J. Nabel, M.D., Ph.D. “The significance of this discovery is clearly worth evaluating in humans and may considerably accelerate future efficacy trials.”

The SIV vaccine regimen used in the two studies was a simplified version of a preventive human HIV vaccine strategy developed by VRC scientists and currently undergoing Phase II human clinical trials in the United States, the Caribbean and sub-Saharan Africa. Current plans call for testing the efficacy of the vaccine in large-scale human clinical trials some time next year.

To examine the theory that some imperfect HIV vaccines may still allow infected people to live longer and healthier lives, Drs. Letvin and Roederer and their colleagues sought to determine if SIV vaccines confer such a survival advantage to monkeys.

They found that the best way to predict survival after a vaccinated monkey is infected with SIV is by measuring, early in infection, levels of a specific subset of immune cells known as the memory CD4+ T cells. Memory CD4+ T cells are T cells that have been activated by bacteria and viruses upon first exposure and are primed to act more quickly upon reinfection. Of the approximately one trillion T cells in the average adult, more than half are memory cells.

Normally, a rapid and significant loss of these memory CD4+ T cells occurs early on in SIV infection: about ten days into the infection, when the levels of virus in the bloodstream are at their peak, up to 80 percent of the memory CD4+ T cells in some tissues became infected, and ultimately, nearly all of those memory CD4+ T cells are lost.

But vaccinating the monkeys can lessen this damage to the immune system, Dr. Roederer and his colleagues found. In their study of six vaccinated monkeys and six unvaccinated monkeys exposed to SIV, the vaccinated group had about 3 to 5 times fewer memory CD4+ T cells infected and destroyed. “If the virus wipes out only a fraction of the memory CD4+ T cells that it might otherwise destroy, that should allow [the animals] to live longer,” Dr. Roederer says. Likewise, he adds, if HIV vaccines can prevent the destruction of these memory cells in humans, it may be possible to provide people with longer, healthier lives.

In Dr. Letvin’s study, he and his colleagues looked at the effect of preserving the memory CD4+ T cells over the long term. A total of 30 monkeys—24 vaccinated and six unvaccinated controls—were infected with SIV and followed for nearly three years. The vaccine helped control the infection for the first 112 days, but thereafter, the virus levels and total CD4+ counts in the vaccinated and unvaccinated animals did not differ significantly.

But the vaccine protected the memory CD4+ T cells from the virus early on, and the levels of memory CD4+ T cells remained at significantly higher levels in the vaccinated animals for the 850 days they were studied.

“This [early protection] had huge consequences for the development of disease,” says Dr. Letvin. “When infection did occur, the monkeys preserved their memory CD4+ T cells better and lived longer.”

Moreover, the researchers found that measuring a subset of the memory CD4+ T cells, so-called central memory CD4+ T cells, could help predict how the monkey would fare in the long run. Since these new studies indicate that the central memory CD4+ T cell counts appear to be a crucial predictor of long-term health, blood samples from human clinical trial participants might now be examined for this marker. That way, says Dr. Letvin, scientists can gauge how well a vaccine will perform simply by measuring the central memory cell levels in the first few months after infection.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)— The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

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References:

N Letvin et al. Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys. Science DOI: 10.1126/science.1124226 (2006).

J Mattapalli et al. Vaccination preserves CD4 memory T cells during acute SIV challenge. Journal of Experimental Medicine DOI: 10.1084/jem.20060657 (2006).

AIDS Drugs Have Saved 3 Million Years of Life
in the United States

HIV Disease Model Details Survival Benefits of HIV Therapies

Increasingly effective HIV therapy—including a decade of highly active antiretroviral therapy (HAART)—has provided 3 million years of extended life to Americans with AIDS since 1989, report researchers funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Rochelle Walensky, M.D., M.P.H., Kenneth Freedberg, M.D., M.Sc., and their colleagues calculated that advances in HIV care have yielded a total survival benefit of 2.8 million years in the United States . The researchers also estimate that drugs to prevent mother-to-child transmission of HIV have averted 2,900 infant infections, saving an additional 137,000 years of life. The model projected that a person initiating HIV therapy in 2003 could expect to live more than 13 years longer than if he or she had been diagnosed in 1988.

The paper by Drs. Walensky and Freedberg, of Massachusetts General Hospital and the Harvard Medical School Center for AIDS Research, and their coauthors has been posted online by The Journal of Infectious Diseases.

"Since the early 1980s, soon after the first reports of what we now know as AIDS, NIH has devoted $30 billion to HIV/AIDS research," says NIH Director Elias A. Zerhouni, M.D. "This study clearly shows the dramatic impact that sustained investment in biomedical research can have in improving the lives of Americans."

"As new HIV therapies have come into the clinic, we have witnessed the transformation of HIV/AIDS from a rapidly fatal disease into a controllable condition," notes NIAID Director Anthony S. Fauci, M.D. "Although the rate of new infections in this country remains unacceptably high, for many people, HIV infection is no longer the death sentence it once was."

"Advances in HIV/AIDS treatments have been striking, particularly over the past decade. Our goal in this study was to quantify the clinical progress in AIDS care in terms of years of life saved," says Dr. Walensky.

with AIDS and accessing health care each year between 1989 and 2003 came from U.S. Centers for Disease Control and Prevention surveillance and other published data.

The investigators defined six eras of AIDS treatment between 1989 and 2003. In the first two periods, 1989 to 1992 and 1993 to 1995, drugs became available to prevent two common infections—Pneumocyctis jirovecii pneumonia and Mycobacterium avium complex. Although the drugs provided an average per-person survival benefit during that time of only 2.6 months, those early eras helped to shape the perception that AIDS was a treatable condition, notes Dr. Freedberg. Drs. Walensky and Freedberg subdivided the HAART era, which began in 1996, into four periods corresponding to increasingly effective HAART and other advances in HIV care.

For each year of the six eras, the investigators ran simulations of HIV disease progression in two equal-sized groups of hypothetical people with AIDS. One group received no therapy, while the other group received all available therapies of that era. The model calculated a per-person survival benefit and a total survival benefit in each era. By 2003, the model projected that an individual beginning treatment that year could expect to live more than 13 years longer than if he or she had been diagnosed in 1988. The total survival benefit for the 24,780 people diagnosed with AIDS and entering care in 2003 was 330,189 years. The total cumulative survival benefit across all eras from all forms of HIV therapy was 2.8 million years.

Dr. Walensky emphatically notes, however, that survival benefits related to therapy are available only to those with known HIV infection. But about one-fourth of people in the United States infected with HIV are unaware of their infection, she adds. "We calculated that a cohort of patients presenting with AIDS at higher CD4 cell counts—simulating slightly earlier entry into care—had an additional gain of 740,000 years of survival," says Dr. Walensky. "These findings underscore the importance of expanded HIV testing and better linkage to care for people who are HIV-infected, so that more of them can realize the life-extending benefits of HIV therapies."

"This type of research can also be used to understand the tremendous survival benefits that can be gained globally by continued rapid expansion of access to these very effective HIV/AIDS treatments in resource-limited settings," adds Dr. Freedberg. "This expansion is of critical importance."

The National Institute on Drug Abuse and the National Institute of Mental Health, parts of the NIH, also provided support for this research.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)— The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

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Reference: RP Walensky et al. The survival benefits of AIDS treatment in the United States. The Journal of Infectious Diseases. Published online June 1, 2006. http://www.journals.uchicago.edu/JID/journal/issues/v194n1/35845/35845.html
Additional Information: NIAID Exploring: Treatment of HIV Infectionhttp://www.niaid.nih.gov/factsheets/treat-hiv.htm