CCL3L1 and HIV/AIDS susceptibility

Bhattacharya, Tanmoy; Stanton, Jennifer; Kim, Eun Young; Kunstman, Kevin; Phair, John P.; Jacobson, Lisa P.; Wolinsky, Steven M.

doi:10.1038/nm1009-1112

Cited by 53 publications

(41 citation statements)

References 12 publications

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“…However, attempts to 164 replicate the data have been inconsistent, with several large studies failing to replicate the data 165 (table 1) (Bhattacharya et al 2009;Lee et al 2010). A recent meta-analysis of nine studies supported 166 an association of lower CCL3L1 with susceptibility to HIV (Liu et al 2010), but this study did not 167…”

Section: Host Copy Number Variation and Hiv 151mentioning

confidence: 82%

Human gene copy number variation and infectious disease

Hollox

Hoh

2014

Hum Genet

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16Variability in the susceptibility to infectious disease and its clinical manifestation can be determined 17 by variation in the environment and by genetic variation in the pathogen and the host. Despite 18 several successes based on candidate gene studies, defining the host variation affecting infectious 19 disease has not been as successful as other multifactorial diseases. Both single nucleotide variation 20 and copy number variation (CNV) in the host contribute to the host's susceptibility to infectious 21 disease. In this review we focus on CNV, particularly on complex multiallelic CNV that is often not 22 well characterised either directly by hybridisation methods or indirectly by analysis of genotypes and 23 flanking single nucleotide variants. We summarise the well-known examples, such as alpha-globin 24 deletion and susceptibility to severe malaria, as well as more recent controversies, such as the 25 extensive CNV of the chemokine gene CCL3L1 and HIV infection. We discuss the potential biological 26 mechanisms that could underly any genetic association and reflect on the extensive complexity and 27 functional variation generated by a combination of CNV and sequence variation, as illustrated by the 28 Fc gamma receptor genes FCGR3A, FCGR3B and FCGR2C. We also highlight some understudied areas 29 that might prove fruitful areas for further research. 30 31

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Section: Host Copy Number Variation and Hiv 151mentioning

confidence: 82%

Human gene copy number variation and infectious disease

Hollox

Hoh

2014

Hum Genet

View full text Add to dashboard Cite

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“…For example, some reports demonstrated an association between high CCL3L1 copy numbers and a reduced prevalence of HIV seropositivity, slower progression to AIDS, and improved recovery of CD4 ϩ T cells (45,(56)(57)(58), whereas other studies and follow-up correspondences failed to detect an association even within the same data set (59)(60)(61). Some researchers have suggested that the CCL3L1 copy number estimation method used in those association studies could be flawed, for example, due to DNA degradation, inconsistent quality among DNA samples, the use of inappropriate DNA amounts in the real-time PCR assay, inappropriate comparison of threshold cycle (C T ) values from samples run in different real-time PCR experimental repeats, or inappropriate rounding of copy numbers to the nearest integer value.…”

Section: Discussionmentioning

confidence: 99%

Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5-Tropic HIV-1 in a Subset of Elite Controllers

Walker

Kurscheid

Joshi

et al. 2015

J Virol

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Elite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4؉ T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4 ؉ T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1␣ (MIP-1␣), CCL3 and CCL3L1, were found to be upregulated. The MIP-1␣, MIP-1␤, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1␣ and/or MIP-1␤ at the protein level. The supernatant from resistant EC cells contained MIP-1␣ and MIP-1␤ and was sufficient to confer R5-tropic resistance to susceptible CD4 ؉ T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry. IMPORTANCEHIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4 ؉ T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals. In the absence of antiretroviral therapy (ART), the majority of HIV-seropositive patients have detectable viral loads (VLs) and experience a slow but inevitable decline in the number of CD4 ϩ T cells, eventually culminating in the development of AIDS. However, in rare individuals (Ͻ1% of the HIV-seropositive population), viral replication is suppressed to extremely low or undetectable levels. These patients, termed elite controllers (ECs), typically retain relatively high CD4 ϩ T cell counts and do not progress to AIDS, even in the absence of ART (1-4). Sequencing of HIV and in vitro functional assays suggest that most ECs possess replicationcompetent virus (5). Long-term nonprogressors (LTNPs), representing ϳ2 to 15% of HIV-seropositive patients, are a second group of individuals with a protective phenotype, in whom the virus continues to rep...

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“…The correlations have intuitive appeal, as ligands of CCR5 have been shown experimentally to inhibit HIV-1 replication (Cocchi et al 1995;Menten et al 1999Menten et al , 2002Nibbs et al 1999;Xin et al 1999). However, the link between CCL3L1 copy number and HIV-1 infection has been called into question by subsequent, independent studies, which have failed to reproduce the correlation (Bhattacharya et al 2009;Urban et al 2009). Likewise, after correcting for known influence of the MHC class I and TRIM5 loci on SIV infection, Lim et al did not find a significant correlation between CCL3L1 copy number and replication of SIVmac in rhesus macaques (Lim et al 2010b).…”

Section: Chemokine Receptors and Chemokinesmentioning

confidence: 99%