HIV proviral DNA integration can drive T cell growth ex vivo

• DOI: 10.1073/pnas.2013194117
• Publication Date: 2020-12-16T22:48:27Z
• Authors: John K. Yoon; Joseph R. Holloway; Daria W. Wells; Machika Kaku; David Jetton; Rebecca Brown; John M. Coffin
• Keywords: STAT3 Transcription Factor; 0301 basic medicine; T-Lymphocytes; Virus Integration; HIV; Biological Sciences; 3. Good health; Clonal Evolution; 03 medical and health sciences; Proviruses; DNA, Viral; Humans; Cells, Cultured; Cell Proliferation

In vivo clonal expansion of HIV-infected T cells is an important mechanism of viral persistence. In some cases, clonal expansion is driven by HIV proviral DNA integrated into one of a handful of genes. To investigate this phenomenon in vitro, we infected primary CD4+ T cells with an HIV construct expressing GFP and, after nearly 2 mo of culture and multiple rounds of activation, analyzed the resulting integration site distribution. In each of three replicates from each of two donors, we detected large clusters of integration sites with multiple breakpoints, implying clonal selection. These clusters all mapped to a narrow region within the STAT3 gene. The presence of hybrid transcripts splicing HIV to STAT3 sequences supports a model of LTR-driven STAT3 overexpression as a driver of preferential growth. Thus, HIV integration patterns linked to selective T cell outgrowth can be reproduced in cell culture. The single report of an HIV provirus in a case of AIDS-associated B-cell lymphoma with an HIV provirus in the same part of STAT3 also has implications for HIV-induced malignancy.