Frequency of CCR5 gene 32-basepair deletion in Chilean HIV-1 infected and non-infected individuals

A 32-basepair deletion polymorphism in the CCR5 chemokine receptor gene (CCR5Delta32) has been identified and shown to have functional significance in determining susceptibility to infection by human immunodeficiency virus type 1 (HIV-1) and possibly in influencing disease progression in HIV-1 positive individuals. These findings led to an interest in studies of DeltaCCR5 allele geographical distribution in human population, for complete understanding of the role of CCR5 in HIV-1 epidemiology. Inter-population variation in CCR5Delta32 frequency may be a significant factor in the prediction of AIDS endemicity. In this report we assessed the frequency of DeltaCCR5 in a Chilean population (63 HIV-1 infected and 62 non-infected individuals). No homozygous CCR5Delta32 individual was identified, and no significant difference was observed between HIV-1 infected (3/63) and non-infected (3/62) individuals for the heterozygote CCR5Delta32 state. This is the first evidence of the contribution of DeltaCCR5 allele to the genetic background of the Chilean population, which is characterized by intense ethnic admixture and by gene flow from the European Spanish gene pool.     

Effect of CCR5-delta32 heterozygosity on the risk of perinatal HIV-1 infection: a meta-analysis

Several studies have investigated whether heterozygosity for a 32-basepair deletion in the CC chemokine receptor 5 gene (CCR5-Delta32 ) affects susceptibility to perinatal HIV-1 infection, but results have been inconclusive. We performed a meta-analysis of published data from 11 studies of HIV-1 perinatally exposed children who were genotyped for the CCR5-Delta32 polymorphism. The crude overall HIV-1 infection rates, by simple data pooling, were 20% (one of five) amongCCR5-Delta32 homozygote children, 39% (131 of 335) among CCR5-Delta32 heterozygote children, and 40% (1408 of 3526) among wild-type CCR5 homozygote children. Compared with wild-type homozygotes, the random effects risk ratio for heterozygotes was 1.04 (95% confidence interval [CI], 0.92-1.17) among all children (N = 3861) and 1.03 (95% CI, 0.90-1.17) among those of European descent (n = 2890). Results were similar when adjusted for the available data on the CCR2-641 polymorphism (n = 1542). The meta-analysis clarifies that perinatal infection is not significantly altered by heterozygosity for CCR5-Delta32 in the child.     

Phenotypic expressions of CCR5-delta32/delta32 homozygosity.

OBJECTIVE: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-delta32/delta32 homozygous genotype has phenotypic expressions other than those related to HIV-1. DESIGN: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-delta32/delta32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-delta32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. RESULTS: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-delta32/delta32 study subjects. Based on blood pressure measurement and treatment history, CCR5-delta32/delta32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were approximately 20% higher in CCR5-delta32/delta32 study subjects than in CCR5-+/+ study subjects (p < .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-delta32/delta32 homozygotes (p < .05), but serum HCV levels did not differ by CCR5-delta32 genotype. CCR5-delta32/delta32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. CONCLUSIONS: CCR5-delta32/delta32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-delta32/delta32 homozygosity does not provide broad protection against viral infections.     

Protective effect of CCR2-64I and not of CCR5-delta32 and SDF1-3'A in pediatric HIV-1 infection

The effects of chemokine and chemokine receptor genetic polymorphisms such as stromal derived factor 1 (SDF1-3'A), CCR2-64I, and CCR5-delta32 associated with HIV-1 transmission and/or rate of disease progression in infected study subjects remain highly controversial and have been analyzed primarily only in adults. We have investigated whether these polymorphisms may provide similar beneficial effects in children exposed to HIV-1 perinatally. The prevalence of CCR2-64I allele was significantly increased (p = .03) and the CCR2-64I genotype distribution was not in Hardy-Weinberg equilibrium, among HIV-1-exposed uninfected infants. Moreover, in the HIV-1-infected group, a delay to AIDS progression was observed among carriers of CCR2-64I allele. This is the first report that suggests a protective role of CCR2-64I allele in mother-to-infant HIV-1 transmission and documents a delay in disease progression, after the child has been infected with HIV-1. However, SDFI-3'A and CCR5-delta32 alleles did not modify the rate of HIV-1 transmission or disease progression in HIV-1-infected children.     

