candidate, but this may not occur within the next decade. In general, HIV disease will become a manageable chronic disease requiring constant medical attention, similar to diabetes. The goal would be to bring this solution to third-world countries.