David Ho: _{HIV researcher}

Person of the year

It was a time of transition in the management of HIV/AIDS. Johnson’s HIV infection had been discovered early and Ho knew that several new, very promising drugs would be entering the clinics shortly. Ho recognized that Johnson could become the example of an HIV survivor, and this prospect looked increasingly possible by the middle of the decade when Ho and his research team achieved a major discovery: A combination of different drugs had a profoundly greater effect in blocking new rounds of the virus compared with one drug alone. By 1996, this combined drug approach was extending the life expectancy of AIDS patients dramatically.

Time Magazine thus named Ho 1996 “Man of the Year,” and he was hailed as the inventor of the “AIDS cocktail.” That term may be misleading, but the combined drug strategy has saved millions of people, including Magic Johnson, who is alive and disease-free as of this writing in 2016. That made Ho’s discovery a turning point in the history of HIV, but the war against the virus is far from over. Since 1981, it has killed 35 million people, and each year another 2 million people become infected.

Many developing areas of the planet lag far behind the West in management and life expectancy of HIV patients. Since the turn of the century, this reality has motivated Ho to work for equality of HIV care around the globe, and it has pushed his research toward an important goal: the development of an HIV vaccine. It’s a tall order, but it’s the next logical step, and Ho’s hard work is motivated by the forces that have been pushing him to achieve goals since his days as an immigrant child.

At the right place and time

“Chance favors the prepared mind,” said 19th century microbiologist Louis Pasteur. It’s a quote that David Ho uses frequently when explaining how his HIV/AIDS research career got started. The history of science is ripe with stories of serendipity, and Ho’s life and career encompass more than one. (Read other accounts of the influence of chance and luck on scientific discovery in our module Scientists and the Scientific Community.)

Ho was born as Ho Da-i in Taichung, Taiwan, in 1952. Serendipitously, that meant he would enter medical research just as the AIDS epidemic was looming on the horizon. But long before that, the union of his parents was itself a chance event.

Ho’s father, Paul Ho, was from mainland China. He had traveled to the island of Taiwan on a whim in 1947, but on arrival he discovered a need for people to teach Mandarin. That made him extend his visit, but then fighting broke out between the Kuomintang (KMT) nationalist government and the communists. The KMT held sway on the island, now called The Republic of China, but the communists took control of the mainland, so the elder Ho could not return home. He married his former student Sonia Jiang in Taiwan, and the couple started a family.

Paul Ho left Taiwan to study in the United States, but his wife and young children stayed behind for eight years while he arranged for them to join him. When the senior Ho landed an engineering job in Los Angeles, the rest of the family could cross the Pacific Ocean and become Americans. At 12, David Ho began the grueling task of learning English in his new country. He was put in English as a Second Language (ESL) classes mostly with students from Spanish-speaking households. Unable to understand his classmates or his teachers, for the first few months he felt unintelligent even though he had been an excellent student in Taiwan. He had also been an extrovert in Taiwan, but in Los Angeles he led an introverted life because of the language barrier. The inability to interact with his English- and Spanish-speaking peers gave Ho an underdog mentality, but eventually he turned that to his advantage. He studied hard, and by the end of high school was at the top of his class. He earned a bachelor of science degree in physics and biology from Caltech in 1974, and then went on to Harvard Medical School, where he earned his MD in 1978. This meant that Ho would be doing residency training and looking for a research focus just as the AIDS epidemic was ready to break out.

A new disease and a new medical researcher

AIDS was first recognized and reported in 1981 when Ho was back in Los Angeles. He was a third-year resident in internal medicine at Cedars-Sinai Medical Center, with plans for a career in medical research. But events leading up to his career had been in play on the molecular level for almost a century. Unknown to human civilization, an early form of the AIDS virus had transferred to human bushmeat hunters from chimpanzees by the first part of the 20th century (Faria et al., 2013). The virus had evolved and grown deadly, and by the middle of the century there had been a handful of cases that now, looking back, can be identified as AIDS. However, since no epidemics had developed, physicians had not taken notice of the disease that would later wreak havoc on world health.