Frequency of CCR5-Delta32 deletion in human immunodeficiency virus type 1 (HIV-1) in healthy blood donors, HIV-1-exposed seronegative and HIV-1-seropositive individuals of southern Brazilian population

The frequency of CCR5-Delta32 allele in human immunodeficiency virus type 1 (HIV-1) infection in the southern Brazilian population was determined in a cross-sectional study carried out from October 2001 to June 2004. Genomic DNA was extracted from peripheral blood cells of 134 healthy blood donors, 145 HIV-1-exposed seronegative individuals, 152 HIV-1-seropositive asymptomatic individuals, and 478 HIV-1-seropositive individuals with AIDS. A fragment with 225 base-pairs of the CCR5 gene was amplified by polymerase chain reaction. The CCR5-Delta32 homozygous deletion was observed in 2 (1.5%) blood donors and in 1 (0.7%) individual HIV-1-exposed seronegative, and was absent among all the HIV-1-seropositive individuals (Fisher's exact test, p=0.0242). The frequency of the homozygous CCR5-Delta32 deletion in the HIV-1-exposed did not differ when compared with that observed in the HIV-1 seronegative blood donors (Fisher's exact test, p=0.6093; OR: 2.18, 95% CI: 0.11-129.6). The wild-type genotype CCR5/CCR5 frequency was higher among the HIV-1-seropositive with AIDS compared to HIV-1 seropositive asymptomatic individuals (Chi-square test, p=0.0263; OR: 2.02, 95% CI: 1.03-3.97). The absence of the homozygous deletion of CCR5-Delta32 among HIV-1-seropositive individuals underscored that this genotype is an important genetic factor associated with the decreased susceptibility to HIV-1 infection. The higher frequency of heterozygosity for the CCR5-Delta32 and the CCR5-Delta32 allele in HIV-1 seropositive asymptomatic compared to HIV-seropositive with AIDS individuals also underscored that this deletion could be associated with the delay of the HIV-1 disease progression in this population. However, the low frequency of CCR5-Delta32 homozygosity observed among HIV-1-exposed seronegative individuals shows that the allele could not explain, by itself, the natural resistance to HIV-1 infection and different mechanisms of protection against HIV-1 infection that must be involved in this population.     

HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion

Homozygosity for the 32 base-pair deletion (Delta32/Delta32) in the CCR5 coreceptor gene is associated with incomplete HIV-1 resistance. Six HIV-1-infected Delta32/Delta32 patients have been reported. We report 2 additional Delta32/Delta32-infected individuals, among 106 seroconverters in a vaccine preparedness study. Like the previous 6, these individuals experienced rapid CD4 decline. However, taken together, the 8 patients have neither uniformly high virus load nor rapid progression to AIDS. We obtained five virus isolates from 1 patient at 5, 6, 7, 10, and 12 months after the estimated time of infection. The earliest isolate exhibits the syncytium-inducing (SI) phenotype and exclusive use of the CXCR4 coreceptor, suggesting acquisition of HIV-1 through this coreceptor. Of the remaining 104 seroconverters, 8 were CCR5-Delta32/+ and 96 were CCR5-+/+. Three CCR5-+/+ seroconverters who showed the uncommon pattern of early SI virus and rapid CD4 decline had uniformly high viral load and more heterogeneous coreceptor usage. These results further support the conclusion that Delta32-mediated resistance is incomplete and is associated with acquisition of exclusively-X4 variants of HIV-1. The pathogenic potential of these viruses may be different from late-stage X4 virus or early X4 virus acquired by individuals with other CCR5 genotypes.     

