Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth

Brumme, Zabrina L.; Sudderuddin, Hanwei; Ziemniak, Carrie; Luzuriaga, Katherine; Jones, Bradley R.; Joy, Jeffrey B.; Cunningham, Coleen K.; Greenough, Thomas C.; Persaud, Deborah

doi:10.1097/qad.0000000000002045

Cited by 18 publications

(21 citation statements)

References 44 publications

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“…7D. Consistent with previous reports (15), these examples also reveal that HLA-susceptible and -adapted forms of the same CTL epitope commonly coexist in the reservoir: 6 of the 9 subtype B-infected individuals harbored at least one epitope where this occurred.…”

Section: Figsupporting

confidence: 90%

“…There, they can persist long term within either the original infected cell or clonal descendants thereof (7)(8)(9)(10). Much of our understanding of HIV persistence is derived from HIV sequences isolated from blood during long-term cART; these studies have revealed that the within-host HIV reservoir is genetically diverse (11)(12)(13), that it frequently contains immune escape mutations (14,15), and that it commonly features clonally expanded cell populations harboring identical proviruses (10,(16)(17)(18)(19).…”

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confidence: 99%

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HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy

Miller

Ponte

Jones

et al. 2019

J Virol

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HIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune-privileged tissues, such as the testes, may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed the proviral burden and genetics in the blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by quantitative PCR, and subgenomic proviral sequences (nef region) were characterized from single templates. HIV diversity, compartmentalization, and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from the blood (396 sequences; 354 nef-intact sequences) and testes (326 sequences; 309 nef-intact sequences) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and the immune escape burden correlated positively between blood and testes. When all intact nef sequences were evaluated, 60% of participants exhibited significant blood-testis genetic compartmentalization, but none did so when the evaluation was restricted to unique sequences per site, suggesting that compartmentalization, when present, is attributable to the clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testis reservoirs. Furthermore, while the testis microenvironment may not be sufficiently unique to facilitate the seeding of unique viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication. IMPORTANCE Two key questions in HIV reservoir biology are whether immune-privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy and, if so, by what mechanism. While our results indicated that blood-testis HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood-tissue data set retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testis reservoirs differ is not via seeding of divergent HIV sequences therein but, rather, via differential clonal expansion of latently infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of a broadly similar magnitude across the blood and testes, clonal expansion represents a challenge. The results support individualized analysis of within-host reservoir diversity to inform curative approaches.

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confidence: 90%

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confidence: 99%

HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy

Miller

Ponte

Jones

et al. 2019

J Virol

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“…Another limitation of this study is that we only included ECs off ART. Thus, we could not match ECs to CPs based on their time on ART, nor did we match ECs to CPs based on their level of diversity or AUC of viremia because this is difficult to control for ( 15 – 17 , 55 , 56 ). Related to the very small reservoir size of ECs, there is limited data on the EC proviral landscape, especially on ART ( 27 , 57 – 59 ).…”

Section: Discussionmentioning

confidence: 99%

Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Pinzone¹,

Weissman²,

Pasternak³

et al. 2021

JCI Insight

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Historically, naive cells have been considered inconsequential to HIV persistence. Here, we compared the contribution of naive and memory cells to the reservoir of individuals with a spectrum of reservoir sizes and variable immunological control. We performed proviral sequencing of ~6000 proviruses from cellular subsets of 5 elite controllers (ECs) off antiretroviral therapy (ART) and 5 chronic progressors (CPs) on ART.The levels of naive infection were barely detectable in ECs and ~300-fold lower compared to CPs. Moreover, the ratio of infected naive to memory cells was significantly lower in ECs.Overall naive infection level increased as reservoir size increased such that naive cells were a major contributor to the intact reservoir of CPs, whose reservoirs were generally very diverse. In contrast, the reservoirs of ECs were dominated by proviral clones. Critically, the fraction of proviral clones increased with cell differentiation, with naive infection predicting reservoir diversity. Longitudinal sequencing revealed that the reservoir of ECs was less dynamic compared to CPs.Naive cells play a critical role in HIV persistence. Their infection level predicts reservoir size and diversity. Moreover, the diminishing diversity of the reservoir as cellular subsets mature suggests that naive T cells repopulate the memory compartment and that direct infection of naive T cells occurs in vivo.

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“…Replication by blood-stage Plasmodium parasites also involves significant epigenetic changes, which are reversed during passage through the mosquito, further underscoring the importance of transmission in counteracting the potentially detrimental effects of within-host selection [34, 35]. This reversal of short-sighted evolution by transmission does require that transmissible varaints not be completely displaced during infection, suggesting that maintaining diversity in a latent viral reservoir [36, 37] or by continuous genetic exchange during colonization [38, 39] are important for ensuring future transmissibility.…”

Section: Discussionmentioning

confidence: 99%

Competitive exclusion strengthens selection for transmissibility and increases the benefit of recombination for within-host adaptation

Jacobs

Weiser

2020

Preprint

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10Pathogens experience selection at multiple scales, given the need to transmit between hosts 11 and replicate within them. This presents the challenge of cross-scale selective conflict when 12 adaptations to one scale compromise fitness at another, such as mutations that improve 13 transmissibility but make individuals less competitive within hosts. Selection operates differently 14 at these scales, with tight transmission bottlenecks subjecting pathogen populations to genetic drift, 15 and large population sizes within hosts enabling efficient selection for beneficial mutations.16 Compounding the reduction in diversity by transmission bottlenecks is the occupant-intruder 17 competitive strategy exhibited by some pathogens, where the first variant to colonize a host 18 prevents later arriving variants from contributing to infection, preventing immigration and turning 19 transmission into a "founder takes all" contest. Here, we used multiple modeling approaches to 20 examine how this behavior affects the efficiency of selection for both transmissibility and within-21 host fitness. We find that in the face of a trade-off, selection for transmissibility is maximized 22 under a tight transmission bottleneck that minimizes within-host competition during colonization. 23 While mutations with increased within-host fitness are favored during within-host replication, an 24 occupant-intruder strategy prevents these mutants from displacing established residents and 25 propagating across the host population, leading to their extinction if they are insufficiently 26 transmissible. Finally, a model of competition on the scale of the host population revealed that 27 competitive exclusion limits the propagation of mutations with improved within-host fitness, 28 unless resident populations can incorporate alleles from intruding variants by recombination. Thus, 29 competitive exclusion may facilitate the improvement and maintenance of pathogen 30 transmissibility, with directional recombination allowing resident populations to mitigate the 31 potential loss of within-host fitness imposed by this occupant-intruder strategy. 32 Author Summary 33 Transmission is a defining feature of infectious diseases, and so a better understanding of how 34 transmissibility evolves is important for improving disease surveillance and prevention. Successful 35 transmission is often achieved by a small number of individuals which, after establishing residency 36 in a host, may prevent newcomers from participating in infection. Here, we use modeling to 37 examine how competitive exclusion of challengers by resident populations affects the balance 38 between within-host competitive ability and transmissibility. We find that competitive exclusion 39 strengthens selection for transmissibility by disproportionately benefitting the first variant to 40 colonize a host and preventing mutants that may be more competitive but less transmissible from 41 displacing established residents. Competitive exclusion also limits the propagation of mutants that 42 impro...

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Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth

Cited by 18 publications

References 44 publications

HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy

HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy

Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Competitive exclusion strengthens selection for transmissibility and increases the benefit of recombination for within-host adaptation

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