But on Ho’s ward at Cedars-Sinai, a patient was admitted with a type of fungal pneumonia called Pneumocystis carinii pneumonia (PCP). The man also had skin lesions that turned out to be an unusual tumor called Kaposi sarcoma (KS). Infectious disease specialists at Cedars-Sinai knew that the combination of PCP and KS had been seen only in people with certain deficiencies in their immune system. These immunodeficiencies could be the result of chemotherapy, drugs to suppress transplant rejection, or an inherited condition, in which case the symptoms appeared during early childhood. But the patient on Ho’s ward had none of these in his history.

The team was puzzled and conducted numerous tests on the patient. Ho chose to be involved in the testing because of his research interests and the unusual nature of the case. They tried antifungal medication and other treatments, but the patient deteriorated and died and within a few weeks. The team was going to label it as an unsolved mystery, but then another patient came into the hospital also with PCP and KS, also with no history of previous immune system deficiency. A third patient came in, then a fourth, and a fifth, all with the same symptoms. This happened over a period of a few months, and the patients had something in common: All were male and homosexual, and they also had extremely deficient levels of a specific type of T-lymphocyte in their blood called CD4 cells. T-lymphocytes are a type of white blood cell that plays an important role in the body’s immune response (Figure 2). The mystery attached to these five patients seemed like the perfect problem for a budding medical researcher, so Ho decided to make it the focus of his research, despite discouraging advice from his professors that the condition was too rare to be the basis of one’s career.

Ho, however, believed that this new disease was scientifically important, so he disregarded the advice and began spearheading efforts at Cedars-Sinai to characterize the illness. He went through the analysis of blood and other tissues in all five patients and led a team that wrote the findings into a report that was issued by Cedars-Sinai Hospital in conjunction with UCLA Medical Center. While this was happening, similar patients also started appearing in hospitals in the Los Angeles area, New York, and San Francisco, but the Cedars-Sinai/UCLA Medical Center report became the basis of the first description of the condition published by the United States Centers for Disease Control and Prevention (CDC). The condition was named acquired immune deficiency syndrome (AIDS) to distinguish it from immune deficiency conditions that were congenital, or present from birth.

To get to the forefront of the new epidemic, Ho traveled to Boston after finishing his Cedars-Sinai residency in 1982 and entered clinical and research fellowship training at Harvard Medical School and Massachusetts General Hospital. He remained there for four years, the last year as an instructor, and then he returned to Los Angeles, this time as a University of California, Los Angeles (UCLA) faculty member. The 1980s was an era of rapid discovery in connection with AIDS, and Ho’s early career was a combination of exploring the current research and generating new discoveries about the AIDS epidemic.

Exploring the cause and treatment of AIDS

As a fellow and faculty member on both coasts, Ho spent most of his time on laboratory and clinical work focused on the diagnosis and management of AIDS patients. Part of his research focused on the contributing agent, namely the HIV virus (Figure 3). Ho was an early researcher to isolate the virus. He contributed to the understanding of how HIV infects cells (Figure 4) and also evaluated the usefulness of azidothymidine (AZT or zidovudine), the first anti-HIV drug, which was approved for AIDS treatment by the US Food and Drug Administration in 1987, just six years after AIDS was recognized. All of this work led to various scientific publications as well as presentations that Ho gave at high-profile AIDS conferences.

In 1990, this drew the attention of a search committee tasked with finding a scientist who specialized in AIDS research. Funded by a grant from philanthropist Aaron Diamond, the committee was looking to form a New York-based AIDS research institute. Ho was contacted by Diamond’s wife, Irene, who was famous for her work in the movie industry. Ho expected to be offered a scientist position, but to his surprise Diamond wanted him to be the director. It was a very unorthodox offer, given that Ho was just 37 years old, but Diamond knew what she was doing. She wanted someone with solid knowledge of science, but who could also present an image of youth and hope for the future.