Population survey of CCR5 delta32, CCR5 m303, CCR2b 64I,and SDF1 3'A allele frequencies in indigenous Chinese healthy individuals,and in HIV-1-infected and HIV-1-uninfected individuals in HIV-1 risk groups

The aim of this study is to determine in indigenous Chinese ethnic groups the frequencies of the chemokine (SDF1 3'A) and chemokine receptors (CCR5 delta32, CCR5 m303, and CCR2b 64I) HIV-1/AIDS restriction alleles. The study includes two cohorts; the first comprised 3165 indigenous healthy subjects representing eight ethnic groups: Han (n = 1406), Uygur (n = 316), Mongolia (n = 134), Hui (n = 386), Tibetan (n = 330), Zhuang (n = 378), Dai (n = 101), and Jingbo (n =114). The second cohort consisted of 330 HIV-1-infected (86 subjects infected by sexual transmission and 198 subjects infected by HIV-1-contaminated blood or by sharing injection equipment; the remaining 46 subjects said nothing about HIV-1 transmission) and 474 HIV-1-uninfected Han Chinese belonging to one of two HIV-1 high-risk groups: intravenous drug users (n = 215) and individuals with sexually transmitted diseases (n = 259). Genotypes for the four genes were obtained using PCR (CCR5 delta32) or PCR-restriction fragment length polymorphism. Randomly selected amplified PCR products were further confirmed by direct DNA sequencing. The variant allele frequencies were determined to be 0% to 3.48% for CCR5 delta32, 0% for CCR5 m303, 16.23% to 28.79% for CCR2b 64I, and 17.70% to 27.76% for SDF1 3'A in Chinese healthy individuals from eight ethnic groups. These findings show that allele frequencies differ among the eight Chinese ethnic groups for CCR5 delta32, CCR2b 64I, and SDF1 3'A and that the CCR5 m303 and CCR5 delta32 mutant alleles were absent or infrequent in Chinese, which may be helpful for studies of specific anti-HIV-1 vaccine trials and coreceptor inhibitor drug targets in Chinese populations. Furthermore, we observed no significant differences in allele or genotypic frequencies between HIV-1-infected and HIV-1-uninfected groups from the Han ethnic group. Our finding is the first reporting that there is likely no effect of the examined polymorphisms in our study on HIV-1 transmission in the Chinese Han population, However, the genetic effects of these and other AIDS-modifying polymorphisms on the pathogenesis and clinical outcome of HIV-1/AIDS diseases is under investigation in Chinese populations.     

Distribution of three HIV-1 resistance-conferring polymorphisms (SDF1-3'A, CCR2-641, and CCR5-delta32) in global populations

Chemokine receptors (CCR5, CXCR4 and CCR2) have been shown to be important co-receptors for HIV infection. Mutations at CCR5 (CCR5-delta2), CCR2 (CCR2-641), and stromal-derived factor SDF1 (SDF1-3'A), a primary ligand for CXCR4, are known to have protective effects against HIV-1 infection and the onset of AIDS symptoms. We studied the three-locus genotype frequency distributions in 70worldwide populations from a sample of 2341 individuals without any known history of HIV-1 infection and AIDS symptoms. From these data, we estimated the risk of AIDS onset (relative hazard, RH) of each population. This survey shows that the substantial allele frequency differences of each of these mutations translate into an extensive variation in relative hazards for AIDS in worldwide populations. However, no evidence of natural selection against the mutant gene carriers is detected. Finally, the combined three-locus genotype data predict the highest relative hazard (RH) in South-East Asia and Africa where AIDS is known to be more prevalent.     

