Amino Acid

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Single Amino Acid Change in HLA-B*35 Accelerates Progression to AIDS

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WESTPORT, CT (Reuters Health) May 31 - A point mutation that affects viral

peptide binding specificity on the major histocompatibility complex HLA-B*35

allele can substantially affect the rate of progression to AIDS following HIV

infection, according to results of a multicenter study.

Dr. Carrington, of the National Cancer Institute, in Frederick, land,

and colleagues conducted survival analyses of 592 white and 219 black

HIV-1-infected patients by comparing two HLA-B*35 subtypes. The HLA-B*35-PY

subtype binds epitopes with tyrosine in position 9. The HLA-B*35-Px subtype

binds several different amino acids other than tyrosine in position 9.

As reported in the New England Journal of Medicine for May 31, the researches

observed a significant association of the HLA-B*35-Px allele with progression to

AIDS in both black and white patients. Further analysis showed that the

previously observed effect of HLA-Cw*04 on progression to AIDS is

" predominantly, if not totally, due to linkage disequilibrium with HLA-B*35-Px, "

the investigators write.

The investigators suggest that the difference in affinity for tyrosine at the

carboxy-terminal position of viral peptides influences the efficiency of the

molecule in presenting HIV-1 epitopes to cytotoxic T lymphocytes. A poor

cytotoxic T-lymphocyte response takes place in patients with HLA-B*35-Px.

" This is the first documentation of the importance of a single-acid difference

in HLA on an infectious disease, " Dr. Carrington said in an interview with

Reuters Health.

In their paper, the investigators suggest that an aggressive therapeutic regimen

should be considered in recently infected patients with the HLA-B*35-Px allele.

However, in the interview, Dr. Carrington said, " I'm not sure that we are ready

to use this [information] diagnostically. It is reasonable to expect HLA to be

one of the most important host genetic determinants in AIDS progression, but

still, we need to account for all important genetic effects before we tell

someone how soon they might progress to AIDS based on HLA alone. "

N Engl J Med 2001;344:1668-1675.

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