The first effective drugs against HIV: Reverse transcriptase inhibitors

HIV belongs to a category of viruses called lentiviruses, which in turn belong to a large viral category called retroviruses. Their genetic material is RNA, and one of the things they do is produce reverse transcriptase, an enzyme that uses the sequence of the RNA to make a strand of DNA of a complementary sequence. That DNA strand is spliced into the DNA of infected cells, and it contains instructions for making new virus particles.

AZT and similar drugs that were later developed are called “Nucleoside reverse transcriptase inhibitors” (NRTI) because they block, or inhibit, reverse transcriptase. They do this by masquerading as one of the building blocks of DNA. These false building blocks terminate DNA synthesis, so the virus cannot copy itself (Figure 5).

In addition to harming the infected individual, the strand of DNA made from HIV integrates into the DNA of certain cell types. In other words, the HIV genes become part of the genome of the infected cells, and it is a daunting task to get the viral genes out of the infected individual. Since AZT works to prevent the viral RNA from being converted into DNA, the hope was that this drug would slow the infection in HIV patients, giving their immune system the edge needed to defeat the virus. (Read more about DNA synthesis in our module DNA III: The Replication of DNA.)

When AZT became available in the United States in 1987, HIV patients did start living longer after developing AIDS – many months or more than a year, instead of a few weeks. Patients with HIV without AIDS who took the drug lived for a much longer time without experiencing symptoms. But there was a problem. After some time – a short period for some patients, longer for others, but it always happened – the drug would stop working.

The birth of the "AIDS cocktail"

In 1994, a new class of drugs was developed that fight HIV by inhibiting enzymes called proteases (Figure 6). The virus uses proteases to cut proteins in various ways, enabling the creation of new virus particles after a cell is infected. Those new viruses go on to infect other cells throughout the person’s body. Given the difference between the two classes of drugs, Ho had the idea to investigate what would happen with combined treatment. Specifically, he and his team looked into combining a protease inhibitor and one or two different reverse transcriptase inhibitors.

The popular term “AIDS cocktail” simply refers to the multiple ingredients in the treatment. Ho is not thrilled with the expression, though; not because it makes him sound like a bartender, but since it implies that his team merely threw the drugs together on a whim. The real basis of the research, however, was the characterization of the HIV virus that Ho and various researchers from other institutions unraveled, for it’s the understanding of the HIV biology that supports the idea of the combination therapy.

A rapidly evolving virus

Researchers studying HIV found that with or without AZT the virus mutated extremely fast. Although the virus could convert its RNA genome into DNA that became part of the infected person’s own genome, it was terrible at making accurate copies of itself. Each time it reproduced in the cells of an infected person, the virus made numerous mistakes, so that it had a very different genetic sequence compared with the sequence of the parent virus that had infected the cells. You might think this would be bad for a virus, but it actually helped HIV to survive. While this reproduction method results in billions or trillions of daughter virus particles that don’t work as well as the parent virus, a few of the trillion have mutations that make them work better. They persist through Darwinian evolution (see our module Charles Darwin II: Natural Selection), and when a person is given AZT, the viral evolution creates altered HIV viruses that resist the drug, and those are the ones that live on. It’s the same thing that happens in antibiotic resistance in bacteria, but with HIV it happens much faster.

Ho and his team demonstrated the details of how HIV reproduces and infects humans. Based on those details, they came up with a biological rationale underlying an important idea: Attacking the virus with different tactics at the same time should kill it off so quickly that adaptation to the drugs would not be possible. The team showed that if you give AZT and another type of reverse transcriptase inhibitor to infected patients, survival is better than if you give only one drug because the virus has more trouble developing resistance. If you also add a protease inhibitor, the virus starts losing the war because it cannot reproduce into daughter virus particles; thus, any AZT resistance mutations would not reach other cells.

