Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2019 Jun 21;10(1):2737.
doi: 10.1038/s41467-019-10659-2.

HIV-1 DNA sequence diversity and evolution during acute subtype C infection

Guinevere Q Lee  1   2   3 , Kavidha Reddy  4   5 , Kevin B Einkauf  1   2 , Kamini Gounder  4   5 , Joshua M Chevalier  1 , Krista L Dong  1   3 , Bruce D Walker  1   2   3   4   6   7 , Xu G Yu  1   2   3   6 , Thumbi Ndung'u  1   4   5   8 , Mathias Lichterfeld  9   10   11   12
Affiliations
Observational Study

HIV-1 DNA sequence diversity and evolution during acute subtype C infection

Guinevere Q Lee et al. Nat Commun. .

Abstract

Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection. Here, we use near-full-length, single genome next-generation sequencing to longitudinally genotype and quantify subtype C HIV-1 DNA in four women identified during acute HIV-1 infection in Durban, South Africa, through twice-weekly screening of high-risk participants. In contrast to chronically HIV-1-infected patients, we found that at the earliest phases of infection in these four participants, the majority of viral DNA genomes are intact, lack APOBEC-3G/F-associated hypermutations, have limited genome truncations, and over one year show little indication of cytotoxic T cell-driven immune selections. Viral sequence divergence during acute infection is predominantly fueled by single-base substitutions and is limited by treatment initiation during the earliest stages of disease. Our observations provide rare longitudinal insights of HIV-1 DNA sequence profiles during the first year of infection to inform future HIV cure research.

PubMed Disclaimer

Conflict of interest statement

M.L. has received speaking and consulting honoraria from Merck & Co., Inc. and Gilead Sciences Inc. T.N. receives research funding support from Gilead Sciences Inc., a pharmaceutical company with interests in HIV cure research. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Clinical and virological characteristics of the four study participants. Longitudinal trends of viral load (dashed black lines), CD4 counts (dotted black lines), absolute frequencies of genome-intact HIV-1 per million PBMCs (orange lines), absolute frequencies of genome-defective HIV-1 (light green lines), and total HIV-1 DNA burden determined by ddPCR (blue lines) are shown. Acute HIV-1 infection was staged according to the classification system of Fiebig et al.
Fig. 2
Fig. 2
Experimental and computational determination of viral genome intactness. a Sample processing pipeline for the generation of near-full-length HIV-1 sequences via single-genome-amplification. b Schematic representation of individual viral sequence analysis steps incorporated in the R-language HIVSeqinR script used for the determination of viral genome intactness in this study. A stable release (ver2.6) used in this study is available in GitHub at https://github.com/guineverelee/HIVSeqinR
Fig. 3
Fig. 3
Cross-sectional analysis of HIV-1 DNA sequences at stage II versus stage V of acute infections. a Absolute frequencies of intact viral genomes detected per million PBMC in indicated study patients at the earliest sampling time points. b Proportions of intact (blue) and defective (orange) viral genomes at the earliest sampling time points available from each of the four FRESH cohort participants. c Proportions of intact (blue) and defective (orange) viral genomes from three chronically-infected individuals who were sampled shortly post-therapy-initiation. d Spectrum of defective HIV-1 DNA sequences at the earliest sampling time points available from each of the four FRESH cohort participants
Fig. 4
Fig. 4
Longitudinal changes in HIV-1 DNA genotypic compositions. a Diagram reflecting a cross-sectional view of all 292 HIV-1 genomes presented in this study from all four patients over all sampling time points (each horizontal line represents one viral genome). Navy blue lines represent intact HIV-1 genomes; other colors represent defective HIV genomes. Asterisk denotes sampling time points at stage II. Hash denotes sampling time points at stage V. b Absolute frequencies of intact HIV-1 DNA sequences per million PBMCs during the 1st year of infection. c Absolute frequencies of defective HIV-1 DNA sequences per million PBMCs during the 1st year of infection. d Relative proportions of HIV-1 DNA sequences during the 1st year of infection
Fig. 5
Fig. 5
Genetic variations among intact HIV-1 DNA genomes detected in this study. a Los Alamos HIV Sequence Database highlighter plots of all intact viral genomes derived in this study across all time points. Each horizontal line represents an intact HIV-1 DNA genome detected in this study spanning HXB2 638-9632. For each patient, a random sequence from the earliest time point was selected to serve as the comparator against the rest of the intra-patient viral genomes (top-most line in each patient, unmarked, master sequence). Vertical strokes represent bases that were different from the master sequence (green A, blue C, orange G, red T, gray gap/deletion). Two genome-intact clonal clusters were detected in Pt 4 and were labeled as 1 and 2 on the right side of the panel. b FastTree2 single precision approximately-maximum-likelihood phylogenetic tree of HIV-1 DNA intact genomes. This method was chosen to resolve full-viral-genome sequences with extreme homology; branch lengths were likely inflated. Sequence-identical viral genomes were marked with (*) and (**)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Walensky RP, et al. The survival benefits of AIDS treatment in the United States. J. Infect. Dis. 2006;194:11–19. doi: 10.1086/505147. - DOI - PubMed
    1. Finzi D, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278:1295–1300. doi: 10.1126/science.278.5341.1295. - DOI - PubMed
    1. Wong JK, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997;278:1291–1295. doi: 10.1126/science.278.5341.1291. - DOI - PubMed
    1. Chun T-WW, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 1997;94:13193–13197. doi: 10.1073/pnas.94.24.13193. - DOI - PMC - PubMed
    1. Siliciano JD, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat. Med. 2003;9:727–728. doi: 10.1038/nm880. - DOI - PubMed

Publication types

MeSH terms