Association Between HIV-1 Tropism and CCR5 Human Haplotype E in a Caucasian Population

Huik, Kristi; Avi, Radko; Uibopuu, Helen; Pauskar, Merit; Margus, Tõnu; Karki, Tõnis; Krispin, Tõnu; Kool, Piret; Talu, Ave; Abel-Ollo, Katri; Uusküla, Anneli; Carrillo, Andrew; He, Weijing; Ahuja, Sunil K.; Lutsar, Irja

doi:10.1097/qai.0000000000000127

Cited by 5 publications

(5 citation statements)

References 34 publications

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“…In the same way that the ORF wt/Δ32 and −2459G/A alleles show differences in phenotypic effects in vitro as well as in HIV/AIDS cohorts, different CCR5 haplotypes influence HIV infection and disease outcomes differently [ 18 , 19 , 20 , 21 , 22 , 23 ]. Among CCR5 haplotypes (HHA–HHG*2), the consistency of the association of HHE homozygosity (E/E diplotype) with an unfavorable outcome across diverse populations is noteworthy: This diplotype was significantly associated with disease acceleration, particularly an accelerated progression to death in Caucasians [ 18 ].…”

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confidence: 99%

“…Even in children from Argentina, there was a strong association between the E/E diplotype and susceptibility to perinatal transmission of HIV-1, accelerated rate of progression to AIDS, and a more rapid progression to death [ 20 ]. A recent study investigating the association between CCR5 haplotypes and HIV tropism in Estonian Caucasians found that HHE was associated with the presence of C-X-C chemokine receptor 4-tropic viruses [ 19 ]. Unfavorable outcomes, ranging from seroconversion to disease progression, associated with HHE have also been reported in other recent studies [ 27 , 28 , 29 ].…”

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confidence: 99%

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CCR5 Promoter Polymorphism −2459G > A: Forgotten or Ignored?

Mehlotra

2019

Cells

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C-C chemokine receptor 5 (CCR5) polymorphisms, particularly a 32-base pair deletion (∆32) in the open reading frame and −2459G > A in the promoter, are well known for their associations with HIV-1 infection and/or disease progression in a variety of studies. In this era of an HIV cure, where all the emphasis is on ∆32, it seems that −2459G > A has been forgotten or ignored. There is significant importance in the incorporation of the CCR5 −2459G > A genotype information into studies evaluating new immunologic and chemotherapeutic strategies, and those designing and implementing better treatment strategies with current antiretroviral therapy, doing so would enable a better understanding of the response to the intervention, due to a mechanistic or constitutive explanation. Until we find a strategy, whether a stem-cell transplantation or CCR5 editing approach or something else, that delivers a cure to the millions, we should make use of every piece of information that may help curtail HIV/AIDS as a threat to public health.

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confidence: 99%

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confidence: 99%

CCR5 Promoter Polymorphism −2459G > A: Forgotten or Ignored?

Mehlotra

2019

Cells

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“…Other studies in Rwanda, Spain, Thailand and Argentina have reported a strong association between this mutation and rapid HIV-1 disease progression (18,19,37) (18). Additionally, in a recent study investigating whether there is association between CCR5 haplotypes and HIV tropism in Estonian Caucasians found that -2459 A/A was associated with the presence of C-X-C chemokine receptor 4-tropic viruses (38). These findings consistently suggest that-2459 A/A leads to accelerated disease progression to AIDS in distinct genetic backgrounds.…”

Section: Discussionmentioning

confidence: 91%

Genetic variations within the CCR5 promoter region among elite and viremic controllers in Uganda

