Effective and targeted latency reversal in CD4⁺ T cells from individuals on long term combined antiretroviral therapy initiated during chronic HIV-1 infection

ABSTRACT

To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most “latency reversal” agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5–20 years on stable cART, HLP could target CD4⁺ T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.

KEYWORDS:

• HIV-1 latency reversal
• latency reversal agent
• virus-like particles
• CD4+ T cells
• chronic HIV-1 infection
• replication-competent latent reservoir
• HIV-1 cure

Acknowledgements

We thank the participants in this study, people living with HIV-1 on long term cART in Canada, Uganda, and the US who graciously provided samples. This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; Canada Research Chairs Program; and by grant awards from the NIH (AI49170), amfAR ARCHE (108838-55-RGRL and 108686-54-RGRL) and CIHR (377790 and 385787) to E.J.A., from CIHR (PJT 149075) to J.F.S.M., and from Gilead (300527) to J.L.P. E.J.A. is the Canada Research Chair in HIV Pathogenesis and Viral Control funded by the CRC program. The authors declare there is no involvement of the funding sources in any part of this study.

Disclosure statement

E.J.A. and J.F.S.M. are the inventors of patent US11596682B2, and E.J.A. of patent AU2007217275A1, both associated with the vectors used in this study. The remaining authors declare no competing interests.

Authors contributions

M.H.N, J.P., and R.C.Y.H. performed all the experimentation with the assistance of R.P., K.K., and Y.L for the primary cell isolations and analyzes, T.B. and E.N. for the HLP cloning and preparations, R.C. for qRT-PCR, T.B. and A.S.O. for bioinformatic analyzes. Participant screening, sample collection, and viral RNA analyzes involved the team at Rakai Health Sciences Program/John Hopkins University/NIAID (S.T., S.J., A.A., T.K., P.B., R.M.G., S.J.R., T.C.Q., A.D.R, J.L.P.), at CWRU (R.A., J.M.J., D.H.C.), and University of Toronto (C.K.). The RHSP/JHU/NIAID team also measured the virus infectious units and proviral DNA content in the participant samples from Uganda. E.J.A., J.F.S.M., M.H.N., J.P., and R.C.Y.H. have directly accessed and verified the underlying data reported in the manuscript. J.F.S.M. and E.J.A. conceptualized the project, interpreted data and together with M.H.N, J.P., and R.C.Y.H., wrote the manuscript. The entire team provided edits and comments to earlier drafts of the manuscript. M.H.N, J.P., and R.C.Y.H. contributed equally to this manuscript as co-first authors.

Additional information

Funding

This work was supported by Canadian Institutes of Health Research: [Grant Number 377790, 385787]; Gilead Sciences: [Grant Number 300527]; National Institutes of Health: [Grant Number AI49170]; amfAR, The Foundation for AIDS Research: [Grant Number ARCHE 108838-55-RGRL, ARCHE 108686-54-RGRL].