CCR5Delta32 genotypes in a German HIV-1 seroconverter cohort and report of HIV-1 infection in a CCR5Delta32 homozygous individual

Abstract

Background: Homozygosity (Delta32/Delta32) for the 32 bp deletion in the chemokine receptor 5 (CCR5) gene is associated with strong resistance against HIV infection. Heterozygosity is associated with protection of HIV-1 disease progression.

Methodology/principal findings: We genotyped a population of 737 HIV-positive adults and 463 healthy controls for the CCR5Delta32 deletion and found heterozygous frequencies of 16.2% (HIV-negative) and 17.5% (HIV-positive) among Caucasian individuals. Analysis of CCR5Delta32 influence on disease progression showed notably lower viral setpoints and a longer time to a CD4 count of <200 microl(-1) in seroconverters heterozygous for the deletion. Furthermore, we identified one HIV-positive man homozygous for the Delta32 deletion.

Conclusions/significance: The protective effect of CCR5 Delta32 heterozygosity is confirmed in a large cohort of German seroconverters. The HIV-infected CCR5 Delta32 homozygous individual, however, displays extremely rapid disease progression. This is the 12th case of HIV-infection in this genotype described worldwide.

Figure 1. Relation of CCR5Δ32 genotype with viral setpoints in 319 Caucasian seroconverters.

Scattered dots represent individual viral setpoints (see Material and Methods for a definition), whereas vertical lines demarcate the median in each genetic group.

Figure 2. Kaplan Meier Analysis of 506 seroconverters showing a relation of CCR5Δ32 genotype with a CD4⁺ T-cell count <200 µl⁻¹.

A CD4⁺ T-cell count <200 µl-1 was documented for n = 57 of 422 individuals homozygous for the wildtype CCR5 genotype, and for n = 9 out of 84 CCR5Δ32 heterozygotes. Data censoring was due to introduction of antiretroviral therapy before a CD4 cell count of 200 µl⁻¹ was reached. The difference between both groups implied by the Kaplan-Meier diagram is reflected in a statistical trend (p = 0.1 as calculated by the Log-Rank test).

Figure 3. Clinical, immunological and viral load characteristics in an HIV-infected patient homozygous for the CCR5Δ32 deletion (patient#12).

Antiretroviral therapy was initiated twice, eight days after diagnosis with efavirenz (EFV), stavudine (d4T) and lopinavir-ritonavir (LPVr) and again, following rapid disease progression, 18 months after diagnosis with Efavirenz and Zidovudine (AZT) plus Lamivudine (3TC). Unbroken line with closed circles: CD4⁺ T-cell counts. Unbroken line with closed diamonds: Plasma viral loads. Broken line with closed circles: CD8⁺ T-cell counts. Blue arrow: negative HIV-1 antibody test. Red arrow: positive HIV-1 antibody test. Black arrows: Proctitis (1) / Shigellosis (2).