Nyiro¹,

Amanya²,

Nabatanzi³

et al. 2020

Preprint

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Background: The importance of the C-C chemokine receptor type 5 (CCR5) in HIV infection and disease progression was recognized with the discovery of the ∆32 allele. Individuals homozygous for this mutation lack functional CCR5, and are almost completely resistant to HIV infection while heterozygous individuals display decreased cell surface CCR5, which slows disease progression. However, this mutation is rare in Africa. Genetic variations within the CCR5 promoter region have been associated with regulation of CCR5 gene expression and could attempt to explain the different disease progression statues seen within Uganda. However, the distribution and impact of these variations are not known within this setting where this population exists. A study done in Rakai, reported a prevalence of LTNPs as 9.1% and another study done by Alex Kayondo in 2018, reported a prevalence of 0.26% of HIV controllers in an Urban HIV ambulatory center in Kampala, Uganda. Reasons for their intrinsic resistance to HIV are not fully understood. We hypothesized that variations in the CCR5 promoter gene could affect CCR5 expression thus impacting on the clinical course of HIV. In this study, we determined the median CCR5 expression by CD4 + T cells and the CCR5 promoter genetic variations that could be associated with delayed progression to HIV/AIDS seen among this study group.Results: There was significant reduction in CCR5 densities on CD4 + T cells among elite and viremic controllers compared to non-controllers. CCR5 Promoter polymorphism − 2459 G/G was highly prevalent among Elite and Viremic Controllers and it is associated with delayed progression to AIDS while − 2459 A/A and − 2132C/T were high prevalent among NCs and they are associated with rapid progression to AIDS.Conclusion: The reduction in CCR5 densities and percentage CCR5 + CD4 + T cells could explain the delayed progression to AIDS among these individuals. The reduction could be accounted for by the mutation 2459 G/G reported in the CCR5 promoter region.

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“…Along the line that the −2459G/A and ORF wt/Δ32 alleles show differences in phenotypic effects in vitro as well as in HIV/AIDS cohorts, different CCR5 haplotypes influence HIV infection and disease outcomes differently (Gonzalez et al, 1999; Huik et al, 2014; Kostrikis et al, 1999; Mangano et al, 2001; Tang et al, 2002a; Tang et al, 2002b). Among the CCR5 haplotypes, the consistency of the associations of HHE homozygosity (E/E diplotype) with unfavorable outcomes is noteworthy.…”

Section: Discussionmentioning

confidence: 99%

“…There was a strong association between the E/E diplotype and susceptibility to perinatal transmission of HIV-1, accelerated rate of progression to AIDS, and a more rapid progression to death in Argentinean children (Mangano et al, 2001). Recently, a study investigating the association between CCR5 haplotypes and HIV tropism in Estonian Caucasians found that HHE was associated with the presence of HIV-1 X4-tropic viruses (Huik et al, 2014). Such consistency across racial/ethnic groups and populations suggest that HHE confers similar effects against distinct genetic backgrounds, and therefore may increase the risk of HIV infection and rate of disease progression in PNG as well.…”

Section: Discussionmentioning

confidence: 99%

CCR2 , CCR5 , and CXCL12 variation and HIV/AIDS in Papua New Guinea

Mehlotra

Hall

Bruse

et al. 2015

Infection, Genetics and Evolution

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Polymorphisms in chemokine receptors, serving as HIV co-receptors, and their ligands are among the well-known host genetic factors associated with susceptibility to HIV infection and/or disease progression. Papua New Guinea (PNG) has one of the highest adult HIV prevalences in the Asia-Pacific region. However, information regarding the distribution of polymorphisms in chemokine receptor (CCR5, CCR2) and chemokine (CXCL12) genes in PNG is very limited. In this study, we genotyped a total of nine CCR2-CCR5 polymorphisms, including CCR2 190G>A, CCR5 −2459G>A and Δ32, and CXCL12 801G>A in PNG (n = 258), North America (n = 184), and five countries in West Africa (n = 178). Using this data, we determined previously characterized CCR5 haplotypes. In addition, based on the previously reported associations of CCR2 190, CCR5 −2459, CCR5 open reading frame, and CXCL12 801 genotypes with HIV acquisition and/or disease progression, we calculated composite full risk scores, considering both protective as well as susceptibility effects of the CXCL12 801 AA genotype. We observed a very high frequency of the CCR5 −2459A allele (0.98) in the PNG population, which together with the absence of Δ32 resulted in a very high frequency of the HHE haplotype (0.92). These frequencies were significantly higher than in any other population (all P-values < 0.001). Regardless of whether we considered the CXCL12 801 AA genotype protective or susceptible, the risk scores were significantly higher in the PNG population compared with any other population (all P-values < 0.001). The results of this study provide new insights regarding CCR5 variation in the PNG population, and suggest that the collective variation in CCR2, CCR5, and CXCL12 may increase the risk of HIV/AIDS in a large majority of Papua New Guineans.

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Association Between HIV-1 Tropism and CCR5 Human Haplotype E in a Caucasian Population

Cited by 5 publications

References 34 publications

CCR5 Promoter Polymorphism −2459G > A: Forgotten or Ignored?

CCR5 Promoter Polymorphism −2459G > A: Forgotten or Ignored?

Genetic variations within the CCR5 promoter region among elite and viremic controllers in Uganda

CCR2 , CCR5 , and CXCL12 variation and HIV/AIDS in Papua New Guinea

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