Clonal expansion of SIV-infected cells in macaques on antiretroviral therapy is similar to that of HIV-infected cells in humans

Abstract

Clonal expansion of HIV infected cells plays an important role in the formation and persistence of the reservoir that allows the virus to persist, in DNA form, despite effective antiretroviral therapy. We used integration site analysis to ask if there is a similar clonal expansion of SIV infected cells in macaques. We show that the distribution of HIV and SIV integration sites in vitro is similar and that both viruses preferentially integrate in many of the same genes. We obtained approximately 8000 integration sites from blood samples taken from SIV-infected macaques prior to the initiation of ART, and from blood, spleen, and lymph node samples taken at necropsy. Seven clones were identified in the pre-ART samples; one persisted for a year on ART. An additional 100 clones were found only in on-ART samples; a number of these clones were found in more than one tissue. The timing and extent of clonal expansion of SIV-infected cells in macaques and HIV-infected cells in humans is quite similar. This suggests that SIV-infected macaques represent a useful model of the clonal expansion of HIV infected cells in humans that can be used to evaluate strategies intended to control or eradicate the viral reservoir.

An analytical pipeline for identifying and mapping the integration sites of HIV and other retroviruses

“…We normally only map the sequence reads to the specific genome that was used in the study. Although most of our work involves HIV and the human genome, the experimental procedures and bioinformatics pipeline we describe here works for any retrovirus/host pair such as MLV in the human genome [7], HIV in the mouse genome [35,41], or HIV or SIV in the macaque genome [42], with proper viral specific primers.…”

The forces driving clonal expansion of the HIV-1 latent reservoir

“…These specific sites recur across individuals not because of preferential integration, as HIV-1 integration into these sites are not enriched during in vitro infections [11]. Similar to HIV-1 integration sites, simian immunodeficiency virus (SIV) with integration into BACH2, MKL2 and STAT5B are found in SIV-infected macaques before ART [107]. Despite that the genomewide distribution of HIV-1 and SIV integration showed a high degree of overlap in vitro, it seems that more integrants are oriented in the convergent orientation of these genes in SIV-infected macaques under suppression, which is opposite from what observed from ART treated HIV-1infected individuals in vivo [11,12,107].…”

“…Similar to HIV-1 integration sites, simian immunodeficiency virus (SIV) with integration into BACH2, MKL2 and STAT5B are found in SIV-infected macaques before ART [107]. Despite that the genomewide distribution of HIV-1 and SIV integration showed a high degree of overlap in vitro, it seems that more integrants are oriented in the convergent orientation of these genes in SIV-infected macaques under suppression, which is opposite from what observed from ART treated HIV-1infected individuals in vivo [11,12,107]. However, more SIV integration site data from long-term treated macaques are needed to determine whether there is positive selection of SIV proviruses integrated in genes associated with clonal expansion in individuals on ART.…”

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

“…To extend our studies to more physiologically relevant models and provide clinical relevance, we first assembled open source, publicly available HIV integration datasets from 11 patients studies (Mack et al 2003;Han et al 2004;Ikeda et al 2007;Maldarelli et al 2014;Wagner et al 2014;Kok et al 2016;Sharaf et al 2018;Coffin et al 2019;Einkauf et al 2019;Garcia-Broncano et al 2019;McManus et al 2019) and 4 studies with primary CD4 + T cells infected ex vivo (Sherrill-Mix et al 2013;Sunshine et al 2016;Ferris et al 2019;Lucic et al 2019) ( Supplemental Table S4). We used these datasets to interrogate the epigenomic landscape of intact vs defective proviruses to provide fundamental principles of differential positioning and regulation of these two proviral classes and to compare their epigenomic landscapes to proviruses in the immortalized (Jurkat T cell) models of latency ( Fig.…”