HIV vaccines

The pursuit to develop a vaccine against HIV has been a subject of some discussion in our class. Unfortunately, it does not seem likely that a vaccine would be able to prevent HIV infection. However, the development of a T-cell vaccine against HIV would be a powerful tool in the toolbox of HIV treatment. A T-cell vaccine aimed at the period of susceptibility directly following infection would lower the initial “burst of viremia” and lead to better patient outcomes. Mellors et al. (1996) found that the viremia measurements at initial infection were powerful predictors of prognosis for progression from HIV to AIDS and for AIDS-related death. Likelihood of transmission to secondary hosts is also predicted by viremia. A vaccine that could lessen the impact of HIV infections in individuals and dampen the spread of the disease would represent an amazing stride forward.

The infection and slow depletion of CD4+ T-cells that characterizes HIV leads to the eventual loss of immune function and overt AIDS. The idea behind Merck’s recent STEP vaccine trial was to immunize recently infected HIV patients with a recombinant adenovirus (serotype 5, hence the name: Ad5) vector carrying three genes contained within the HIV genome: gag, pol, and nef. There are only 9 identified genes within the viral genome of HIV. This immunization would prime the T-cells to recognize the virion and preempt systemic invasion. The results of the trial were abysmal. Of 3000 high-risk patients that were initially enrolled, randomized, blinded and treated, 82 people were infected with HIV over the course of 90 weeks. Efficacy of the treatment was based on viral load setpoint and HIV infection rates. 4.6% of treatment cases went on to develop HIV, while 3.1% of placebo controls developed HIV. Perhaps the vaccine was worse than futile, but actually increased the incidence of infection. As a result, Merck halted the trial.

Vaccines of this vector variety have been found to be effective in eliciting immune responses in Rhesus monkeys. However, many human populations have been found to have pre-existing immunity to Ad5. This immunity limits the immunogenicity of recombinant Ad5 vaccines and might explain the failure of the STEP trial. However, the creation of chimeric vectors may restore the immunogenicity of the Ad5 viral coat.

On a related note, resistance to progression of HIV-1 infection has been found to be associated with the allele HLA-B*5701. This emphasizes the important role that class I-restricted CD8+ T-cells can play in resistance to disease progression.

References

STEP Study Summary; Press briefing, November 7, 2007. http://www.hvtn.org/media/pr/STEPPressbriefingNov2007.pdf

M.I. Johnson and A.S. Fauci. 2007. An HIV Vaccine – Evolving Concepts. New England Journal of Medicine 356:2073-2081.

J.W. Mellors, C.R. Rinaldo Jr., P. Gupta, R.M. White, J.A. Todd, L.A. Kingsley. 1996. Prognosis in HIV-1 Infection Predicted by the Quantity of Virus in Plasma. Science 272(5265): 1167-1170.

HIV virus sequence compendium 2005. http://www.hiv.lanl.gov/content/hiv-db/COMPENDIUM/2005/0.pdf. Accessed: 11/21/2007.

Conrad.org. Novel Adenovirus Vector-Based Vaccines for HIV-1. D. Barouch presenting, November 17, 2006. http://www.conrad.org/pdf/BiomarkersMtg.Barouch.pdf

Migueles, S.A. et al. 2000. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. PNAS Immunology 97(6): 2709-2714.

Good news from the virology frontlines

To date, HIV treatment regimens have primarily targeted virus enzymes or the process of virus-cell fusion, but not the integrated proviral DNA. Current highly antiretroviral therapy (HAART) targets the viral reverse transcriptase, protease and fusion proteins and this regime has transformed HIV-1 infection into a chronic disease and curtailed the mobidity of infected individuals⁽¹⁾…that is, if you have access to antiretroviral drugs.

Since traditional vaccine aproaches have, up to date, failed miserably⁽²⁾, new therapeutic interventions must be brought to the clinic.

A new attractive alternative has just been published⁽³⁾ which is the specific erradication of the integrated HIV-1 provirus⁽⁴⁾ in the host’s DNA.

In brief, the authors evolved a CRE recombinase⁽⁵⁾⁽⁶⁾ which specifically recognizes sequences present in HIV-1 Long Terminal Repeats (LTRs)⁽⁷⁾ and “splices out” the proviral DNA in cells infected with HIV-1.