The patient’s immune system also comes into play. With drugs working through different tactics, the immune system becomes strong enough to fight back. A kind of equilibrium results in which the infection can be kept under control so that a person who is HIV-positive does not develop AIDS. They can go on living AIDS-free, so long as their blood is monitored and they and their doctors do a good job at keeping the levels of the drugs high enough all the time. The situation is similar to diabetes, where the disease will kill the patient if not detected early and managed vigilantly, but if the treatment is aggressive and constant, the patient can go on living for many years. Also, if the treatment is good, the level of HIV in a person’s body fluids remains so low that they cannot infect other people through sexual activity. On account of this approach, by the late 1990s the survival of HIV-positive patients was soaring and the rates of transmission of the virus to other people were dropping in the United States and other Western countries. This trend continued into the early 2000s as additional drugs were introduced. But sadly, the situation was not the same in the developing world, nor among populations in the US that did not have good access to HIV screening and care.

Working for equality in health

Ho’s beginnings as an immigrant in Los Angeles set the stage for him to possess a deep awareness of racial tensions and inequality. Back in Taiwan, the union between his parents, Paul Ho and Sonia Jiang, was considered to be intermarriage due to Sonia being native Taiwanese and Paul a mainlander. In the 1940s and 50s, such couples were scorned, similar to a black-white couple in the US South during the same time period. This meant that the children were scorned as well, so there was no real place for the family to fit into Taiwanese society. For this reason, Paul Ho went to the US to improve his education and then sent for the rest of the family. They lived in the Watts neighborhood of Los Angeles at first, where young David went to school with mostly African American children. Soon, they moved to another area of Los Angeles that had a mixed population consisting of many ethnic groups, but the need to be in ESL classes placed Ho mainly with children who spoke Spanish at home.

Ho broke prejudicial barriers on a couple of occasions, the first being in residency when he insisted on making the mysterious disease the focus of his career. While the reason for objection by his professors was that the condition appeared to be very rare, there also was an understood stigma connected with the fact that the earliest patients were all homosexual. This did not matter to Ho, who was drawn to the topic purely because of the science. He also broke racial and age barriers when he became director of the Aaron Diamond AIDS Research Center (Figure 7). At that time, though many Asians were leaders in science, it was unusual for an Asian American to have a directorship position.

In the early 2000s, Ho’s career was soaring. He had been Time Magazine’s “Man of the Year,” he was at the top of his scientific field, and he had made several public appearances with Magic Johnson. But now he was thinking about how he might help the land of his heritage. It was clear that HIV survivability, early detection, and prevention were improving in the United States for people who had access to care, and publicity events with Johnson were helping to extend that progress to the US inner cities. But the developing world was lagging behind. In many places, including China, HIV was spreading rampantly and there was a stigma attached to being HIV-positive as there had been in the US during the 80s. Furthermore, the aggressive multi-drug treatments were not available or were not being used.

To make a difference in Asia, Ho started working with not just one basketball star but two. The Diamond Center formed a partnership with the William J. Clinton Foundation, Harvard University, Tsinghua University, and the Yale-China Association for a program called the Chinese AIDS Initiative to promote AIDS awareness throughout China. Touring the country, towering over Ho and even over Magic Johnson, was Chinese basketball star of the Houston Rockets, Yao Ming, at 2.29 m, or seven and a half feet tall (Figure 8).

The idea was to speak with people around China, spread awareness, begin treating people with the multi-drug regimen, and demonstrate that such patients could be managed and kept alive even in rural villages. They started off modestly with just 80 HIV patients. The pilot program was a success, and the Chinese health authorities have been working increasingly with Ho and other Americans to expand the effort.

Through all of this, Ho has won numerous awards, including the Presidential Citizens Medal in 2001, while he has continued to do what he loves most, directing and managing research. For years, the research has involved an increasing number of new scientists and graduate students learning from Ho’s mentorship. Still, an HIV vaccine is Ho’s ultimate goal. With research, HIV awareness promotion, and international travel, it’s quite a workload, but Ho welcomes it and continues forward at full speed.