Charting HIV's rapidly changing journey in the body

December 12, 2008

HIV is so deadly largely because it evolves so rapidly. With a single virus as the origin of an infection, most patients will quickly come to harbor thousands of different versions of HIV, all a little bit different and all competing with one another to most efficiently infect that person's cells. Its rapid and unique evolution in every patient is what allows HIV to evade the body's defenses and gives the virus great skill at developing resistance to a pantheon of antiviral drugs.

"A huge amount of HIV diversity accumulates in the body of a patient with HIV, and it's a big reason why HIV is such a powerful virus," said Ha Youn Lee, Ph.D., assistant professor of Biostatistics and Computational Biology at the University of Rochester and corresponding author of the study.

Lee and colleagues have settled a longstanding question about just how HIV morphs in the body. In a paper published Dec. 12 in PLoS Computational Biology, scientists show that HIV evolution in the body does not occur at a constant rate. Rather, the virus's rate of change suddenly slows when the level of crucial immune cells known as CD4+ T-cells falls in a patient.

The team suggests several possible reasons for why HIV slows its evolution later in the disease process. One is that there are simply fewer immune cells left for the virus to infect. Another possibility is that since the immune system is no longer as effective targeting the virus, the virus no longer feels the "selective pressure" of the immune system, and the virus slows its evolution in response.

Picture a criminal on the lam. When the police are out in force, the criminal must change his disguise more and more to survive, but when fewer police are present, the criminal can change his disguise less often. In the case of HIV, the virus actually eliminates the "police officers" - CD4+ T-cells patrolling the body. As time goes on and fewer immune cells are present to flag HIV, the virus no longer has the need to evolve as rapidly as it did when the cells were out in force.

"In a person with a strong immune system, the virus is constantly on the run - it has to change to survive," said co-author Thomas Leitner, Ph.D., of Los Alamos National Laboratory, who studies viral and bacterial evolution. "But even in a person who has lived with HIV for a decade or more, in most cases, at some point, the immune system weakens. The virus notices and evolves accordingly. It's a very dynamic process."

While the research shows that the virus is creating fewer new versions of itself late in the disease process, the researchers say the clinical implications of the research are unclear. Since the virus's ability to evolve is at the heart of the drug-resistance capability that makes HIV so deadly, the work could help scientists who are trying to figure out new ways to stop the virus.

"It's possible that this work would have some implications for our understanding of drug resistance late in the disease process," said Lisa Demeter, M.D., a University of Rochester virologist not involved in the study. "When HIV is evolving more slowly in a patient, that patient is less likely to develop resistance to treatment so quickly," said Demeter, an expert on how HIV develops resistance and professor of Medicine in the Infectious Diseases Division.

Scientists have debated the pace of change of HIV in the body. Some studies have suggested that the virus evolves slowly in people who live many years with HIV before developing AIDS, while other studies showed that the virus evolves quickly in those patients.

To address the issue, the team developed a mathematical and computational model of how HIV evolves in the body. They tested the model by analyzing the blood from 15 HIV patients whose blood was sampled every few months for anywhere from three to 12 years. The data came from the HIV Sequence Database at Los Alamos National Laboratory, which holds more than 250,000 genetic sequences of HIV from patients around the globe.

The team found that the when the immune system is relatively healthy, the HIV virus evolves at a constant and rapid rate, but when a patient's CD4+ cells decrease, HIV's rate of evolution slows. The shift occurs long before a patient is considered to have AIDS, which is indicated when the CD4+ level drops to 200 cells per microliter of blood. The finding was true of 13 of 15 of the patients.

The team focused its attention on 600 nucleotides of the RNA that make up HIV's env gene, which codes for the protein's outer envelope that the virus uses to bind onto the cells of the host. In the team's study, on average, slightly less than one mutation per month occurred per patient in this swath of the HIV genome during the time when CD4+ levels were relatively high and the rate of change was constant.

