Patterns and rates of viral evolution in HIV-1 subtype B infected females and males

Dapp, Michael J.; Kober, Kord M.; Chen, Lennie; Westfall, Dylan H.; Wong, Kim; Zhao, Hong; Hall, Breana; Deng, Wenjie; Sibley, Thomas H.; Ghorai, Suvankar; Kim, Katie; Chen, Natalie; McHugh, Sarah; Au, Lily; Cohen, Mardge H.; Anastos, Kathryn; Mullins, James I.

doi:10.1371/journal.pone.0182443

Cited by 20 publications

(41 citation statements)

References 108 publications

(148 reference statements)

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“…Next we looked at absolute nonsynonymous and synonymous substitution rates at the within-host level. Estimated rates of within-host viral evolution varied considerably among individuals ( Fig 2 ), and were consistent with previous measures of within-host rates of viral evolution for subtype B infected individuals in gag [ 4 ] and the gp120 region of env [ 4 – 6 ]. The comparatively large uncertainty in the estimates of within-host evolutionary rates are most likely due to the short gene regions analyzed and lower rates of evolution compared to gp120.…”

Section: Resultssupporting

confidence: 85%

“…To understand the natural history of within-host HIV-1 infection, historical samples from untreated individuals are needed. The few datasets that exist, where multiple (>2) within-host sequenced samples are available, including from early infection, and spanning years rather than months, include nine subtype B individuals from North America [ 1 ], ten individuals from Europe, where eight were infected with subtype B, and two were infected with subtypes C and AE, respectively [ 2 , 3 ], and four female individuals from North America infected with subtype B [ 4 ]. Here, we add considerably to this small but important body of data by presenting longitudinal deep-sequencing data from 34 untreated individuals living in Rakai, Uganda, representing infection with pure subtypes A and D, and a variety of inter-subtype recombinants, thus expanding both the geographical regions and the viral subtypes for which data are available.…”

Section: Introductionmentioning

confidence: 99%

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Evolution of HIV-1 within untreated individuals and at the population scale in Uganda

et al. 2018

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HIV-1 undergoes multiple rounds of error-prone replication between transmission events, resulting in diverse viral populations within and among individuals. In addition, the virus experiences different selective pressures at multiple levels: during the course of infection, at transmission, and among individuals. Disentangling how these evolutionary forces shape the evolution of the virus at the population scale is important for understanding pathogenesis, how drug- and immune-escape variants are likely to spread in populations, and the development of preventive vaccines. To address this, we deep-sequenced two regions of the HIV-1 genome (p24 and gp41) from 34 longitudinally-sampled untreated individuals from Rakai District in Uganda, infected with subtypes A, D, and inter-subtype recombinants. This dataset substantially increases the availability of HIV-1 sequence data that spans multiple years of untreated infection, in particular for different geographical regions and viral subtypes. In line with previous studies, we estimated an approximately five-fold faster rate of evolution at the within-host compared to the population scale for both synonymous and nonsynonymous substitutions, and for all subtypes. We determined the extent to which this mismatch in evolutionary rates can be explained by the evolution of the virus towards population-level consensus, or the transmission of viruses similar to those that establish infection within individuals. Our findings indicate that both processes are likely to be important.

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Section: Resultssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Evolution of HIV-1 within untreated individuals and at the population scale in Uganda

et al. 2018

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“…1e). These observations indicate strong molecular clock signal in the data, and are consistent with increases in root-to-tip divergence and population viral diversity that typify within-host HIV evolution [53,54].…”

Section: Resultssupporting

confidence: 75%

Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

et al. 2020

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The HIV accessory protein Nef downregulates the viral entry receptor CD4, the Human Leukocyte Antigen (HLA)-A and-B molecules, the Serine incorporator 5 (SERINC5) protein and other molecules from the infected cell surface, thereby promoting viral infectivity, replication and immune evasion. The nef locus also represents one of the most genetically variable regions in the HIV genome, and nef sequences undergo substantial evolution within a single individual over the course of infection. Few studies however have simultaneously characterized the impact of withinhost nef sequence evolution on Nef protein function over prolonged timescales. Here, we isolated 50 unique Nef clones by single-genome amplification over an 11-year period from the plasma of an individual who was largely naïve to antiretroviral treatment during this time. Together, these clones harbored nonsynonymous substitutions at 13% of nef's codons. We assessed their ability to downregulate cell-surface CD4, HLA and SERINC5 and observed that all three Nef functions declined modestly over time, where the reductions in CD4 and HLA downregulation (an average of 0.6% and 2.0% per year, respectively) achieved statistical significance. The results from this case study support all three Nef activities as being important to maintain throughout untreated HIV infection, but nevertheless suggest that, despite nef's mutational plasticity, within-host viral evolution can compromise Nef function, albeit modestly, over prolonged periods.

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“…KEYWORDS HIV, clonal expansion, diversity, genetic compartmentalization, reservoir, testes T he HIV reservoir, a small pool of primarily CD4 ϩ T cells that harbor replicationcompetent virus despite long-term suppressive combination antiretroviral therapy (cART) (1), is the major barrier to cure. During untreated infection, HIV populations evolve within the host (2)(3)(4)(5), and individual viral sequences are continually archived into the reservoir as integrated proviruses (6). There, they can persist long term within either the original infected cell or clonal descendants thereof (7)(8)(9)(10).…”

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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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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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Patterns and rates of viral evolution in HIV-1 subtype B infected females and males

Cited by 20 publications

References 108 publications

Evolution of HIV-1 within untreated individuals and at the population scale in Uganda

Evolution of HIV-1 within untreated individuals and at the population scale in Uganda

Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

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

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