Evidence for recent selection of the CCR5-delta 32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews

Recent studies have shown higher frequencies of the CCR5-delta 32 allele and the CCR5-delta 32/delta 32 genotype, which confers protection against HIV infection, in northern Europe as compared to Mediterranean countries. Here, we analyse the prevalence of CCR5-delta 32 in 922 HIV seronegative blood donors in Israel to verify its frequency in Jews of Ashkenazi and Sephardi origin. A significant difference (P < 0.001) was found between the CCR5-delta 32 allele frequency in Ashkenazi (13.8%) vs (4.9%) Jews. In contrast, no significant difference was observed in the frequency of the CCR2-641 mutation between Ashkenazi (9.2%) and Sephardi (13.4%) Jews. Using the Island model we calculate that a minimal genetic migration rate of 3% per generation would have been necessary if the higher CCR5-delta 32 prevalence in Ashkenazi is to be fully explained by mixing with the indigenous north-European populations. This putative migration rate is 20-fold higher than that currently estimated from other genes, and would correspond to a non-realistic minimal current admixture of 80%. Thus, our results suggest that a positive selection process for CCR5-delta 32 should have occurred in northern Europe at most a 1000 years ago, after the Ashkenazi Jews separated from their Sephardi kin and moved to north Europe.     

Partial protective effect of CCR5-Delta 32 heterozygosity in a cohort of heterosexual Italian HIV-1 exposed uninfected individuals

Despite multiple sexual exposure to HIV-1 virus, some individuals remain HIV-1 seronegative (exposed seronegative, ESN). The mechanisms underlying this resistance remain still unclear, although a multifactorial pathogenesis can be hypothesised. Although several genetic factors have been related to HIV-1 resistance, the homozigosity for a mutation in CCR5 gene (the 32 bp deletion, i.e. CCR5-Delta32 allele) is presently considered the most relevant one. In the present study we analysed the genotype at CCR5 locus of 30 Italian ESN individuals (case group) who referred multiple unprotected heterosexual intercourse with HIV-1 seropositive partner(s), for at least two years. One hundred and twenty HIV-1 infected patients and 120 individuals representative of the general population were included as control groups. Twenty percent of ESN individuals had heterozygous CCR5-Delta 32 genotype, compared to 7.5% of HIV-1 seropositive and 10% of individuals from the general population, respectively. None of the analysed individuals had CCR5-Delta 32 homozygous genotype. Sequence analysis of the entire open reading frame of CCR5 was performed in all ESN subjects and no polymorphisms or mutations were identified. Moreover, we determined the distribution of C77G variant in CD45 gene, which has been previously related to HIV-1 infection susceptibility. The frequency of the C77G variant showed no significant difference between ESN subjects and the two control groups.     

Role of the CCR5 delta 32 allele in resistance to HIV-1 infection in west Africa

OBJECTIVE: To determine the frequency of the mutant CCR5 delta 32 allele in high-risk HIV-seronegative Africans as compared with the general African population, and to assess its in vitro protective efficacy against HIV-1 infection. STUDY DESIGN: In the homozygous form, the CCR5 delta 32 allele confers resistance to macrophage-tropic (M-tropic) strains of HIV-1. Assuming that genetic characteristics favoring HIV resistance would prevail in a high-risk HIV-seronegative population, we examined the CCR5 genotypes of female commercial sex workers (CSWs) from Dakar, Senegal, who have remained uninfected for an elongated period. METHODS: The CCR5 genetic profile of study participants was determined by polymerase chain reaction (PCR) amplification of genomic DNA followed by sequencing. Peripheral blood mononuclear cells (PBMCs) were infected with different strains of HIV-1 and monitored by p24 enzyme-linked immunosorbent assay (ELISA). RESULTS: We confirmed the presence of two CCR5wt/delta 32 genotypes among 139 individuals (1.44%). PBMCs from these 2 heterozygous individuals were also found to be less susceptible to in vitro infection by an M-tropic HIV-1 primary isolate. CONCLUSIONS: Evidence was found of an increased prevalence of the CCR5wt/delta 32 genotype in a high-risk HIV-seronegative cohort in West Africa. Furthermore, reduced susceptibility to HIV-1 infection among heterozygous individuals supports a role for 32-bp CCR5 deletion in HIV-1 resistance.     

