As with SDF-1 beta, there are variant alleles within the coding regions of the chemokine receptors CCR5 and CCR2. As you recall, CCR5 and CCR2 are coreceptors for M-tropic HIV. The variants for CCR5 and CCR2 are CCR5-delta 32 and CCR2-641 respectively. These mutant alleles are dominant and protective. In fact, 25 to 30% of HIV positive survivors who don't contact AIDS for >16 years have one or both of these protective variants instead of the alternate form of the respective coreceptors.

So the question experimenters had was how does SDF1- 3'A/3'A compare in its protective effect to the CCR5 and CCR2 variants? When SDF1- 3'A/3'A is present in concert with one or both of the protective variants for CCR5 and CCR2, is the protective effect on the individual a sum of those provided individualy by the variants?

To answer such questions, the experimenters conducted an analysis of the genotypes of a group of individuals. The survivability values of individuals with different genotypes (combination of protective and non-protective variants for SDF1-beta, CCR5 and CCR2) were compared to each other and plotted against time from seroconversion.

 

Crefully observe the protective effects of each genotype. In each figure, which genotype provides the greatest protection?

Pink Correct. According to the AIDS 1993 definition as the endpoint, about 43% of the individuals are AIDS free after 18 years from seroconversion. According to the endpoint defined by the AIDS definition from 19987, about 85% of the total individuals remain AIDS free. Finally with death as the endpoint, nearly all 100% of the individuals survive. This genotype (3'A/3'A, one or more CCR5/CCR2 protective genotypes) offers the greatest protection. or Orange Incorrect. The protective effect by this genotype (3'A/3'A, +/+ at CCR5/CCR2) is not the greatest. or Green Incorrect. The protection offered by this genotype (SDF1 +/+, one or more CCR5/CCR2 protective genotypes) is not the greatest. or Blue Incorrect. The protection offered by this genotype (SDF1 +/+, +/+ at CCR5/CCR2) is not the greatest.

Why is the protective effect of "Pink" genotype greater than that of "Orange" genotype? (hint: compare the two genotypes)

Answer The "Pink" genotype codes for a protective variant form of CCR5/CCR2 in addition to the protective SDF1-3'A/3'A variant. The "Orange" genotype also codes for the SDF1-3'A/3'A varaint but not for the protective variants of CCR5/CCR2.

What does this say about the protective effects of more than one variant?

Answer It shows that when there is more than one protective variant present, there is a greater degree of protection. This indicates that there is a cumulative and combined effect in cases where there is more than one protective variant present.

Now compare the protective effects of the "Orange" genotype to the "Green" genotype. Which of the two provides more protection (only consider the graphs reflecting the endpoint as defined by the definition of AIDS from 1987 and death)? Orange Correct. Of the individuals who have the 3'A/3'A, +/+ at CCR5/CCR2 genotype approximately 54% of the individuals are AIDS free (according to the 1987 definition endpoint) and 73% are alive. or Green Incorrect. Of the individuals who have SDF1+/+, one or more CCR5/CCR2 protective genotypes, only 34% are AIDS free (according to the 1987 AIDS definition) and only 45% of the total are alive.

What do the levels of protection provided by "Orange" (3'A/3'A, +/+ at CCR5/CCR2) and "Green"

(SDF1 +/+, one or more CCR5/CCR2 protective genotypes) suggest? Answer The protective effects of SDF1-3'A/3'A variant is greater than that of one or both protective variants of the CCR5 and CCR2 coreceptors.

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