HIV therapy: Heading down the home straight or for a dead end?

4. February 2014

Already two decades ago AIDS researchers were talking about the possibility of curing the disease and eradicating HIV. New inhibitors and strategies, after much frustration, again seem to have aroused hope for an end of this plague. Are the expectations justified?

At times one can believe that in Germany the topic does not matter any more. And if so, then only as a matter of sexual intercourse between men. In fact, each year approximately 2,500 people in Germany end up getting infected with HIV. The number of infected homosexual men is increasing. Nevertheless, the disease appears only from time to time on the list of important health topics. AIDS for us is no longer a sentence to early death. Successful antiretroviral therapy prolongs the life of an infected person to an almost “normal number” of years.

“What we need for a world without AIDS”

And yet even optimistic HIV experts use the word “cure” only reluctantly and it leaves their lips only alongside careful paraphrasing, because an effective means of expelling the virus once and for all from the body does not yet exist. Even though there are around the world 15 clinical trials registered which have a “cure” as their target, and a vaccine trial in Thailand has produced a decline in infections by about a third; the number of cases in which the virus left the human body is limited to a few exceptional instances. With this as the background, a major conference was held a few weeks ago in San Francisco, in which the experts on the subject discussed: “What do we need for a world without AIDS?”

Reservoir of dormant viruses much greater than was thought

In recent months, again and again articles appeared in the literature which actually spoke of the possibility of getting rid of all HIV particles which have at some point colonised the body, or of not letting them go into a state of propagation despite the carrier being a high risk source of infection. There was talk of new antibodies that could potentially also neutralise the virus in the latent (resting) state. Nevertheless the pool of inactive virus particles is said to be likely to be much larger than was previously believed.

This has been shown for instance by a study done by Robert Siliciano and his colleagues at the Johns Hopkins Medical School in Baltimore, recently published in “Cell”. Following previous methods, about one percent of those viruses that have embedded their genetic material into the genome of their host T-lymphocytes is able to be activated. These viruses make it to the active reproductive phase. The rest, as it was assumed previously, due to DNA defects would not be capable of doing so. An incorrect assumption, as it now turns out, for about twelve percent of the integrated viral genome is apparently intact. Using a bit of molecular genetic assistance, the researchers were able to cobble together replicable viruses. This means that up to 60 times as many sleeping but competent viruses are apparently evaded by current antiretroviral treatments.

Mutation-resistant antibodies

Another outcome from two groups at Harvard and Bethesda on the other hand makes a more optimistic statement, based in the fact that new antibody cocktails obviously work much better than those before. This has been shown through experiments with infected macaque monkeys carrying a hybrid virus of SIV (Simian Inmmunodeficiency Virus) and HIV in their bloodstream. The antibodies brought the virus not only rapidly out of the circulation, but also ensured a long-lasting virus-free state for several months, as long as the antibody levels were uniformly high. Mutations at the agent’s point of attack, a previously very successful defence strategy of microbes, were not found in the two studies. Rather, it turns out that after the completion of treatment the viral titre is significantly lower than before. However what makes the new therapy option especially interesting is that the amount of cell-associated HIV DNA, i.e. virus particles that are waiting in the host cell to make their impact, suffers a drop in volume.

Successful treatment of infected monkeys

“The results of the two publications could revolutionise efforts to find a cure for AIDS, irrespective of all precautious views”. This bold prophecy comes from Louis Picker and Steven Deeks in an accompanying comment to the two research reports in “Nature”. For several years, reports on these new effective antibodies have floated about through the AIDS literature: approximately in one fifth of cases the HIV carrier produces antibodies with neutralising properties, nevertheless mostly after two to four years. In the time up until this point, virus and immune system are involved in a race. While the viral envelope is constantly changing under the sustained attack of the host, the defence system is driven to develop immunoglobulins with ever greater match-up accuracy with respect to the antigens present. However, only a handful of neutralising antibodies isolated so far can keep the infection at bay. And even these do not work against all known strains of HIV, but only against about 70 percent of the known 162 strains.

The virus-block in macaques was achieved using a cocktail of such antibodies. After successful experiments also using smaller animals, human studies should soon follow. First of all a preventive vaccine is intended. Such injections are intended to protect newborns from the virus-infected mother, and adults who are exposed in their environment to a great risk of infection.

Combination of ART and antibody cocktail

If one asks experts how a future successful AIDS therapy might look, most speak in favour of a combination of “traditional” anti-retroviral treatment and the use of a new generation of antibodies. The weakness of the previous methods lay mainly in reaching the latent virus reservoir. Whereas attacking the pathogen during its growth and spread has been quite successful, the remote concealment of intact, but not active, virus represents a major problem This is something most experts thus hope that neutralising antibodies can better solve than do existing active agents.

“A nose” for HIV-1

At the end of November “Immunity” finally published one French working group’s results which deliver further information on reaching latent viruses. Of the two major types of HIV, only the less pathogenic type 2 multiplies in dendritic cells, whereas HIV-1 evades the “nose” of these defence cells and devotes itself only to the T-cells. In the type 1 capsid the key which the dendritic cells need for the activation of defence against HIV seems to be missing. With some changes to the envelope of type 1, the immune system reacts with an effective response – it should be mentioned, also when a mixed infection of type 1 and type 2 is present. Armed with this knowledge, the researchers have hopes for finding new agents in order to also generate successful defence against type 1 virus.

Biomedicine + social components

In general, as the experts at the “AIDS free World “conference agreed in San Francisco, not only are new insights into the weaknesses and vulnerabilities of the virus itself needed, but also the development of appropriate therapy on a large scale, not only to successfully combat the virus, but that is also accessible to millions of those affected especially in Africa and Asia. Quite simple measures also come into the picture here such as routine tests for infection, or male circumcision as a preventative measure, as Congress President Anthony Fauci from the National Institute of Allergy and Infectious Diseases explained. Finally, as Fauci adds, one must prevent infants getting infected from their mothers. “Biomedical interventions must go hand in hand with human behaviour and social aspects, in order to create an AIDS-free world“.

Healed HIV patient

A few years ago doctors in Berlin healed an HIV-infected lymphoma patient by way of a bone marrow transplantation. The genome of the donor was mutated in both chromosomes at the docking site for HIV, the CCR5 receptor. In France as well it seems that one antiretroviral treatment when initiated very early led to such a low viral titre that the body was able to fight back against the invader, even without medication for many years.

Worldwide, approximately 35 million people are infected with the virus, around one in twenty of them die every year: too many people to permit winding back the commitment to finding a cure for the disease, just because Europe is one of the lesser affected regions. After many years in which the media has reported regularly about failed trials in the fight against the AIDS epidemic, the latest messages again at least foster a little courage.

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