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Pervasive genomic recombination of HIV-1 in vivo.

ABSTRACT: Recombinants of preexisting human immunodeficiency virus type 1 (HIV-1) strains are now circulating globally. To increase our understanding of the importance of these recombinants, we assessed recombination within an individual infected from a single source by studying the linkage patterns of the auxiliary genes of HIV-1 subtype B. Maximum-likelihood phylogenetic techniques revealed evidence for recombination from topological incongruence among adjacent genes. Coalescent methods were then used to estimate the in vivo recombination rate. The estimated mean rate of 1.38 x 10(-4) recombination events/adjacent sites/generation is approximately 5.5-fold greater than the reported point mutation rate of 2.5 x 10(-5)/site/generation. Recombination was found to be frequent enough to mask evidence for purifying selection by Tajima's D test. Thus, recombination is a major evolutionary force affecting genetic variation within an HIV-1-infected individual, of the same order of magnitude as point mutational change.

SUBMITTER: Shriner D

PROVIDER: S-EPMC1470992 | biostudies-other | 2004 Aug

REPOSITORIES: biostudies-other

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Pervasive genomic recombination of HIV-1 in vivo.

Shriner Daniel D Rodrigo Allen G AG Nickle David C DC Mullins James I JI

Genetics 20040801 4

Recombinants of preexisting human immunodeficiency virus type 1 (HIV-1) strains are now circulating globally. To increase our understanding of the importance of these recombinants, we assessed recombination within an individual infected from a single source by studying the linkage patterns of the auxiliary genes of HIV-1 subtype B. Maximum-likelihood phylogenetic techniques revealed evidence for recombination from topological incongruence among adjacent genes. Coalescent methods were then used t ...[more]

PMID: 15342499

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Project description:Jak-STAT, Ras, Notch pathway genes and CD44 are frequently mutated in HIV-associated PBL, and together with transcriptomic features distinguish the disease from closely related B-cell cancers. Plasmablastic lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma associated with immunodeficiency in the context of human immunodeficiency virus (HIV) infection or iatrogenic immunosuppression. While a rare disease in general, the incidence is dramatically increased in regions of the world with high HIV prevalence. The molecular pathogenesis of this disease is poorly characterized. Here, we defined the genomic features of PBL in a cohort of 110 patients from South Africa (15 by whole-exome sequencing and 95 by deep targeted sequencing). We identified recurrent mutations in genes of the JAK–STAT signaling pathway, including STAT3 (42%), JAK1 (14%), and SOCS1 (10%), leading to its constitutive activation. Moreover, 24% of cases harbored gain-of-function mutations in RAS family members (NRAS and KRAS). Comparative analysis with other B-cell malignancies uncovered PBL-specific somatic mutations and transcriptional programs. We also found recurrent copy number gains encompassing the CD44 gene (37%), which encodes for a cell surface receptor involved in lymphocyte activation and homing, and was found expressed at high levels in all tested cases, independent of genetic alterations. These findings have implications for the understanding of the pathogenesis of this disease and the development of personalized medicine approaches. Significance: Plasmablastic lymphoma is a poorly studied and extremely aggressive tumor. Here we define the genomic landscape of this lymphoma in HIV-positive individuals from South Africa and identify pervasive mutations in JAK–STAT3 and RAS–MAPK signaling pathways. These data offer a genomic framework for the design of improved treatment strategies targeting these circuits. See related commentary by Küppers, p. 23. This article is highlighted in the In This Issue feature, p. 5

Dataset Information

Pervasive genomic recombination of HIV-1 in vivo.

Publications

Pervasive genomic recombination of HIV-1 in vivo.

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