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 (delta32) in the CCR-5 gene renders this coreceptor non-functional. Heterozygosity for this deletion [delta32/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 delta32/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 delta32/wt genotype was 23%. Subjects with the delta32/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 log10 versus 4.91 log10 copies/ml; P < 0.01) and a lower prevalence of the delta32/wt genotype (19 versus 29%; P=0.067) compared with individuals with SI virus. When the material was further subdivided, subjects with the delta32/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 delta32/wt genotype and NSI virus. A significantly higher proportion of subjects with NSI virus with delta32/wt and wt/wt CCR-5 genotype had been immunized with recombinant gp160.


CONCLUSIONS
In summary, the delta32/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.
Bratt
G
G
Gay Men's Health Clinic, Department of Dermatovenereology, Söder Hospital, Stockholm, Sweden.
Leandersson
A C
AC
Albert
J
J
Sandström
E
E
Wahren
B
B
D016915:AIDS Vaccines / Q000276:immunology; D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D002461:Cell Line, Transformed; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005500:Follow-Up Studies; D005838:Genotype; D019302:HIV Envelope Protein gp160 / Q000276:immunology; D015658:HIV Infections / Q000401:mortality / Q000503:physiopathology* / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D019713:Receptors, CCR5 / Q000235:genetics*; D011994:Recombinant Proteins / Q000276:immunology; D017384:Sequence Deletion; D014614:Vaccines, Synthetic / Q000276:immunology; D019562:Viral Load
D016915:AIDS Vaccines; D019302:HIV Envelope Protein gp160; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic