Replies to post #65686 on Biotech Values

[Preciouslife1]

An HIV Vaccine — Challenges and Prospects

Margaret I. Johnston, Ph.D., and Anthony S. Fauci, M.D.
http://content.nejm.org/cgi/content/full/359/9/888?query=TOC

Now well into the third decade of the pandemic of human immunodeficiency virus (HIV) and AIDS, we have seen dramatic successes in the treatment of HIV-infected persons in the United States and many other countries. Yet the pandemic still rages, with 2.7 million new infections in 2007. Indeed, for every infected person who began receiving antiretroviral therapy in 2007, 2.5 people were newly infected with HIV. Historically, vaccines have been among the most effective public health interventions, preventing the spread of viral infections. But an HIV vaccine has thus far been elusive and the quest disappointing and frustrating, prompting some to wonder whether an effective vaccine will ever be added to the HIV-prevention toolbox.

Although many viral infections cause severe illness and even death over a period of days to weeks, such infections typically induce immune responses involving both neutralizing antibodies that prevent further viral replication and cytotoxic T lymphocytes that recognize and eliminate infected cells that produce progeny virus. Such responses ultimately control and eliminate the virus effectively. Immunologic memory is established, and the person is left with protective immunity against subsequent infection with the same virus; this immunity is usually complete and long lasting.

Typically, vaccine development is based on this successful experiment of nature. An iterative approach of fundamental research coupled with empirical testing of immunogens leads to the identification of a product that, when given in an appropriate formulation and dose before exposure, induces immune responses that mimic the response to natural infection and protect recipients from the development of clinically apparent disease when they are exposed to the virus. Historically, the development of vaccines has relied heavily and successfully on empirical testing.

The situation is strikingly different with HIV infection.
For the most part, the natural immune response against HIV is completely inadequate and, once primary infection is established, fails to eradicate the virus. With uncommon exceptions, HIV disease is relentlessly progressive, and virtually no one has a spontaneous recovery.
Unlike other viruses for which we have successful human vaccines, HIV quickly integrates itself into the DNA of the host cell, where, in some cells, it remains latent and essentially invisible to the immune system. Because latency is established very early — within days to weeks after infection — the window of opportunity wherein HIV remains vulnerable to eradication through the immune response is very short.1 Once latency is established, it has not yet been possible to eradicate the virus, even in patients receiving highly active antiretroviral therapy for extended periods.


Structure of HIV.
An interactive graphic is available at www.nejm.org.

The extraordinary mutability and resulting genetic diversity of HIV, which is substantially more complex than that of other human viruses, also present a formidable obstacle to immune control. By the time the body produces antibodies directed at the outer HIV envelope protein, which is the key target for neutralizing antibodies, the protein has mutated in such a way that the circulating antibodies cannot neutralize it. New antibodies are induced, but new mutations repeatedly enable the virus to evade the immune system. Furthermore, although broadly neutralizing antibodies could persist in the host and potentially neutralize the virus even as it mutates, these are rarely found in vivo and are apparently difficult to induce, since their epitopes tend to be conformationally masked and not readily accessible for immune recognition and response.

The initial empirical approach of immunizing with VaxGen's AIDSVax, a recombinant form of the outer glycoprotein-120 (gp120) portion of the HIV envelope, which was based on a strategy that was successful with hepatitis B, failed to protect volunteers from infection, apparently because the vaccine did not induce broadly neutralizing antibodies.3 A combination vaccine composed of priming doses of Sanofi Pasteur's vCP1521, a recombinant canarypox viral vector, followed by a boosting dose of both the vector and VaxGen's AIDSVax, induces both T cells and antibodies and is now being tested in a large-scale clinical trial in Thailand; results are expected at the end of 2009.