Distribution of the CCR5 gene 32-base pair deletion and CCR5 expression in Chinese minorities

China has an ethnically diverse population. Genetic differences may contribute to disparities in the efficiency of HIV transmission. To further characterize this risk, we examined the HIV-related genetic diversity in the predominant Han Chinese and in six minority groups. We searched for the delta32-CCR5 mutation, a common cause of relative HIV resistance in the white population. In addition, CCR5 receptor expression was measured. Blood samples were obtained from adults belonging to the Han, Meng, Zang, Weiwuer, Zhuang, Yi, and Dai ethnic groups. Polymerase chain reaction analysis was performed on genomic DNA samples. Surface expression of CCR5 on peripheral blood mononuclear cells was measured by flow cytometry. One-way ANOVA was used to determine mean statistical differences. Samples from 10 members of each minority were examined. A delta32-CCR5 heterozygote phenotype was detected in one Weiwuer subject, but no mutations were found in the other 69 subjects studied. The mean CCR5 expression of cells harvested from the Dai minority was greater than that of cells from all other minorities studied, for both CD3+CCR5+ and CD4+CCR5+ sets (p < .01, one-way ANOVA). The delta32-CCR5 mutation seems to be rare in most Han Chinese and the minority populations studied. CCR5 expression appears to be greater in the Dai minority than in the other minorities investigated. The mechanism for this increased expression requires further study.     

Frequency of CCR5 gene 32-basepair deletion in Croatian normal population

A 32-basepair deletion polymorphism in the CCR5 chemokine receptor gene (CCR5 TROKUT 32) could increase the resistance to HIV-1 infection or delayed progression to AIDS. This mutant allele is common among Caucasians of Western European descent, but has not been observed in people of African or Asian ancestry. Genetic studies provided in European countries have shown a highest prevalence in Nordic countries and the lowest in the Southern European and Mediterranean populations. We genotyped 303 randomly selected healthy Croatians for the prevalence of CCR5 TROKUT 32 mutation. CCR5 TROKUT 32 allele frequency in Croatia of 7.1% fits in the observed European north/south gradient. This first report of CCR5 TROKUT 32 mutation in Croatian population provides additional information on its frequency and geographical distribution in Slavic populations in South-Eastern Europe. Moreover, our data may have important implications for the prediction and prevention of HIV/AIDS in a tourist country such as Croatia.     

Homozygous and heterozygous CCR5-Delta32 genotypes are associated with resistance to HIV infection

OBJECTIVE: To investigate evidence for resistance to HIV-1 infection associated with the heterozygous genotype CCR5-+/Delta32 and with the homozygous genotype CCR5-Delta32/Delta32, which results in a nonfunctional CCR5 receptor. DESIGN: Cohort study of initially HIV-seronegative high-risk individuals from eight different cities. Enrollment data were analyzed to investigate the association of demographic factors and risk behaviors with CCR5 genotypes on the assumption that increased genotype prevalence among persons with histories of longer or more intensive exposure to HIV would indicate HIV resistance associated with that genotype. Longitudinal data were analyzed to investigate the association of HIV seroincidence with CCR5 genotypes. The cohort of 2996 individuals included 1892 men who have sex with men (MSM), 474 male injection drug users (IDUs), 347 women at heterosexual risk, and 283 female IDUs. MEASUREMENTS: CCR5 genotype, HIV serostatus, demographic factors, and risk behaviors during the 6 months before enrollment, followed by measurement of HIV seroincidence during the subsequent 18 months (for men) and 24 months (for women). RESULTS: Forty (1.3%) subjects were homozygous CCR5-Delta32/Delta32 and 387 (12.9%) were heterozygous CCR5-+/Delta32. All but 1 CCR5-Delta32/Delta32 individuals and 51 CCR5-+/Delta32 individuals were Caucasian. Among 1531 Caucasian MSM, CCR5-+/Delta32 individuals were present more frequently (22.3%) among those reporting unprotected receptive anal intercourse than among those not reporting this risk (15.9%) (p =.002), suggesting a selective advantage of the heterozygous genotype. CCR5-+/Delta32 individuals also had a significantly reduced relative risk of HIV seroconversion adjusted for unprotected receptive anal intercourse compared with CCR5-/+ individuals (relative risk = 0.30, 95% confidence interval [CI]: 0.08-0.97). CCR5-Delta32/Delta32 prevalence among Caucasian MSM was significantly associated with age among subjects recruited from high HIV seroprevalence cities (New York City and San Francisco) (odds ratio [OR] for each decade increase in age = 2.57, CI: 1.56-4.21) but not among those recruited from lower HIV prevalence sites (Boston, Chicago, Philadelphia, Seattle, and Providence/Pawtucket, Rhode Island) (OR = 1.20, CI: 0.75-1.89). CONCLUSIONS: Cross-sectional and longitudinal analyses indicated that among high-risk HIV seronegative MSM, CCR5-+/Delta32 and CCR5-Delta32/Delta32 are associated with protection against HIV infection. These findings imply that strategies aimed at reducing susceptibility to HIV infection by blocking CCR5 receptor sites need not seek blockage of all receptor sites to achieve an imperfect but substantial degree of protection.     

