Review 2: "Differences in HIV-1 Reservoir Size, Landscape Characteristics and Decay Dynamics in Acute and Chronic Treated HIV-1 Clade C Infection"

Celine Gubser

doi:doi:10.1162/2e3983f5.c2d530c8

Reviewers praised the innovative techniques and writing, highlighting the study's novel approach of combining early ART treatment with clade B and C infections. Concerns were raised about limited provirus sampling, technical issues with PCR assay, and robustness of conclusions.

by Celine Gubser

Published onAug 03, 2024

Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection

by Kavidha Reddy, Guinevere Q. Lee, Nicole Reddy, Tatenda J.B. Chikowore, Kathy Baisley, Krista L. Dong, Bruce D. Walker, Xu G. Yu, Mathias Lichterfeld, and Thumbi Ndung’u

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Published on Feb 20, 2024
www.medrxiv.org

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Abstract Background Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs.Methods We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation.Results Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir.Conclusions Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: Lifelong ART is associated with side effects and financial challenges, especially in low- to middle-income countries most affected by the epidemic. While early ART in HIV-1 subtype C infection did not affect reservoir seeding, it was still linked to faster decay of intact viral genomes, reduced genetic complexity, and immune escape in reservoirs, suggesting that when combined with other interventional strategies, it is more likely to achieve an effective HIV cure.

This is a beautiful study which conducted a longitudinal analysis of HIV-1 subtype C reservoir characteristics in a cohort of 35 women identified with hyperacute HIV infection in South Africa, allowing for the study of reservoir establishment, virus evolution and CTL response from early stages. A group of 11 participants started ART at ~456 days post onset of viremia while a second group of 24 participants started ART after ~1 day post onset of viremia. In PBMC, HIV-1 DNA was measured by ddPCR and viral genomes were analysed by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. The authors show there was a steady decline in total HIV DNA over ART treatment of 1 year in early treated persons, whereas no significant change was observed in the late treated group. Treatment initiation in both late and early infection led to a more rapid decay of intact viral genomes compared to defective ones. Early ART also reduced the phylogenetic diversity of intact genomes and limited the seeding and persistence of immune escape variants in the reservoir.

Review 2: "Differences in HIV-1 Reservoir Size, Landscape Characteristics and Decay Dynamics in Acute and Chronic Treated HIV-1 Clade C Infection"

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