A successful vaccine will probably need to induce both broadly neutralizing antibodies and cytotoxic T lymphocytes. Since the former have remained elusive, however, empirical approaches have focused on vaccine candidates that primarily induce cytotoxic T lymphocytes. Such vaccines would not be expected to prevent infection but could control virus levels, reduce the early destruction of CD4+ T cells in gut-associated lymphoid tissue, and delay disease progression, as has been seen in certain nonhuman-primate models.
Furthermore, if persons immunized before being exposed to HIV were rendered less infectious because of decreased virus levels, the risk of secondary transmission might also be reduced. But several caveats need to be emphasized.

First, the concept that a "T-cell vaccine" can affect HIV disease in humans remains unproved. Only one T-cell vaccine, Merck's MRKAd5 HIV-1 gag/pol/nef trivalent vaccine, has been tested, in two efficacy trials. The first was referred to as the STEP trial (ClinicalTrials.gov number, NCT00095576 [ClinicalTrials.gov] ) and was conducted in North America, South America, the Caribbean, and Australia; the second, called Phambili (ClinicalTrials.gov number, NCT00413725 [ClinicalTrials.gov] ), was conducted in South Africa.
Both trials were terminated ahead of schedule when data from the STEP trial showed that the vaccine failed to prevent HIV infection and failed to lower virus levels in vaccinated volunteers who became infected. Unexpectedly, post hoc analyses of the STEP trial also found a trend toward a greater number of new infections among vaccine recipients than among placebo recipients. The highest relative risk of HIV infection among vaccinees appeared to be among men who, at enrollment, were both uncircumcised and had naturally acquired neutralizing antibodies against the vaccine vector, adenovirus type 5 — whereas no apparent increased risk of HIV acquisition was observed among circumcised men with no neutralizing antibodies against the adenovirus at enrollment.

The effectiveness of the immune response to a T-cell vaccine may vary from person to person, just as the immune response to HIV infection does, and this variation may be strongly related to HLA haplotype. Thus, a T-cell vaccine may augment the body's genetically determined natural ability to respond to HIV, resulting in varying levels of control that depend on the person's HLA haplotype. In other words, such vaccines may only be effective in people with favorable HLA haplotypes.

Classic viral vaccines, such as those for polio, smallpox, and measles, enable the vaccinee to avoid the development of clinical disease, to clear the infection completely, and to remain protected against subsequent exposure to that virus. The vaccination of a substantial proportion of the population reduces the number of infected people and the likelihood that a nonvaccinated person will come into contact with an infectious person. This "herd effect" can result in a dramatic decrease in the spread of infection even when only a portion of susceptible persons are vaccinated. If an HIV vaccine does not prevent infection but instead slows disease progression by lowering virus levels, the probability of secondary transmission may be reduced but not eliminated. Some level of viral replication will probably remain. HIV will inevitably mutate and probably eventually escape from immune control, increasing the risk of secondary transmission. Thus, any herd effect of a T-cell vaccine may be transient.

The failure of the first T-cell vaccine to affect the risk of infection or viral levels has led to a reexamination of the direction of the HIV-vaccine field and, in particular, of the balance between fundamental-discovery research and more empirical development efforts. Since an empirical approach is less compelling for HIV than for other human viruses, from which it differs so fundamentally, this reexamination has pointed to a need to emphasize fundamental questions of HIV-vaccine discovery and discovery-related research.

Understanding why the body does not readily develop broadly neutralizing antibodies during natural infection might suggest vaccine designs that induce such antibodies.
In essence, we must do better than natural infection in inducing effective immune responses. The existence of rare monoclonal antibodies that possess broad neutralizing capability indicates that, although we have thus far failed to achieve it, induction of such antibodies should be possible. For example, x-ray crystallography has revealed how HIV uses the CD4 receptor to enter cells and how the broadly neutralizing b12 antibody binds to part of the CD4-binding site to neutralize HIV effectively. Determining the structure of the trimeric form of the envelope protein is currently a research priority and is expected to yield additional insights. Efforts to design novel envelope immunogens include the use of a "scaffold" protein unrelated to the HIV envelope to which conformation-dependent conserved regions of the envelope are added, ensuring their exposure to and recognition by the immune system.