This piece of work is quite interesting as proof-of-principle but it’s unlikely to be of immediate therapeutic use, although other authors have been able to engineer Cre recombinases which are cell membrane permeable and can even cross the blood-brain barrier⁽⁸⁾.

Stay tuned…

References:

1) Lalezari JP et al. “Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America.” N Engl J Med. 2003 May 29;348(22):2175-85. Epub 2003 Mar 13

2) http://www.nature.com/news/2007/071114/pdf/450325a.pdf

3) Sarkar, Indrani et al. “HIV-1 proviral DNA excision using an evolved recombinase” Science. 2007 Jun 29;316(5833):1912-5

4) For a small review on the life cycle of a retrovirus: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.1437

5) For more on CRE recombinase:

http://en.wikipedia.org/wiki/Cre_recombinase

(6) Glaser S, et al “Current issues in mouse genome engineering.” Nat Genet. 2005 Nov;37(11):1187-93.

(7) For more on LTR’s please visit:

http://www.stanford.edu/group/nolan/tutorials/retcl_3_ltrs.html

(8) Jo, Dawoong et al. “Epigenetic regulation of gene structure and function with a cell-permeable Cre reombinase” Nat Biotechnol. 2001 Oct;19(10):929-33

Something to chew on (with your turkey)

When you are sitting down to your Thanksgiving dinner, and already dreaming about the soup that will be made out of the leftovers, chew on this (slightly silly) tid-bit...chicken soup has anti-inflammatory properties! In a special report (CHEST 2000, 118:1150-1157), Rennard et al. studied the effects of chicken soup on neutrophil chemotaxis in vitro. Sure, in vivo would be better, but that's for another study!
The study prepared a tasty soup (with matzoh balls) from scratch and tested it at different stages of preparation, and compared this to commercially available soups.
Overall, chicken soup was found to inhibit neutrophil chemotaxis compared to media in a concentration-dependent manner. (and luckily, chicken soup was not toxic to neutrophils)
When comparing the commercially available soups (13 different brands) to the homemade soup, the authors found that most inhibited chemotaxis, but some (such as Campbell's Ramon noodles, chicken flavor) enhanced chemotaxis.
Overall, a nice warm bowl of chicken (or turkey) soup may decrease inflammation as well as loosening nasal secretions (due to the vapor), and perhaps improve cilia function (CHEST 1978;10:408-410)

Happy Thanksgiving!!

Where is the peanut allergy vaccine?

In our last class, Dr. Cohen mentioned that some anti-IgE antibodies have been tested in people with food allergies, most interestingly in people with allergies to peanuts. Peanut allergies seem to be on the rise in children in recent years, and can substantially decrease the quality of life for a person (and the families of people) with such allergies. A study published by Leung et al., in 2003 examined the effects of a humanized IgG monoclonal antibody against IgE called TNX-901. This antibody prevents IgE from binding to the Fc receptor on mast cells.

A placebo-controlled, double blind food challenge established that four subcutaneous injections (450 mg) of TNX-901 every four weeks (for a total study time of 16 weeks) raised the allergen tolerance threshold from one-half peanut to nine peanuts in subjects. While this is not enough to allow a person with peanut allergies to begin eating peanuts regularly, it is probably sufficient to prevent a deadly reaction in case of accidental exposure – and provide some peace of mind for those that must vigilantly avoid peanut exposure.

Although the results of the initial study were very promising, a legal battle over infringement rights between the drug’s maker Tanox, Inc., and Novartis and Genentech has shelved the drug indefinitely. A similar anti-IgE drug, omalizumab, is approved to treat asthma and is sometimes used off-label for those with extreme food allergies (for more on the mechanisms of this drug see Holgate et al., 2005). However, drug trials approving its use in food allergies, and thus insurance coverage for those who need it for such reasons, remain a few years off. In the end, it seems a drug that was fast-tracked because of its promising initial results has been delayed by years because of legal issues.

Holgate ST et al. (2005). Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy. 35(4):408-16.

Leung DY et al. (2003). Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med. 348(11):986-93.