人PBMCs内表达CCR5Delta32蛋白对HIV-1辅受体抑制作用的研究

目的:在人PBMCs内表达CCR5Delta32蛋白,研究其对细胞表面HIV-1辅受体CCR5和CXCR4的抑制作用。方法:构建pLenti-CCR5Delta32慢病毒载体,包装后产生重组慢病毒。将其转染PBMCs,Western blot检测目的蛋白的表达。继续培养靶细胞,FACS分析细胞表面CCR5和CXCR4分子的变化。结果:成功构建了pLenti-CCR5Delta32慢病毒载体,包装后产生重组慢病毒。将其转染PBMCs,Western blot检测到目的蛋白的表达。FACS分析表明,靶细胞内目的蛋白的表达对靶细胞表面辅受体CCR5和CXCR4的产生起抑制作用,抑制率在转染后第6天达到高峰(CCR5的抑制率为51.69%,CXCR4的抑制率为61.05%)。结论:靶细胞内目的蛋白的成功表达及其对靶细胞表面HIV-1辅受体CCR5和CXCR4产生的抑制作用,为后续的AIDS基因治疗研究奠定了基础。     

Association of CCR5 delta32 deletion with early death in multiple sclerosis.

PURPOSE: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 delta32 deletion in this disorder. METHODS: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 delta32 deletion allele. RESULTS: An increased frequency of 32-bp deletion allele was found to be associated with early death (P = 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58). CONCLUSION: A strong association of the CCR5delta32 deletion with early death could serve as a prognostic marker for MS.     

HIV-1 clones resistant to a small molecule CCR5 inhibitor use the inhibitor-bound form of CCR5 for entry

Human immunodeficiency virus type 1 (HIV-1) infection can be inhibited by small molecules that target the CCR5 coreceptor. Here, we describe some properties of clonal viruses resistant to one such inhibitor, SCH-D, using both chimeric, infectious molecular clones and Env-pseudotypes. Studies using combinations of CCR5 ligands, including small molecule inhibitors, monoclonal antibodies (MAbs) and chemokine derivatives such as PSC-RANTES, show that the fully SCH-D-resistant viruses enter target cells by using the SCH-D-bound form of CCR5. However, the way resistance to SCH-D and other small molecule CCR5 inhibitors is manifested depends on the target cell and the nature of the assay (single- vs. multi-cycle). In multi-cycle assays using primary lymphocytes, SCH-D does not inhibit resistant molecular clones, and it can even enhance their infectivity modestly. In contrast, the same viruses (as Env-pseudotypes) are significantly inhibited by SCH-D in single-cycle entry assays using U87-CD4/CCR5 cells, resistance being manifested by incomplete inhibition at high SCH-D concentrations. When a single-cycle, Env-pseudotype entry assay was performed using either U87-CD4/CCR5 cells or PBMC under comparable conditions, entry was inhibited by up to 88% in the former cells but by only 28% in the PBMC. Hence, there are both cell- and assay-dependent influences on how resistance is manifested. We also take this opportunity to correct our previous report that SCH-D-resistant isolates are also substantially cross-resistant to PSC-RANTES [Marozsan, A.J., Kuhmann, S.E., Morgan, T., Herrera, C., Rivera-Troche, E., Xu, S., Baroudy, B.M., Strizki, J., Moore, J.P., 2005. Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). Virology 338 (1), 182-199]. A substantial element of this resistance was attributable to the unappreciated carry-over of SCH-D from the selection cultures into analytical assays.     

