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CHAVI: Injecting New Ideas

Center for HIV/AIDS Vaccine Immunology (CHAVI) is now in its second year of funding. This virtual consortium comprising 94 investigators at 51 institutions and sites in the U.S., Europe, Africa, and Australia is led by Dr. Barton Haynes of Duke University. Currently 12 observational studies have been planned at 13 clinical sites, of which 6 studies are in progress. CHAVI is divided into groups or "discovery teams." The advances achieved by three discovery teams are highlighted in this report:

Search for Human Gene Variants

The team of geneticists seeks to find the genetic differences that affect how well an individual’s immune system controls HIV in the earliest phase of infection. By uncovering the genetic factors that allow some people to hold down their viral load, scientists hope to design a vaccine that stimulates those protective immune responses against the virus. Data for this effort comes from two largely Caucasian patient groups or "cohorts": 600 patients in EuroCHAVI and 500 patients enrolled in Multi Center AIDS Cohort Study (MACS) in the US. The first group serves as the "discovery" cohort for unearthing new genes, while the second acts as the "replication" cohort where the results from the discovery cohort are further confirmed.

Using Illumina’s Human Hap 550 BeadChip that contains over 550,000 single letter differences in DNA, called single nucleotide polymorphisms (SNPs), the entire genome of the patients was analyzed. In the EuroCHAVI cohort, HLA B5701 allele carrying individuals have the most favorable immune responses to HIV, with this gene accounting for almost 10% of the total variability seen in viral load set-point. Another newly discovered variant in the MHC loci in this population explains about 6% of viral load set-point variability. Thus more than 15% of the observed variability in set-point was accounted for in this study which more than doubles the known fraction of variability (Science 317, 944, 2007). The genome of the MACS cohort is still in analysis. BeadChips that provide good coverage of African genetic variation are also being assembled for performing similar genetic analyses in Africans.

Signature of Transmitted virus 

By studying the sequence of the virus transmitted from donor to recipient, virologists, computational biologists and statisticians hope to develop a new generation of vaccines that will provoke protective immune responses against the virus that actually initiates the infection. Viruses being studied include those isolated from recently infected patients in South Africa, Malawi, Trinidad, North Carolina, and the U.S. Blood Bank Industry cohorts. The classification system devised by Fiebig et al. (AIDS 17, 1871, 2003) is used to differentiate persons with acute HIV infection from those with viruses that may already have evolved in response to the earliest host immune responses. Upon alignment of 4260 clade B envelope sequences from 195 individuals, more than half of whom were determined to be acutely infected, some amino acid changes were found that appear to characterize the evolution from acute (transmitted) virus to the viruses commonly found in early infection. All of the sequences and the consensus analysis of the signature motifs in the transmitted virus will be publicly available soon. Dr. Barton Haynes says, "the Clade C dataset is coming right behind."

Analyzing Antibody Production during Acute Infection

The B-cell discovery team intends to crack the viral mechanisms that delay protective antibody production after HIV infection. Studying the U.S. Blood Bank Industry cohort, researchers learnt that non-neutralizing antibodies targeting the gp41 region of the viral envelope first appear at 10 days after virus is first detected, just as viral replication reaches its initial peak. Non-neutralizing antibodies that bind to the V3 loop emerge at 15 days post-infection, followed by antibodies against the CD4 binding site and membrane proximal region of the viral envelope at 30 days. Neutralizing antibodies to the circulating virus do not begin to appear until 45 days after virus attack. To explain this lack of early induction of neutralizing antibodies, the team is exploring if the cellular byproducts of apoptosis of gut CD4+ T cells at peak viral load inhibit antibody production by B cells.

 

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Last Updated September 03, 2008