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.