CCR5△32、CCR5m303、CCR2-64I、SDF1-3''A基因多态性对中国HIV-1感染者预后的影响

目的研究CCR5A32、CCR5m303、CCR2-64I、SDF1—3’A基因多态性对中国HIV-1感染者预后的影响。方法对在深圳地区发现的HIV-1感染者进行流行病学调查，应用PCR／RFLP技术分析感染者CCR5G32、CCR5m303、CCR2-64I、SDF1-3’A4种基因的多态性，对部分人群进行HIV-1血浆病毒载量和CD4^＋细胞计数的检测，判断感染者的潜伏期，使用SPSS11．0统计软件分析基因多态性对感染者病毒载量和潜伏期的影响。结果在189例HIV-1感染者中没有发现CCR5A32和CCR5-m303突变基因型，SDF1—3’A的等位基因频率为26．14％，CCR2—64I的等位基因频率为19．82％。方差分析发现，CCR2-64I基因野生型与杂合型的两组HIV-1感染者人群病毒载量对数的大小差异无统计学意义（P=0．272），两组人群潜伏期的长短差异无统计学意义（P=0．662）。SDF1基因野牛型、杂合型和纯合型的3组HIV-1感染者人群病毒载量对数的大小差异有统计学意义（P=0．001），但3组人群潜伏期的长短差异无统计学意义（P=0．228）。结论CCR2-64I基因突变对中国汉族HIV-1感染者病毒载量没有明显影响，因而也不影响感染者的潜伏期。SDF1-3’A基因突变对于病毒载量有降低作用，但对延长感染者潜伏期可能没有作用。     

CCR5 genotype and resistance to vertical transmission of HIV-1.

A human gene has been identified that affects susceptibility to HIV-1 infection. The gene codes for CCR5, the coreceptor for macrophage-tropic strains of HIV-1. Individuals who are homozygous for a deleted, mutant form of the gene, delta32, display a high degree of natural resistance to sexual and parenteral transmission of HIV-1. To investigate whether delta32 plays a role in vertical transmission, we determined the CCR5 genotype of 552 children born to infected mothers in the United States and correlated the genotypes with HIV-1 infection status. Of these children, 13% were white, 30% Latino, and 56% African American, reflecting the ethnic makeup of infected women in the United States. The delta32 gene frequency varied among these groups, ranging from 0.08 in whites to 0.02 in both Latinos and African Americans. Approximately 27% of the children in each ethnic group were infected. Four children were identified as delta32 homozygotes, two uninfected whites (3.77%) and two uninfected Latinos (1.68%). None of the infected children displayed the delta32 homozygous genotype. Among Latinos and whites, the number of uninfected children who carried the homozygous delta32 mutation was significantly greater than that predicted by the Hardy-Weinberg equilibrium (p < .001 for Latinos, p = .044 for whites). This association was noted in Latino and white children whose mothers were either treated or untreated with zidovudine. These data document the occurrence of the homozygous delta32 genotype among children of HIV-1-infected mothers and suggest that this mutant genotype may confer protection from mother-to-child transmission of HIV-1. They also suggest that sexual, parenteral, and vertical transmission all involve processes that use CCR5 as a coreceptor for primary HIV-1 infection. Therefore, blocking the CCR5 receptor may provide an additional strategy to prevent HIV-1 vertical transmission.