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. 2022 Feb 1;36(2):205-214.
doi: 10.1097/QAD.0000000000003088.

Evaluation of HIV-1 reservoir size and broadly neutralizing antibody susceptibility in acute antiretroviral therapy-treated individuals

Brian Moldt  1 , Huldrych F Günthard  2   3 , Kimberly A Workowski  4 , Susan J Little  5 , Joseph J Eron  6 , Edgar T Overton  7 , Clara Lehmann  8   9   10 , Casper Rokx  11   12 , Michael J Kozal  13 , Rajesh T Gandhi  14 , Dominique L Braun  2   3 , Aiyappa Parvangada  1 , Jiani Li  1 , Ross Martin  1 , Lisa Selzer  1 , Stephanie Cox  1 , Nicolas Margot  1 , Hui Liu  1 , Debbie Slamowitz  1 , Tariro Makadzange  1 , Sean E Collins  1 , Romas Geleziunas  1 , Christian Callebaut  1
Affiliations

Evaluation of HIV-1 reservoir size and broadly neutralizing antibody susceptibility in acute antiretroviral therapy-treated individuals

Brian Moldt et al. AIDS. .

Abstract

Objective: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies.

Methods: Four cohorts with participants who initiated ART during acute infection or during chronic infection were enrolled in a cross-sectional, noninterventional study. Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIV DNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene.

Results: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection.

Conclusion: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.

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Conflict of interest statement

B.M., A.P., J.L., R.M., L.S., S.C., N.M., H.L., D.S., T.M., S.E.C., R.G., and C.C. are employees and stockholders of Gilead Sciences, Inc. H.F.G. has received unrestricted research grants from Gilead Sciences and Roche; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Merck and ViiV Healthcare; and grants from SystemsX, and the National Institutes of Health. The institution of H.F.G. received educational grants form Gilead Sciences, ViiV, MSD, Abbvie, and Sandoz. S.J.L. received grants for investigator initiated studies from Gilead outside of the submitted work. E.T.O. received honoraria from ViiV, Merck, and Theratechnologies outside of the submitted work. C.L. received honoraria and travel grants from Janssen, Gilead, ViiV, and Merck outside of the submitted work. C.R. received honoraria and travel grants and grants for investigator-initiated studies from Gilead, ViiV, Janssen-Cilag, and Merck outside the context of the submitted work. M.J.K. received research support from Gilead and ViiV Healthcare. R.T.G. receives grant funding from the Harvard University Center for AIDS Research (NIH P30 AI060354) and the AIDS Clinical Trials Group (NIH/NIAID 2 UMAI069412–09). D.L.B. received honoraria and travel grants from Gilead, ViiV, and Merck outside of the submitted work.

Figures

Fig. 1.
Fig. 1.. Intact Proviral DNA Assay, Total HIV DNA Assay, and Quantitative Viral Outgrowth Assay HIV reservoir measurement per cohort.
Frequency per million CD4+ cells for (a) intact HIV DNA, (b) 3′ deleted/hypermutated HIV DNA, (c) 5′ deleted HIV DNA, (d) total HIV DNA from IPDA, (e) total HIV DNA from THDA, and (f) IUPM from QVOA. Lines represent median values. 3′ del/hyper HIV DNA, 3′ deletions and/or hypermutation HIV DNA; 5′ del HIV DNA, 5′ deletions HIV DNA; IUPM, infectious units per million cells. P values for comparison with cohort 4 are based on two-sided Wilcoxon rank-sum tests.
Fig. 2.
Fig. 2.. Association between Intact Proviral DNA Assay, Total HIV DNA Assay, and Quantitative Viral Outgrowth Assay HIV reservoir measurements.
IUPM, infectious units per million cells; rs, rho. rho and P values for associations between HIV reservoir measurements are calculated based on Spearman’s correlations. Imputed values excluded in analysis.
Fig. 3.
Fig. 3.. HIV envelope diversity.
Diversity was evaluated by average pairwise distance analysis for (a) PBMC provirus from all participants, (b) PBMC provirus per cohort, (c) outgrowth virus from all participants, and (d) outgrowth virus per cohort. Data shown as a box and whisker plot including all data points except for c shown as a dot plot. P values for comparison with cohort 4 are based on Wilcoxon rank-sum tests.
Fig. 4.
Fig. 4.. Viral susceptibility to V3-glycan targeting bNAbs per cohort.
Viral susceptibility to the bNAbs PGT121, EVM, and 10–1074 was based in the presence of the N332 glycosylation motif and the D325 residue in the HIV envelope in (a) PBMC provirus and (b) outgrowth virus.
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