Considering genetic profiles in functional studies of immune responsiveness to HIV-1
Introduction
Host genetic variability is a fundamental component determining the fate of individuals exposed to many pathogenic microorganisms. Examples of genetic mutations that have high penetrance of protection among exposed individuals include those identified in the β-globin and duffy antigen receptor for chemokines (DARC) genes [1], [2]. Single mutations in each of these genes have undergone positive selection in regions of Africa endemic for malaria because of their extreme protective effects against Plasmodium falciparum and Plasmodium vivax, respectively. More recently, a mutation in the chemokine receptor gene, CCR5, has been shown to provide strong protection from infection with HIV-1 [3], [4], [5], [6], but the frequency of the genotype rendering this effect (CCR5Δ32/CCR5Δ32) is quite low (about 1%). Other factors are likely to account for the majority of individuals protected from HIV infection. Unlike the clear mechanisms by which genotypes of β-globin, DARC, and CCR5 cause protection against particular pathogens, genetic resistance to infectious diseases in general is likely to involve an exceedingly complex array of host genetic effects that are complicated further by pathogen diversity and environmental factors.
A number of host genetic variants have now been identified that show significant association with HIV disease progression, and to a much lesser extent with resistance to infection. Because of relatively sparse information regarding genetic resistance to HIV-1 infection, the remainder of this review will address only the genetic associations with disease progression after infection. Although some of these genetic effects are quite significant, their influence tends to be weak and detectable only in large cohorts that are well defined with regard to clinical parameters. These findings fulfill predictions of the complex genetic interactions between host and pathogen. Despite this complexity, there is now sufficient information regarding the genetic influence on AIDS progression that these genetic factors should be controlled for when designing experiments to test functional correlates of disease resistance.
Here we provide a brief review of the reported genetic associations with progression to AIDS and the association of overall genetic risk values to illustrate the importance of these effects collectively on the development of AIDS progression. Allele frequencies and relative hazard (RH) values for each of the individual variants used to generate a composite RH in this report are presented in Table 1, Table 2, Table 3. Selection of the variants used in this study was based on significance of the genetic association between each variant and progression to AIDS in the cohorts routinely used in the Laboratory of Genomic Diversity at the National Cancer Institute. Detailed descriptions of these associations [3], [7], [8], [9], [10], [11], [12], [13], [14] and the cohorts used in these studies [15], [16], [17], [18], [19] have been reported previously. We included each host genetic variant as a covariate in the Cox model to generate the most accurate RH values possible based on our current knowledge of these effects on this disease in our cohorts. Given the strength of the association between composite RH values and disease progression, we strongly suggest that genetic variation among subjects be taken into account in clinical trial involving HIV.
Section snippets
CCR5-Δ32 and CCR2-64I
The CCR5 gene became an obvious disease gene candidate for potential influence on HIV-1 infection upon discovery that CCR5 serves as a co-receptor for isolates of HIV-1 that generally initiate infection (R5 isolates) [20], [21], [22], [23], [24]. CCR5 contains a single open reading frame (exon 4) of only 1055 base pairs and a common, severe mutation characterized by a 32 base pair deletion, CCR5-Δ32, was rapidly identified [3], [4], [5], [6]. The deletion begins in the region encoding the third
Composite genetic risk associates strongly with AIDS progression
The optimum strategy for taking genetic background into account in a study of functional differences relating to disease progression is to match cases and controls for all genetic variants believed to influence progression. However, as more genetic factors affecting progression are identified, it will be increasingly difficult to find enough subjects who are identical with respect to all factors judged to be important. An alternate strategy would be to match cases and controls by similar
Conclusions
Data regarding the host genetic effects on HIV pathogenesis have been accumulating at a relatively rapid rate since the identification of CCR5-Δ32, a severe deletion in one of the two primary co-receptors for the virus. The contribution of host genetics in addition to variation in the virus and environmental factors has now been clearly demonstrated. As illustrated herein, the composite effect of eight genetic factors on AIDS progression is substantial. Controlling for known genetic effects is
Acknowledgements
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This project has been funded in whole with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000.
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