Vaccine candidates that induce broadly reactive cytotoxic T lymphocytes and neutralizing antibodies will not be effective unless the responses they elicit can contain the virus during the narrow window of opportunity before viral latency is established. Better understanding of the earliest steps of HIV infection could elucidate the role of innate and mucosal immune responses in the control of HIV infection and suggest how those responses might be manipulated — to widen the window of opportunity for viral eradication, to prevent HIV from advancing to the gut-associated lymphoid tissue, or both.

We may not be able to develop an HIV vaccine that is highly effective in the classic sense of successful viral vaccines. If we do, it will be in the face of enormous scientific challenges. To tackle these challenges we must turn to fundamental research to a degree that has not been required in the development of vaccines for other viral diseases. We remain cautiously optimistic that a substantial increase in our understanding of HIV infection and disease will lead to creative ideas about how to design an effective HIV vaccine.

Selected Obstacles to HIV-Vaccine Development and Their Implications.

Obstacles

The window of opportunity for the immune system to clear the initial infection is narrow, since HIV integrates and establishes latent infection within days or weeks.

Destruction of CD4+ T cells begins early after infection.

Enormous genetic diversity and mutations that occur with replication enable HIV to avoid immune surveillance.

Conserved antibody targets on the outer envelope protein are "hidden" from immune recognition.

Implications

Rational, empirical approaches to vaccine development have not been successful to date.

Fundamental questions regarding HIV disease and the host response to the virus need to be answered.

Fresh new ideas beyond the scope of classic vaccinology are urgently needed.

No potential conflict of interest relevant to this article was reported.

Source Information

Dr. Johnston is the director of the Vaccine Research Program in the Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, and Dr. Fauci is the director of NIAID.

An interview with Anthony Fauci is available at www.nejm.org

References

Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A 1998;95:8869-8873. [Free Full Text]
Burton DR, Desrosiers RC, Doms RW, et al. HIV vaccine design and the neutralizing antibody problem. Nat Immunol 2004;5:233-236. [CrossRef][ISI][Medline]
Johnston MI, Fauci AS. An HIV vaccine -- evolving concepts. N Engl J Med 2007;356:2073-2081. [Free Full Text]
Goulder PJR, Watkins DI. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 2008;8:619-630. [CrossRef][ISI][Medline]
Fauci AS, Johnston MI, Dieffenbach CW, et al. HIV vaccine research: the way forward. Science 2008;321:530-532.

[grandpatb]

H.I.V. Is Spreading in New York City at Three Times the National Rate, a Study Finds
By SEWELL CHAN
NYTimes August 27, 2008

The virus that causes AIDS is spreading in New York City at three times the national rate — an incidence of 72 new infections for every 100,000 people, compared with 23 per 100,000 nationally — according to a study released on Wednesday by the city’s Department of Health and Mental Hygiene.

The findings, based on a new formula developed by the federal Centers for Disease Control and Prevention, estimated that 4,762 New Yorkers contracted H.I.V. in 2006, the most precise estimate the city had ever offered.

But the city stressed that because the method of estimating infections was new, it could not be said definitively whether the number of new infections in the city had increased or decreased from previous years.

Blacks, and men who have sex with other men, are the groups at greatest risk of contracting H.I.V., the study found. A summary of the new data:

¶Men accounted for 76 percent of new H.I.V. infections and women for 25 percent. (The figures exceed 100 percent because of rounding.)

¶Blacks made up 46 percent of the newly infected; Hispanics, 32 percent; and whites, 21 percent. (Figures for other racial or ethnic groups were not provided.)

¶Those under age 20 made up 4 percent of the newly infected; those 20 to 29 years old, 24 percent; those 30 to 39 years old, 29 percent; those 40 to 49 years old, 29 percent; and those 50 and older, 15 percent.

¶Sex between men was the main cause in 50 percent of new infections; high-risk heterosexual sex in 22 percent; intravenous drug use in 8 percent; and unknown or uncertain causes in 18 percent.

Manhattan accounted for 35 percent of new infections; Brooklyn, 26 percent; the Bronx, 19 percent; and Queens, 17 percent.

