AIDSWEEKLY Plus, Monday, 10 February 1997
Daniel J. DeNoon, Senior Editor
A person's genetic makeup determines the rate at which HIV disease progresses.
Researchers I.P.M. Keet of the University of Alabama, Birmingham, and colleagues compared the human leukocyte antigen (HLA) types of three cohorts of homosexual men (MACS, n=139; DCG, n=102; and Amsterdam, n=140) who have been enrolled in prospective studies since they first seroconverted to HIV.
"The allele/haplotype-TAP combinations found in our analysis to be consistently correlated with time to AIDS probably are true, or close surrogates of, genetic determinants of HIV-1 disease progression," Keet et al. wrote in their presentation abstract for the 4th Conference on Retroviruses and Opportunistic Infections, held January 22-26 in Washington, D.C.
Associations in combined analysis, and in two of the three cohorts, separately, were considered probable. Associations in combined analysis and in all three of the cohorts separately were considered proven.
HLA types proven linked to longer time to AIDS were A32+TAP2.3, B27, and B57.
The HLA type proven linked to shorter time to AIDS was A24+TAP2.1.
HLA types probably linked to longer time to AIDS were haplotype DRB1(*)0700-DQB(*)0303+TAP2.3, DRB1(*)0801- DQB(*)0400, and DRB1(*)1300-DQB(*)0603+TAP2.3.
HLA types probably linked to shorter time to AIDS were A3+TAP1.2, A23+no TAP2.3, A26+no TAP2.3, B8+TAP2.1, B38, B60, and DRB1(*)1400-DQB(*)0503.
In a recent article (Lancet, 1996;348:933-37, see AIDS Weekly Plus, November 18, 1996), Duke University AIDS Center researcher Barton F. Haynes suggested that HLA or HLA- associated gene expression could determine the HIV epitopes to which CTL and/or T-helper cells respond, determine which TCR regions are used in anti-HIV T-cell responses, and regulate anti-HIV cytokine responses.
"The large number of HIV variants available for transmission and the possible immunodominant nature of what may be protective anti-HIV T-cell responses have suggested the need for HLA-based HIV subunit vaccines," Haynes wrote.
To create such vaccines, researchers will have to consider several variables, including the HLA molecules expressed by the vaccine's target population, the T-cell epitopes of the vaccine immunogen, the HLA-restricting elements of the immunogen's T-cell epitopes, and the HIV variants endemic in the area where the vaccine will be used.
To account for all of these variables, Haynes argued, HLA- based vaccines will have to contain a mixture of immunogens that not only represent the relevant regional HIV variants, but also contain enough T-cell epitopes that can bind to the HLA molecules expressed on the target population's antigen- presenting cells (APC).
"Such a mixture of immunogens could range from a mixture of non-HIV vectors expressing HIV proteins to mixtures of HIV recombinant proteins and/or synthetic peptides," he proposed.
These HLA-based vaccines would have several consequences, according to Haynes:
* Not all members of a vaccine cohort will have the particular HLA antigens needed to present the HIV epitope in the immunogen.
* Not all HIV variants can be represented in the immunogen.
* Vaccines would have to be designed individually for each of the geographic regions - and possibly even for specific intraregion ethnic groups - in which they are deployed.
* The HLA-based vaccines are unlikely to be 100 percent effective.
Developmental steps include analysis of the HLA types present in the cohort to be vaccinated, analysis of the HLA class I CTL epitopes restricted by HLA types in the cohort, and analysis of the HIV types in the area where the vaccine cohort is located. - by Daniel J. DeNoon, Senior Editor
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