Association of the CCR5Delta32 Mutation With Improved Response to Antiretroviral Therapy

Valdez, Hernán; Purvis, Scott F.; Lederman, Michael M.; Fillingame, Melissa; Zimmerman, Peter A.

doi:10.1001/jama.282.8.734

Cited by 58 publications

(41 citation statements)

References 5 publications

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“…The implication is that these markers influence disease progression, in large part by modulating virus concentration soon after seroconversion. These findings confirmed the previously observed influence on viral RNA level of G*2 and F*2 haplotypes and their combination, in some cases, even under potent anti-retroviral treatment (4,6,14,22,27,54,62,72). In the TSS, the F*2 effect was reported for African-Americans, but not Caucasians, in whom F*2 is less frequent; the paucity of subjects in the TSS with the F*2/G*2 genotype may explain the inability to detect its effect in Caucasians (20).…”

Section: Discussionsupporting

confidence: 91%

“…More specifically, evidence that acquisition of virus may be impeded by G*2 heterozygosity (this study and references 42 and 43) and enhanced by homozygosity for either the D (36) or the E (here and 41) haplotype in both ethnic Africans and Caucasians may encourage research on coreceptor polymorphisms in the interest of prevention as well as treatment. Reported detection of CCR5-G*2 (⌬32)-mediated effects during potent antiretroviral therapy (4,22,54,72) have already implied that genetic typing may inform clinical decision making, particularly for patients with atypical responses to therapeutic agents. Table 5.…”

Section: Discussionmentioning

confidence: 99%

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Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Tang

Shelton²,

Makhatadze

et al. 2002

J Virol

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At the CC (␤) chemokine receptor 2 (CCR2) and CCR5 loci, combinations of common single-nucleotide polymorphisms (SNPs) and a 32-bp deletion (⌬32) form nine stable haplotypes (designated A through G*2).The distribution of these CCR2-CCR5 haplotypes was examined among 703 participants in the Multicenter AIDS Cohort Study (MACS), the District of Columbia Gay (DCG) Study, and the San Francisco Men's Health Study (SFMHS). Highly exposed and persistently seronegative (HEPS; n ‫؍‬ 90) Caucasian men from MACS more frequently carried heterozygous G*2 (⌬32) genotypes (especially A/G*2) and less frequently carried the homozygous E/E genotype compared with 469 Caucasian seroconverters (SCs) from the same cohort (P ‫؍‬ 0.004 to 0.042). Among 341 MACS Caucasian SCs with 6-to 12-month human immunodeficiency virus type 1 (HIV-1) seroconversion intervals and no potent antiretroviral therapy, mean plasma HIV-1 RNA level during the initial 42 months after seroconversion was higher in carriers of the E/E genotype and lower in those with the 64I-bearing haplotype F*2 or the ⌬32-bearing haplotype G*2 (and especially genotypes A/G*2 and F*2/G*2). A multivariable model containing these CCR markers showed significant composite effects on HIV-1 RNA at each of four postconversion intervals (P ‫؍‬ 0.0004 to 0.050). In other models using time to AIDS as the endpoint, the same markers showed more modest contributions (P ‫؍‬ 0.08 to 0.24) to differential outcome during 11.5 years of follow-up. Broadly consistent findings in the larger MACS Caucasian SCs and the smaller groups of MACS African-American SCs and the DCG and SFMHS Caucasian SCs indicate that specific CCR2-CCR5 haplotypes or genotypes mediate initial acquisition of HIV-1 infection, early host-virus equilibration, and subsequent pathogenesis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Tang

Shelton²,

Makhatadze

et al. 2002

J Virol

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“…Genetic polymorphism clearly plays a role in influencing both the acquisition of HIV and the course of disease in the years following initial infection (3,23). Although studies have evaluated the influence of genetic polymorphism on outcomes of highly active antiretroviral therapy treatment of HIV infection (8,23,39,42) and hypersensitivity to treatment (17,19), an understanding of more global factors influencing efficacy of HIV therapy based on pharmacogenomic approaches is not well developed (6). Regarding CCR5 inhibitors, relatively little is known about how these compounds function in different individuals with varying CCR5 genotypes.…”

Section: Vol 78 2004 Psc-rantes Blocks R5 Hiv Infection Of Langerhamentioning

confidence: 99%

PSC-RANTES Blocks R5 Human Immunodeficiency Virus Infection of Langerhans Cells Isolated from Individuals with a Variety ofCCR5Diplotypes

