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. 2015 Sep 15;212(6):904-8.
doi: 10.1093/infdis/jiv136. Epub 2015 Mar 9.

HIV-1 Superinfection Resembles Primary Infection

Daniel J Sheward  1 , Roman Ntale  2 , Nigel J Garrett  3 , Zenda L Woodman  4 , Salim S Abdool Karim  5 , Carolyn Williamson  6
Affiliations

HIV-1 Superinfection Resembles Primary Infection

Daniel J Sheward et al. J Infect Dis. .

Abstract

The relevance of superinfection as a model to identify correlates of protection against human immunodeficiency virus (HIV) depends on whether the superinfecting transmission resembles primary infection, which has not been established. Here, we characterize the genetic bottleneck in superinfected individuals for the first time. In all 3 cases, superinfection produced a spike in viral load and could be traced to a single, C-C chemokine receptor 5-tropic founder virus with shorter, less glycosylated variable regions than matched chronic viruses. These features are consistent with primary HIV transmission and provide support for the use of superinfection as a model to address correlates of protection against HIV.

Keywords: HIV; T/F; correlates of protection; founder; superinfection; transmitted.

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Figures

Figure 1.
Figure 1.
Identification of the transmitted/founder superinfecting envelopes, before recombination with the primary virus. A, Maximum likelihood phylogeny depicting the presence of 2 strains separated phylogenetically by epidemiologically unlinked viruses in participants CAP237 (circles), CAP256 (triangles), and CAP281 (squares). The phylogeny was reconstructed using env sequences from CAP237, CAP256, CAP281 along with 58 subtype C sequences from 30 individuals, including 24 participants from the CAPRISA [Centre for the AIDS Programme of Research in South Africa] 002 cohort. B–D, Viral load (solid black lines) and CD4 cell counts (dotted gray lines) over time are shown for the 3 superinfected participants: CAP237 (B), CAP256 (C), and CAP281 (D). The limit of detection for the viral load assay was 400 copies/mL. In each case, the detection (+) or absence (−) of the superinfecting virus in sequences from single-genome amplification (SGA) and strain-specific polymerase chain reaction (ssPCR) is indicated. The estimated window of superinfection is shown, based on the 95% confidence interval for the estimated time since a most recent common ancestor (tMRCA) for the early (nonrecombinant) superinfecting viral sequences. ART, initiation of antiretroviral therapy. E–G, Similarity of the consensus of the early superinfecting env sequences from CAP237 (E), CAP256 (F), and CAP281 (G), to sequences from an alignment of subtype C sequences (including sequences from the CAPRISA 002 cohort and the primary infecting viruses). Over all windows (100–base pair [bp] windows with a 5-bp shift), the superinfecting viruses are not more similar to the primary virus (black line) than would be expected for unlinked sequences (gray lines), indicating the absence of recombinant regions inherited from the primary virus. Insets depict highlighter plots of the early single-genome env sequences of the superinfecting viral populations indicative of a “star” phylogeny of near identical sequences in each case.
Figure 2.
Figure 2.
Superinfecting (SI) transmitted/founder viruses have envelopes with shorter (A), less glycosylated (B) variable regions than do viruses sampled 3 years after infection. *P < .05; †P < .01. Abbreviation: PNLGs, potential N-linked glycosylation sites.
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