AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 21, Number 2, 2005, pp. 111–114 © Mary Ann Liebert, Inc. Association of CCR5 Human Haplogroup E with Rapid HIV Type 1 Disease Progression MING LI, 1 RUIGUANG SONG, 2 SILVINA MASCIOTRA, 1 VINCENT SORIANO, 3 THOMAS J. SPIRA, 1 RENU B. LAL, 1 and CHUNFU YANG 1 ABSTRACT The combination of unique single nucleotide polymorphisms in the CCR5 regulatory and in the CCR2 and CCR5 coding regions, defined nine CCR5 human haplogroups (HH): HHA–HHE, HHF*1, HHF*2, HHG*1, and HHG*2. Here we examined the distribution of CCR5 HH and their association with HIV infection and disease progression in 36 HIV-seronegative and 76 HIV-seropositive whites from North America and Spain [28 rapid progressors (RP) and 48 slow progressors (SP)]. Although analyses revealed that HHE frequencies were similar between HIV-seronegative and HIV-seropositive groups (25.0% vs. 32.2%, p  0.05), HHE fre- quency in RP was significantly higher than that in SP (48.2% vs. 22.9%, p  0.002). Survival analysis also showed that HHE heterozygous and homozygous were associated with an accelerated CD4 cell count decline to less than 200 cells/L (adjusted RH 2.44, p  0.045; adjusted RH  3.12, p  0.037, respectively). These data provide further evidence that CCR5 human haplogroups influence HIV-1 disease progression in HIV- infected persons. 111 INTRODUCTION T HE FINDING THAT CHEMOKINE RECEPTORS ARE USED BY HIV VIRUSES as coreceptors for cellular entry led to the discov- ery that host genetic factors can influence susceptibility to HIV infection or the rate of disease progression after initial infec- tion. Allelic polymorphisms in either the chemokine receptors or ligands have been associated with altered HIV disease pro- gression or infection. 1–3 Several chemokine-related genes en- code allelic variants that either delay (CCR5-32 and CCR2- 64I) 4–8 or accelerate (CCR5 P1/P1 and HHE) progression to AIDS in HIV-1-infected persons 1,9–11 or affect vertical transmission (CCR5-2132). 12 However, polymorphisms in chemokine ligands or CCR genes, other than the CCR5-32 in relation to HIV transmission, and disease progression have been difficult to interpret because of the study designs and diverse populations. The best characterized genetic polymorphism is the CCR5- 32 allele, which represents a 32-base pair deletion that shifts the reading frame of the CCR5 gene. Homozygosity for CCR5- 32 confers high resistance to HIV-1 infection. 13,14 Persons who are heterozygous for the CCR5-32 have delayed pro- gression to AIDS or death, 4–7,15 although some studies have not confirmed this association. 16,17 A survival analysis of CCR5-32 and CCR2-64I reveals that both alleles exert a dominant effect that postpones the onset of AIDS by 2–4 years. 15 Several genetic polymorphisms have been identified in the CCR5 regulatory or promoter region that may affect HIV trans- mission or disease progression possibly through effects on lev- els of CCR5 expression. 18–20 An evolutionary-based analysis of CCR5 promoter polymorphisms combined with CCR5-32 and CCR2-64I mutations identified stable CCR5 human hap- logroups. 11,21 These investigators established that certain hap- logroups differentially influence HIV-1 transmission and dis- ease progression in different racial groups. For example, HHE was associated with faster disease progression in white co- horts. 11 However, a cohort study in an African population from Uganda revealed no association between CCR5 haplogroups and the rate of disease progression. 21 To further investigate complex interactions between CCR5 human haplogroups and HIV disease progression, we analyzed CCR5 promoter poly- 1 Division of AIDS, STD, and TB Laboratory Research and 2 Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Pre- vention, Centers for Disease Control and Prevention, Atlanta, Georgia 30333. 3 Service of Infectious Diseases, Hospital Carlos III, E-28029, Madrid, Spain.