That's a very rapid rate of change for one small portion of a virus, especially one so prolific: Every day, the HIV virus population in an infected person - up to 10 billion viral particles - copies itself and recreates 95 percent of its particles. With all that reproducing, and without a high regard for accuracy, one change leads to another, and the results are astounding: Most patients have literally many thousands of different types of HIV virus in their bodies.

"Every single person on Earth who is infected with HIV has his or her own unique HIV population," said Leitner.

As the virus mutates, giving birth to viral offspring called quasispecies, it presents an ever-changing face to the immune system, which is continually adapting itself to keep up with the onslaught. The immune system does a remarkable job fending off the assault, killing most of the viral particles every day. Even so, some of the virus is able to elude the body's defenses and ultimately devastates the immune system in most patients.

University of Rochester Medical Center

---

---

	The Immune System by Peter Parham (Author) The Immune System, Third Edition emphasizes the human immune system and synthesizes immunological concepts into a comprehensible, up-to-date, and reader-friendly account of how the immune system works.  Written for undergraduate, medical, veterinary, dental, and pharmacy students in immunology courses, it makes generous use of medical examples to illustrate points.  The Third Edition has been extensively revised and updated and includes two new chapters on innate and adaptive immunity, which explore the physical, cellular, and molecular principles underlying these responses to infection.  It also features enhanced coverage of aspects of innate immunity such as the complement system, Toll-like receptors, defensins, and C-reactive protein; the role of dendritic cells in...
	In Defense of Self: How the Immune System Really Works by William R. Clark (Author) We live in a sea of seething microbial predators, an infinity of invisible and invasive microorganisms capable of setting up shop inside us and sending us to an early grave. The only thing keeping them out? The immune system. William Clark's In Defense of Self offers a refreshingly accessible tour of the immune system, putting in layman's terms essential information that has been for too long the exclusive province of trained specialists. Clark explains how the immune system works by using powerful genetic, chemical, and cellular weapons to protect us from the vast majority of disease-causing microbes-bacteria, viruses, molds, and parasites. Only those microbes our bodies need to help us digest food and process vitamins are admitted. But this same system can endanger us by...
	How the Immune System Works (Blackwell's How It Works) by Lauren M. Sompayrac (Author) Understanding the immune system is crucial for both medical and bioscience students, with new research revealing yet more secrets year on year. Many books offer in-depth introductions to the subject, but How the Immune System Works remains uniquely popular for its personable and practical overview of the nuts and bolts of the immune system. This third edition provides a perfect introduction to the essential principles of the immune system, covered in humorous but highly informative 'lectures' accompanied by clear and accessible illustrations. It is perfect for exam preparation or as an enjoyable overview of a difficult subject. Both students and instructors will welcome the clarity and authority that Lauren Sompayrac brings to this timely revision.
	How the Immune System Works, Includes FREE Desktop Edition (BLACKWELL'S HOW IT WORKS SERIES) by Lauren M. Sompayrac (Author) How the Immune System Works is not a comprehensive textbook. It’s the book thousands of students have used to help them understand what’s in their big, thick, immunology texts. In this book, Dr. Sompayrac cuts through the jargon and details to reveal, in simple language, the essence of this complex subject. Fifteen easy to follow lectures, featuring the uniquely popular humorous style and engaging analogies developed by Dr Sompayrac, provide an introduction to the ‘bigger picture’, followed by practical discussion on how each of the components interacts with one another. Now featuring full-color diagrams, this book has been rigorously updated for its fourth edition to reflect today’s immunology teaching and includes updated discussion of B and T cell memory, T cell...
	90 Day Immune System Revised: This vital life-saving information will help you: Protect your body from diseases and early aging Maximize your ... and surveys Boost your vitality and b by Janet Maccaro (Author) GIVE YOURSELF 90 DAYS TO... Build and strengthen your immune system. Bring your body's system into proper balance Experience disease-free living. No matter what your health has been in the past, there is something you can do right now to give your entire body a complete makeover! Dr. Janet explains how you can improve the quality of your life with: Imagine what your life could be like with a complete immune system makeover! You best days of health are ahead of you. What are you waiting for?
