CHAVI, a consortium of research groups, was organized in 2005 to carry out “Big Science” projects that would illuminate the path to HIV vaccine development. The collaborative efforts of the group have enabled CHAVI to make discoveries that would not have been achieved by each individual investigator working alone. The findings generated by CHAVI have provided better understanding of the early events that follow HIV infection, and thus of the hurdles that must be overcome by a successful HIV vaccine.
The body deploys innate immune mechanisms as frontline troops against assault by a pathogen. These responses induced at the start of HIV infection may influence the subsequent course of the disease directly, or through their impact on adaptive immunity. Given the importance of this linkage, understanding innate immune responses in the initial stages of HIV infection may give insight into the types of responses that promote or hobble disease resistance. Thus, if a vaccine strategy can optimally harness the effectors of the innate immune system in the early stages of infection and appropriately program the adaptive immune system the resulting response may afford timely resistance against the pathogen.
Led by Persephone Borrow, CHAVI’s Innate Discovery Team found that HIV infection unleashes a systemic “cytokine storm” that peaks around day seven to ten post-infection, and coincides with the rising viral load (J. Virol. 83: 3719, 2009.) This conclusion comes from a study from 35 people newly infected with HIV. Blood samples taken from these individuals before and every three to seven days after infection were tested to analyze the levels of 30 cytokines and chemokines, the innate immunity mediators, along with viral load measurements. These measurements were compared to control samples from patients with hepatitis B or C virus infections, in whom no such dramatic rise in cytokine levels was observed. The findings imply that the cytokine storm that rages in the early stages of HIV infection fails to clear the virus, and may fuel the ensuing immune activation, viral replication, and ultimately immune exhaustion.
HIV also triggers apoptosis, a programmed cell death mechanism in CD4 T cells and other immune cells earlier than previously known. In plasma samples from the cohort mentioned above, researchers found a marked increase in the levels of four byproducts of T cell death, TRAIL, Fas ligand, TNF receptor type 2, and the remnants of broken cell membranes called plasma microparticles. On an average, TRAIL levels peak at day 7, while the other three byproducts peak at day 15, coincident with the peak viral load. The microparticles were found tosuppress IgG and IgA production by B cells (J. Virol. 82: 7700, 2008.) To successfully stop HIV, B cells must produce antibodies that prevent viral entry into cells. Because cell death byproducts generated early in infection impair B cell function, a successful vaccine must intervene very soon after HIV infection.
HIV primarily infects T cells that bear CD4 molecules on their surface. The viral envelope consists of proteins gp 120 and its companion, gp41. Gp120 latches onto CD4, which triggers a shape change in gp41 that facilitates fusion of viral coat with the host cell membrane. To nip HIV infection in the bud, the weapon of choice is neutralizing antibodies that bind these envelope proteins on circulating viral particles and prevent entry into cells. However, little is known about the mechanism by which virus exerts its early effects on B cells, the cellular factories that churn out antibodies.
Analysis of blood and small intestine tissue samples from HIV-infected patients revealed that as early as 17 days after infection, HIV depletes the pool of naïve B cells, the precursors of mature antibody producing cells. By day 47 post-infection the proliferating clusters of B cells in the gut, called Peyer’s patches have also been ravaged (PLoS. Med. 6: e1000107, 2009.) HIV appears to destroy many of microenvironments that nurture B cell development. The CHAVI B cell Discovery Team found that the initial antibody response to HIV is feeble. The first antibodies show up at day 8 after infection in the form of antibody-coated virus, followed by the appearance at day 13 post-infection of gp41 binding antibodies. Gp120 binding antibodies first appear at day 28 after infection (J. Virol. 82: 12449, 2008.) None of these early antibodies neutralize the circulating viral particles. It takes about 12 weeks for neutralizing antibodies to appear, which is too late to prevent infection. These findings suggest that to generate neutralizing antibodies, B cell niches must be protected. Other immune defenses must be fortified so that they can deal with the virus effectively before it disables any part of the immune system.
Led by George Shaw, Beatrice Hahn, and Bette Korber the Transmitted Virus Team sequenced the genome of viral particles in the plasma of 12 individuals prior to emergence of HIV-specific immune responses. In nearly 80% of cases, infection stemmed from a single founder virus (J. Exp. Med. 206: 1273, 2009.) Painstakingly CHAVI has shown that potent, early CD8 T cell responses to HIV reduce the viral load in the initial phase of infection, but the viral genome mutates and evolves to evade this immune pressure. In three individuals, the CHAVI T cell Discovery Team led by Andrew McMichael, matched the changes in the founder virus genome sequence to the specific CD8 T cell response in each subject. Such work was only possible because of the exhaustive virus sequencing work done by the CHAVI Transmitted Virus Team on specimens from the same subjects. Mathematical modeling of HIV evolution in these same subjects then suggested that the reduction in viral load in the acute phase could be attributed at least in part to killing of infected cells by CD8 T cells (J. Exp. Med. 206: 1253, 2009.) This study implies that an effective HIV vaccine will have to stimulate T cells that target a broad range of epitopes so that the ever-changing virus cannot hide.
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Last Updated November 09, 2009