Correspondence

MHC Class I Molecules and Progression to AIDS

N Engl J Med 2001; 345:924-925September 20, 2001

Article

To the Editor:

Gao et al. (May 31 issue)1 report the identification of specific HLA-B*35-Px subtypes as responsible for the association between HLA-B*35 and rapid progression to AIDS, and they stress the importance of homozygosity for HLA-B*35 as a predictor of even more rapid progression. Their extensive analysis confirms the known protective effect of the HLA-B*27 and B*57 subtypes against progression to AIDS, at least in whites.2

Unlike Gao and colleagues, we think that there is an important influence of numerous major-histocompatibility-complex (MHC) gene products. The A1,B8,DR3 haplotype, for instance, has repeatedly been shown to be associated with fast progression to human immunodeficiency virus (HIV) disease and rapid loss of CD4 T cells,3,4 and several other HLA haplotypes can predict disease progression.2 Caution should be exercised before early, aggressive antiretroviral therapy is recommended for HLA-B*35–positive patients. We have been following an HIV-infected woman without symptoms since her seroconversion in 1991 (she is now 37 years old). She has never received antiretroviral therapy and still has a high CD4 cell count (606 per cubic millimeter, 36.6 percent of total lymphocytes) and CD4:CD8 ratio (0.91), despite being homozygous for HLA-B*35. Perhaps the presence of HLA A2,A26 alleles in her haplotype counteracts the effects of HLA-B*35, since A2 is common in frequently exposed HIV-seronegative persons5 and A26 may confer resistance to the progression of HIV disease.2

Francesca Cainelli, M.D.
Ercole Concia, M.D.
Sandro Vento, M.D.
University of Verona, 37138 Verona, Italy
francescacainelli@yahoo.it

5 References

1. 1

   Gao X, Nelson GW, Karacki P, et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med 2001;344:1668-1675
   Full Text | Web of Science | Medline

2. 2

   Kaslow RA, Carrington M, Apple R, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996;2:405-411
   CrossRef | Web of Science | Medline

3. 3

   Kaslow RA, Duquesnoy R, VanRaden M, et al. A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection: a report from the Multicenter AIDS Cohort Study. Lancet 1990;335:927-930
   CrossRef | Web of Science | Medline

4. 4

   McNeil AJ, Yap PL, Gore SM, et al. Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. QJM 1996;89:177-185
   Medline

5. 5

   Malkovsky M. HLA and natural history of HIV infection. Lancet 1996;348:142-143
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: To date, over 50 papers have been published that attempt to associate HLA haplotypes with the rate of progression to AIDS. Because of low statistical power and small samples, the results of many cannot be considered rigorously validated. Among the strongest associations are the influence of HLA class I homozygosity and the codominant influence of HLA-B*35. The goal of our recent report was to demonstrate that the previously reported effect of B*351 could be connected directly to the peptide-binding specificity of certain HLA-B*35 subtypes. We are, of course, aware of several other genetic factors that mitigate progression to AIDS, including the genes encoding CC chemokine receptors 5 and 2, interleukin-10, and stromal-cell–derived factor 1 as well as other HLA alleles, and we described them in our cohorts.1,2 These factors may counteract each other, which could be the case for the HLA-B*35–homozygous woman described by Cainelli et al. This patient's AIDS-free survival for 10 years is remarkable. In our experience with six patients homozygous for HLA-B*35 in five cohorts, five progressed to an AIDS-defining condition in less than 6 years and the other one in less than 10 years.

We agree that multiple genetic and viral influences should be considered when a therapeutic regimen for an HIV-infected patient is chosen. We believe that B*35-Px is one of the more influential factors.

Mary Carrington, Ph.D.
Xiaojiang Gao, Ph.D.
Stephen O'Brien, Ph.D.
National Cancer Institute, Frederick, MD 21702
carringt@mail.ncifcrf.gov

2 References

1. 1

   Carrington M, Nelson GW, Martin MP, et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999;283:1748-1752
   CrossRef | Web of Science | Medline

2. 2

   O'Brien SJ, Nelson GW, Winkler CA, Smith MW. Polygenic and multifactorial disease gene association in man: lessons from AIDS. Annu Rev Genet 2000;34:563-591
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Shu Li, Hongli Jiao, Xu Yu, Amie J Strong, Yiming Shao, Yongtao Sun, Marcus Altfeld, Yichen Lu. (2007) Human Leukocyte Antigen Class I and Class II Allele Frequencies and HIV-1 Infection Associations in a Chinese Cohort. JAIDS Journal of Acquired Immune Deficiency Syndromes 44:2, 121-131
   CrossRef