CCL3L1 and CCL4L1: variable gene copy number in adolescents with and without human immunodeficiency virus type 1 (HIV-1) infection

Shao, Wenshuo; Tang, Jianming; Song, Wei; Wang, C; Li, Y; Wilson, Craig M.; Kaslow, Richard A.

doi:10.1038/sj.gene.6364378

Cited by 47 publications

(41 citation statements)

References 55 publications

(72 reference statements)

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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: 96%

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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Section: Discussionmentioning

confidence: 96%

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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“…This is significant because copy number of both genes can be different on a single chromosome. 14,25 However, the number of copies of CCL3L and CCL4L is, in general, positively correlated within populations. Thus, although in this study, we focused on the therapeutic correlates of CCL4L gene copy number, CCL3L gene dosage may also contribute to the LT rejection effect.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation

et al. 2009

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Lung transplantation (LT) has become an accepted therapy for selected patients with advanced lung disease. One of the main limitations to successful LT is rejection of the transplanted organ where chemokines are pivotal mediators. Here, we test the relationship between copy number variation (CNV) in the CCL4L chemokine gene and rejection risk in LT patients (n ¼ 161). Patients with no acute rejection showed a significantly lower mean number of CCL4L copies than patients that showed acute rejection (1.66 vs 1.96, P ¼ 0.014), with an even greater number of gene copies seen in patients with more than one episode of acute rejection (1.66 vs 2.30, P ¼ 0.001). Additionally, patients with X2 CCL4L copies had a significantly higher risk of acute rejection compared with patients that had 0-1 CCL4L copies (odds ratio 2.65; 95% confidence interval, 1.33-5.28; P ¼ 0.0046). A combined analysis of CCL4L CNV and the rs4796195 CCL4L single nucleotide polymorphism demonstrated that the effect of CCL4L copy number in acute rejection is mainly because of the number of copies of the CCL4L1 allelic variant. This finding constitutes the first report of CNV as a correlate factor in allograft rejection.

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“…A recent study of genomic copy number varition of Asian men with congenital bilateral absence of the vas deferens (CBAVD) but without the most common CFTR-associated mutant did identify CNV in genes possibly associated with the disorder [Lee et al 2009]. Initial studies of CNVs have shown associations in complex disorders such as systemic lupus, HIV acquisition, and breast cancer [Yang et al 2007;Shao et al 2007;Frank et al 2007].…”

Section: Discussionmentioning

confidence: 99%

SPANX Gene Variation in Fertile and Infertile Males

Hansen

Eichler

Fullerton

et al. 2010

Systems Biology in Reproductive Medicine

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Protein expression data suggests that the SPANX gene family is expressed throughout spermatogenesis, including post-meiotic expression, consistent with a potential role in sperm development. The genomic architecture of this region is unstable and past studies have found evidence of variation in this gene family. This study used a novel assay to evaluate copy number variation (CNV) in SPANX gene family, in fertile and infertile men. The case group was comprised of 50 oligozoospermic and 50 azoospermic men, and the control group was comprised of 67 normozoospermic men with children. The assay, real-time quantitative PCR, evaluated CNV of the entire gene cluster containing all four SPANXA-E genes and with SPANXB, found exclusively in maturing sperm. While variation was found in both groups, average CNV patterns did not differ between fertile and infertile males. As this was a targeted assay, it was limited in scope to detect further CNV at a genome-wide level which is an area of increasing interest in the field of genomics.

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CCL3L1 and CCL4L1: variable gene copy number in adolescents with and without human immunodeficiency virus type 1 (HIV-1) infection

Cited by 47 publications

References 55 publications

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

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

Copy number variation in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation

SPANX Gene Variation in Fertile and Infertile Males

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