World AIDS Day
Keeping HIV at bay
Millions of people are infected with HIV, and will develop AIDS in the absence of therapy. LMU’s Maximilian Münchhoff studies HIV’s effects on the immune system, which are of fundamental relevance to the search for an effective vaccine.
Maximilian Münchhoff was in the headlines recently – and the headlines were positive, although the news from his field of research is seldom good. The LMU virologist works on AIDS, an infectious disease that has already claimed the lives of 35 million people. AIDS is caused by the Human Immunodeficiency Virus (HIV), a so-called retrovirus which invades cells of the immune system. But Münchhoff’s latest findings show that not everyone infected with HIV goes on to develop AIDS.
Before moving to LMU, he worked for four years in various hospitals in Durban on South Africa’s east coast. The city lies in the region KwaZulu-Natal. “It is regarded as one of the major hotspots of the AIDS pandemic. Up to 30% of the population is infected with HIV,” he says. As a postdoc, he was a member of a research team led by immunologist Philip Goulder of the University of Oxford, which focused on a particular subgroup of HIV carriers -- children who are infected but remain disease-free. “It was not at all easy to find them,” he says. Indeed, most of them were identified by chance after their mothers had begun to show symptoms of the disease and were forced to seek help. The average age of the participants at the start of the study was 8 years – and they were all healthy.
These children are very exceptional. In the absence of therapy, well over 99% of those infected with HIV go on to develop AIDS. Indeed, the disease normally progresses much more rapidly in children. The virus specifically attacks so-called CD4 T cells of the immune system, replicates within them, and integrates its genome into their nuclear DNA. The immune system reacts to the pathogen by activating uninfected CD4 cells. Unfortunately, activated cells are even more susceptible to infection by HIV, so immune activation initiates a vicious circle which promotes the spread of the virus and leads to progressive depletion of the vital T cells. Ultimately, the immune system becomes unable to respond effectively to otherwise relatively innocuous agents: The virus’s victims have an Acquired Immune Deficiency Syndrome (AIDS).
Antiretroviral therapy drastically reduces the level of HIV released into the blood, but the virus survives in long-lived CD4 memory cells that act as viral reservoirs. “In healthy HIV-infected children, on the other hand, the virus is found primarily in short-lived cell populations which are derived from these long-lived progenitors,” Münchhoff explains. This means that they retain sufficient numbers of healthy memory cells to keep them supplied with functional short-lived immune cells. Consequently, their immune systems retain their functional competence in the presence of high levels of circulating virus. This is very reminiscent of what is seen in the sooty mangabey, the natural host for the Simian Immunodeficiency Virus (SIV), which gave rise to HIV. Infected mangabeys also show no overt signs of disease – although viral replication continues. The study of the Durban cohort, with Münchhoff as first author, appeared in the journal Science Translational Medicine in September 2016 and was widely noted in the media.
In April 2016, Münchhoff joined Oliver Keppler’s research group at LMU’s Max von Pettenkofer Institute. Keppler, who holds the Chair of Virology there, focuses on HIV’s interaction with its host, and in particular on the role of so-called restriction factors that limit virus replication. “The question is whether or not there is anything special about these factors in infected children who remain healthy,” says Münchhoff.
Some 36.7 million people are known to be infected with HIV. “Meanwhile, more than 20 different drugs have been developed that are highly effective against AIDS,” Münchhoff points out. Patients can now survive for decades, although the drugs can only reduce the virus load and have deleterious side-effects. Although these agents are not easily available everywhere, the United Nations estimates that about 16 million AIDS patients now have access to them.
Münchhoff became involved in the treatment of AIDS patients before he completed his medical studies. During his practical year, he worked for four months as a pediatrician in Cape Town. “That was when I first became interested in infectious diseases and in the fate of HIV-infected children,” he says. His research work now lies at the interface between the laboratory bench and the patient’s bedside, and he now knows that members of the South African study cohort make highly potent anti-HIV antibodies. “To work out how they manage to do so, we must take a closer look at the B cells that make these antibodies. The results should be of interest in the context of vaccine development.”
An effective vaccine must induce the formation of broadly neutralizing antibodies, because HIV is highly mutable. Every infection initiates a new cycle of mutation and selection, which is driven by the nature of the immune response, and new variants are transmitted to the next victim. In 2013 Münchhoff was a co-author of a study which showed that HIV has become less virulent, and less infectious over the years – another piece of good news. Nevertheless, AIDS remains a life-threatening disease which requires lifelong therapy.
In countries in which antiretroviral therapy is not easily accessible, AIDS is tantamount to a death sentence. Münchhoff has worked with children who had full-blown AIDS, and investigated how malnutrition potentiates the effects of the virus on the immune system. “Although they received therapy, many of these children died. That was difficult to bear,” he recalls. Moreover, it cannot be excluded that infected but clinically healthy children may yet develop the disease. “The immune system undergoes several changes during puberty, and levels of immune activation could increase at that point.” Since it became clear that they harbor circulating HIV, these children have been regularly monitored. “Ten years ago, few hospitals in South Africa could provide any therapy. That is why we were able to find infected children of this age who had never received antiretroviral treatment. Now every child under the age of 5 who is diagnosed with AIDS is treated immediately. Had they been born a few years later, the kids in our study cohort would already have been treated,” Münchhoff muses. They were lucky to survive -- and their discovery has given researchers new hope in the battle to defeat HIV. Nicola Holzapfel
Dr. Maximilian Münchhoff works in the Virology Section of LMU’s Max von Pettenkofer Institute.