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Review 1: "Gene Dysregulation among Virally Suppressed People Living with HIV Links to Non-AIDS Defining Cancer Pathways"

The reviewer points out several limitations, including the constraints of whole-blood transcriptomics, the absence of clinical phenotyping, and the relevance of integrating heritability data to "inflammatory" diseases.

Published onJun 30, 2024
Review 1: "Gene Dysregulation among Virally Suppressed People Living with HIV Links to Non-AIDS Defining Cancer Pathways"
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Gene dysregulation among virally suppressed people living with HIV links to non-AIDS defining cancer pathways
Gene dysregulation among virally suppressed people living with HIV links to non-AIDS defining cancer pathways

Abstract Combination antiretroviral therapy (ART) has changed the landscape of the HIV epidemic by providing an effective means for viral suppression to people living with HIV (PLWH). Understanding living with HIV as a chronic disease requires an improved understanding of how HIV and/or ART impacts susceptibility to and development of co-occurring conditions. Genome-wide gene expression (transcriptome) differences provide a key view into biological dysregulation associated with living with HIV. Here we present the first whole blood transcriptome-wide study comparing gene expression profiles between virally suppressed PLWH and HIV negative individuals (N=555). We identify 566 genes and 5 immune cell types with differential proportions by HIV status, which were significantly enriched for immune function and cancer pathways. Leveraging quantitative trait loci (QTL) for these HIV status-associated genes, partitioned heritability, and colocalization analyses, we observed limited genetic drivers of these relationships. Our findings suggest that gene dysregulation does not return to a pre-infection state for virally suppressed PLWH, and that persistent gene dysregulation is broadly associated with immune function and cancer pathways, highlighting potential biological drivers for these causes of excess mortality and targets for pharmacological preventative treatment among PLWH.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


Review: Quach et al's investigation into people with HIV (PWH) undergoing antiretroviral therapy (ART) utilizing whole blood transcriptomics reveals pivotal insights. The study, encompassing an impressive 555 patients, boasts significant breadth. However, the clinical characterization appears rudimentary. All PWH are labeled "HIV+", ignoring highly relevant differences between PWH progressing to AIDS before treatment initiation versus those treated during primary infection. Such distinctions bear immense implications for opportunistic infections, cardiovascular events, cancer risks, and beyond.

Despite the extensive laboratory analyses undertaken by the authors, the limitations of whole blood transcriptomics become apparent. The pursuit of enriched Gene Ontology (GO) terms, while extensive, yields results of constrained scientific utility. Moreover, the narrative linking cellular processes to various functions lacks evidential strength.

The authors' attempt at cell deconvolution holds promise, particularly in the context of HIV's heterogeneity. Nonetheless, the absence of robust clinical phenotyping impedes validation.

Additionally, while commendable, the endeavor to integrate heritability data remains enigmatic in its relevance to diverse conditions like asthma, Crohn's disease, rheumatoid arthritis (RA), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The classification of these disparate ailments as "inflammatory" appears tenuous.

Regrettably, the authors overlook significant shortcomings, failing to delineate the limitations of their clinical cohort adequately. Furthermore, the discussion's focus on potential intracellular pathways neglects critical caveats, including the uncertainty surrounding assumptions inherent in the transition from whole blood transcriptomics to intracellular pathways, particularly in the context of HIV's impact on cellular composition. Thus, differential regulatory pathways across cell types may obscure or amplify signals unpredictably.

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