MT-2 tropism and CCR-5 genotype strongly influence disease progression in HIV-1-infected individuals

Background: The beta-chemokine receptor CCR-5 is the coreceptor for cellular entry by non-syncytium-inducing (NSI) HIV-1 strains that dominate early in infection. A 32 base-pair deletion (Delta 32) in the CCR-5 gene renders this coreceptor non-functional. Heterozygosity for this deletion [Delta 32/wild-type (wt)] is associated with slow disease progression. The purpose of this study was to document the combined impact on HIV-1 disease progression of the CCR-5 genotype and the biological phenotype of HIV-1. Methods: In a cross-sectional study of 258 HIV-1-infected Swedish individuals, the CCR-5 genotype (wt/wt or Delta 32/wt) was determined by polymerase chain reaction and the biological phenotype [NSI or syncytium-inducing (SI)] of virus isolates was determined in the MT-2 cell assay. Clinical status, HIV-1 RNA levels in plasma, CD4+ lymphocyte counts, and rate of CD4+ lymphocyte decline, based on retrospective analysis of CD4+ lymphocyte counts, were also recorded. None of the individuals were treated with protease inhibitors. Results: The prevalence of the Delta 32/wt genotype was 23%. Subjects with the Delta 32/wt CCR-5 genotype more often carried SI virus than subjects with the wt/wt genotype (49 versus 35%; P = 0.067), but there were no differences between the two groups in prevalence of AIDS, viral load, CD4+ lymphocyte count or CD4+ slope. NSI virus isolates were found in 159 (62%) out of 258 individuals. Individuals with NSI had lower prevalence of AIDS (39 versus 19%; P < 0.01), higher CD4+ lymphocyte counts (289 +/- 188 x 10(6)/l versus 153 +/- 162 x 10(6)/l; P = 0.001), lower viral loads (median, 4.45 log(10) versus 4.91 log(10) copies/ml; P < 0.01) and a lower prevalence of the Delta 32/wt genotype (19 versus 29%; P = 0.067) compared with individuals with SI virus. When the material was further subdivided, subjects with the Delta 32/wt genotype and SI virus had the highest prevalence of AIDS (P < 0.001), lowest CD4+ lymphocyte count (P = 0.0001) and highest viral load (P = 0.023) whereas the opposite was true for subjects with the Delta 32/wt genotype and NSI virus. A significantly higher proportion of subjects with NSI virus with Delta 32/wt and wt/wt CCR-5 genotype had been immunized with recombinant gp160. Conclusion: In summary, the Delta 32/wt CCR-5 genotype has a protective effect against HIV-1 disease progression that appears to be limited to individuals carrying HIV-1 variants with NSI phenotype. Immunization with recombinant gp160 tended to reduce the frequency of SI phenotypes. (C) 1998 Lippincott-Raven Publishers.