Abstract
BackgroundHuman Endogenous Retroviruses type K HML-2 (HK2) are integrated into 117 or more areas of human chromosomal arms while two newly discovered HK2 proviruses, K111 and K222, spread extensively in pericentromeric regions, are the first retroviruses discovered in these areas of our genome.MethodsWe use PCR and sequencing analysis to characterize pericentromeric K111 proviruses in DNA from individuals of diverse ethnicities and patients with different diseases.ResultsWe found that the 5′ LTR-gag region of K111 proviruses is missing in certain individuals, creating pericentromeric instability. K111 deletion (−/− K111) is seen in about 15% of Caucasian, Asian, and Middle Eastern populations; it is missing in 2.36% of African individuals, suggesting that the −/− K111 genotype originated out of Africa. As we identified the −/−K111 genotype in Cutaneous T-cell lymphoma (CTCL) cell lines, we studied whether the −/−K111 genotype is associated with CTCL. We found a significant increase in the frequency of detection of the −/−K111 genotype in Caucasian patients with severe CTCL and/or Sézary syndrome (n = 35, 37.14%), compared to healthy controls (n = 160, 15.6%) [p = 0.011]. The −/−K111 genotype was also found to vary in HIV-1 infection. Although Caucasian healthy individuals have a similar frequency of detection of the −/− K111 genotype, Caucasian HIV Long-Term Non-Progressors (LTNPs) and/or elite controllers, have significantly higher detection of the −/−K111 genotype (30.55%; n = 36) than patients who rapidly progress to AIDS (8.5%; n = 47) [p = 0.0097].ConclusionOur data indicate that pericentromeric instability is associated with more severe CTCL and/or Sézary syndrome in Caucasians, and appears to allow T-cells to survive lysis by HIV infection. These findings also provide new understanding of human evolution, as the −/−K111 genotype appears to have arisen out of Africa and is distributed unevenly throughout the world, possibly affecting the severity of HIV in different geographic areas.
Highlights
Human Endogenous Retroviruses type K HML-2 (HK2) are integrated into 117 or more areas of human chromosomal arms while two newly discovered HK2 proviruses, K111 and K222, spread extensively in pericentromeric regions, are the first retroviruses discovered in these areas of our genome
Detection of a −/−K111 [Δ Long Terminal Repeat (LTR)-gag] genotype in cutaneous T-cell lymphoma (CTCL) patients As we discovered the −/−K111 genotype in CTCL cells, we collected DNA from patients with CTCL and Sézary syndrome (Sz) to determine whether the lack of centromeric 5′ K111 LTR-gag (−/−K111 genotype) is prevalent in this disease
DNA from CTCL patients was screened for the K111 provirus using a forward primer P1, which binds to the flanking centromeric repeats (CER):D22Z3 region, and a reverse primer P4, which binds in K111 gag (Fig. 1a)
Summary
Human Endogenous Retroviruses type K HML-2 (HK2) are integrated into 117 or more areas of human chromosomal arms while two newly discovered HK2 proviruses, K111 and K222, spread extensively in pericentromeric regions, are the first retroviruses discovered in these areas of our genome. The Human Endogenous Retrovirus HERV-K HML-2 (HK2), first discovered in teratocarcinoma cell lines [1] and sequenced in 1986 [2], is one of the most recent retrovirus groups to have entered the genome of the primate lineage. HK2 proviruses, which use a Lys tRNA as a primer for reverse transcription, were discovered in human cells due to their similarity to the Mouse Mammary Tumor Virus (MMTV) These proviruses have 5′ and 3′ long terminal repeats (LTRs) that were identical at the time of integration but accumulated mutations over time. Mining of data generated by Generation sequencing from the Cancer Genome Atlas Project and the WGS500 project uncovered 17 new HK2 proviruses Some of these HK2 proviruses are present polymorphically in only 2 of 358 individuals studied and some in over 95% of individuals [19]. Two other nearly intact proviruses, notably K113 [21, 22] and K115 [23] theoretically could be able to produce infectious viral particles, but studies have shown these viruses are not capable of replication
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