	The Immune System by Peter Parham (Author) The Immune System, Second Edition has been designed for use in immunology courses for undergraduate, medical, dental, and pharmacy students. This class-tested and successful textbook synthesizes the established facts of immunology into a comprehensible, coherent, and up-to-date account of how the immune system works, rather than presenting immunology as a chronology of experiments and discoveries. Emphasizing the human immune system the text has been designed to break down the barriers which often divide basic and clinical immunology. The reader-friendly text, section and chapter summaries, and full-color illustrations make the book accessible and easily understandable to students. The Immune System is adapted from Immunobiology by Janeway, Travers & Walport.
	Digestive Wellness: Strengthen the Immune System and Prevent Disease Through Healthy Digestion, Fourth Edition by Elizabeth Lipski (Author) The definitive guide to healthy digestion! Digestive Wellness explains how your digestive system works and what to do when it doesn’t. You’ll find practical solutions to all the common gastrointestinal disorders (and many other conditions) and expert guidance on the newest advances in testing and diagnosis, nutrition, and natural therapies. Plus, you’ll learn how faulty digestion can affect the human body systemically, from migraines and skin issues to fibromyalgia and chronic fatigue syndrome. “Dr. Lipski offers a practical toolkit to support each of us—clinicians and patients—to return to wellness by bringing our gastrointestinal system back into balance and harmony. I believe that you will deeply benefit from joining Dr. Lipski on this journey toward digestive...
	Basic Immunology Updated Edition: Functions and Disorders of the Immune System With STUDENT CONSULT Online Access, 3e (Basic Immunology: Functions and Disorders of the Immune System) by Abul K. Abbas MBBS (Author), Andrew H. Lichtman MD PhD (Author) This updated 3rd edition of Basic Immunology provides a readable and concise introduction to the workings of the human immune system, with emphasis on clinical relevance. The format makes learning easy with short, easy-to-read chapters, color tables, key point summaries, and review questions in every chapter. You'll get the latest coverage on regulatory T cells, biology of the Th17 subset of CD4+ T cells, and more. The full-color artwork, comprehensive glossary, and clinical cases are just some of the features that reinforce and test your understanding of how the immune system functions. Student Consult online access lets you search the full text online and pursue further study through integration links. Covers the most up-to-date immunology information including regulatory T cells, and...
	The Immune System Cure: Optimize Your Immune System in 30 Days-The Natural Way! by Lorna Vanderheaghe (Author) What causes one person to catch a cold or flu and another to avoid it? Why do serious outbreaks of infectious diseases leave some individuals untouched? What allows someone to be incapacitated by allergies? The answer lies within nature itself-our immune system. The Immune System Cure provides simple techniques for supercharging your immune system to resist and prevent disease. Through diet, exercise, stress reduction and nutritional supplements, including plant sterols and sterolins, you can harness the power of your immune system in just 30 days and help it combat: Antibiotic-resistant bacteria Fibromyalgia Allergies Hepatitis C Tuberculosis Cancer Rheumatoid arthritis and other autoimmune diseases Chronic fatigue syndrome and more Now you can maintain a healthy...
	Super Immunity: The Essential Nutrition Guide for Boosting Your Body's Defenses to Live Longer, Stronger, and Disease Free by Joel Fuhrman (Author) Why do some of us get sick with greater frequency than others? What makes us more susceptible to illness? Are we doomed to get sick when our coworkers and family members do? Is there a secret to staying healthy? Joel Fuhrman, M.D., a leading expert and board-certified medical specialist in prevention and reversing disease, offers a comprehensive guide to superior health. Based on the latest scientific research, Super Immunity shows us how we can become almost totally resistant to colds, influenza, and other infections. The evidence is overwhelming: we can supercharge our immune system to protect our bodies against disease—everything from the common cold to cancer. Nutritional science has made phenomenal strides and discoveries in recent years, and when this new...