As the health department has repeatedly noted, gay minority men were particularly at risk. For example, of new H.I.V. infections among men under age 30 who have sex with men, 77 percent were in black or Hispanic men, as were 59 percent of new H.I.V. infections among men ages 30 to 50 who have sex with men.

Over all, the study found some interesting differences between national and local rates of new H.I.V. infections.

Nearly two-thirds of the city’s new infections occurred in people 30 to 50 years old. Nationally, people under 30 accounted for 41 percent of new infections, compared with 28 percent in New York City.

Also, within New York City, whites were infected at four times the national rate, Hispanics at three times the national rate, and blacks at almost twice the national rate.

The health department said in a news release:

“The analytic technique is new, and the estimates may be imprecise, but even a rough gauge of H.I.V. incidence is a valuable tool for understanding — and combating — the spread of H.I.V. The health department’s new estimate includes 2006 incidence figures for different age groups, racial groups and both genders. By repeating the exercise for subsequent years, researchers may be able to discern increases and decreases over time, and target their prevention efforts accordingly.”

Over the past year, the health department has warned that H.I.V. infections among young gay men have risen and that unsafe sex remains common.

[Preciouslife1]

What HIV Needs: Identification Of Human Factors May Yield Novel Therapeutic Targets For HIV

http://www.sciencedaily.com/releases/2008/10/081002171916.htm

The Salk Institute for Biological Studies and Burnham Institute for Medical Research today announced 295 host cell factors that are involved in human immunodeficiency virus (HIV) infection. The study, published in the Oct. 3 issue of Cell, could lead to the development of a new class of HIV therapeutics aimed at disrupting the human-HIV interactions that lead to viral infection.

The research, a collaborative effort between the laboratories of Sumit K. Chanda, Ph.D, previously at the Genomics Institute of the Novartis Research Foundation (GNF) and now at Burnham and John Young, Ph.D. at Salk, combined several layers of genome-wide analysis to identify cellular proteins that aid the virus in establishing an infection.

"HIV has just nine genes, coding for 15 proteins, compared to bacteria, which harbor several thousand genes, or humans, with over 20,000 genes," said Chanda, associate professor in the Infectious & Inflammatory Disease Center at Burnham and an adjunct faculty member at Salk. "We have known for a long time that HIV hijacks our cellular proteins to complete its life cycle. This study now lays out its flight plan."

Young, professor in the Infectious Disease Laboratory at Salk added, "Due to viral resistance, there is an urgent need for new classes of therapies aimed at preventing the virus from infecting new cells as opposed to merely keeping viral replication in check. To develop more effective therapies for HIV infection and AIDS we must identify and characterize the cellular factors that participate in early steps of HIV-1 replication and prevent the virus from becoming established."

Although more than two dozen drugs are available for the treatment of HIV infection, there is a growing need for new antiviral therapies. Recent studies indicate that HIV remains "hidden" in a latent form, even after long-term suppression with highly active antiretroviral therapy.

In the study, the team of researchers used short-interfering RNA (siRNA) which, when introduced into a cell, silences cellular gene expression, one gene at a time. Using high throughput transfection technology available at GNF and at Burnham, more than 144,000 siRNAs (6 siRNAs for each gene in the human genome) were screened for their effects on HIV-1 infection. Data from the siRNA genomic screen was combined with information from large-scale, protein-protein interaction databases to identify key protein complexes that affect discrete steps in the early stages of HIV infection.

"The integration of these systems-based analyses allowed us to build, for the first time, a functionally validated map of host-pathogen interactions that are required for viral infection," said Renate König, Ph.D., of Burnham, the first-author on the study.

Other coauthors on the study included Drs. Daniel Elleder of the Salk Institute for Biological Studies, Yingyao Zhou of the Genomics Institute of the Novartis Research Foundation, Tracy Diamond and Frederic Bushman of University of Pennsylvania, and Trey Ideker of the University of California, San Diego.

The study was supported by a grant from the U.S. National Institutes of Health and the University of Pennsylvania Center for AIDS research.