Kawamura

Bruce

Abraha

et al. 2004

J Virol

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Topical microbicides that effectively block interactions between CCR5؉ immature Langerhans cells (LC) residing within genital epithelia and R5 human immunodeficiency virus (HIV) may decrease sexual transmission of HIV. Here, we investigated the ability of synthetic RANTES analogues (AOP-, NNY-, and PSC-RANTES) to block R5 HIV infection of human immature LC by using a skin explant model. In initial experiments using activated peripheral blood mononuclear cells, each analogue compound demonstrated marked antiviral activity against two R5 HIV isolates. Next, we found that 20-min preincubation of skin explants with each RANTES analogue blocked R5 HIV infection of LC in a dose-dependent manner (1 to 100 nM) and that PSC-RANTES was the most potent of these compounds. Similarly, preincubation of LC with each analogue was able to block LC-mediated infection of cocultured CD4 ؉ T cells. Competition experiments between primary R5 and X4 HIV isolates showed blocking of R5 HIV by PSC-RANTES and no evidence of increased propagation of X4 HIV, data that are consistent with the specificity of PSC-RANTES for CCR5 and the CCR5؉ CXCR4 ؊ phenotype of immature LC. Finally, when CCR5 genetic polymorphism data were integrated with results from the in vitro LC infection studies, PSC-RANTES was found to be equally effective in inhibiting R5 HIV in LC isolated from individuals with CCR5 diplotypes known to be associated with low, intermediate, and high cell surface levels of CCR5. In summary, PSC-RANTES is a potent inhibitor of R5 HIV infection in immature LC, suggesting that it may be useful as a topical microbicide to block sexual transmission of HIV.

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“…We previously observed that the CCR5 D32 deletion was predictive of a higher immunological and virological response rate to HAART, at 6 and 12 months, in a population of 166 HIV-1-infected patients with advanced disease who were protease inhibitor naïve [23]. A better response in heterozygotes has also been observed in some studies [20,[24][25][26] but not in all [23,[27][28][29].To clarify the impact of the CCR5 D32 deletion on the response to HAART, we analysed here whether the presence of the CCR5 D32 allele affected the immunological and virological outcome after HAART initiation in a larger population of HIV-1-infected patients with a longer followup after HAART initiation; this longer follow-up allowed us to investigate whether D32 heterozygotes also had a better clinical prognosis after HAART initiation. …”

mentioning

confidence: 70%

Improved virological response to highly active antiretroviral therapy in HIV‐1‐infected patients carrying the CCR5 Δ32 deletion

et al. 2007

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BackgroundPatients heterozygous for the C-C chemokine receptor 5 (CCR5) D32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 D32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. Patients and methodsWe included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of serconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan-Meier survival curves, with AIDS and death as outcomes. ResultsThe D32 heterozygous patients (n 5 83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P 5 0.01; and 60 vs 44% at 12 months, P 5 0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. ConclusionsCCR5 D32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the D32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis. Introduction C-C chemokine receptor 5 (CCR5), a receptor for the bchemokine RANTES, macrophage inflammatory protein (MIP)-1a and MIP-1b, is the most important chemokine receptor used by R5 HIV-1 strains for entry into CD4 cells.A 32-bp deletion (CCR5 D32) in the gene encoding the CCR5 coreceptor has been described [1][2][3]. Homozygous CCR5 D32/CCR5 D32 subjects are highly resistant to HIV-1 infection, although a few cases of infection have been reported [4][5][6]. Heterozygotes (CCR5 wt/CCR5 D32) are susceptible to HIV-1 infection, but progress more slowly to AIDS and death than wild-type patients (CCR5 wt/CCR5 wt) [7][8][9][10] 213 expression at the cell surface is diminished in D32 heterozygous patients and early plasma HIV-RNA viral load is lower in these patients than in wild-type patients [11]; this may explain why spontaneous HIV disease progression is slower in heterozygotes [9,10]. Since 1996, the use of highly active antiretroviral therapy (HAART) has provided substantial immunological (in terms of CD4 increase), virological (in terms of decrease in viral load) and clinical benefits to HIV-1-infected patients [12][13][14][15][16][17][18][19][20][21][...

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Association of the CCR5Delta32 Mutation With Improved Response to Antiretroviral Therapy

Cited by 58 publications

References 5 publications

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

PSC-RANTES Blocks R5 Human Immunodeficiency Virus Infection of Langerhans Cells Isolated from Individuals with a Variety ofCCR5Diplotypes

Improved virological response to highly active antiretroviral therapy in HIV‐1‐infected patients carrying the CCR5 Δ32 deletion

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