HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels

Eller, Michael A.; Opollo, Marc Sam; Liu, Meilin; Redd, Andrew D.; Eller, Leigh Anne; Kityo, Cissy; Kayiwa, Joshua; Laeyendecker, Oliver; Wawer, Maria J.; Milazzo, Mark; Kiwanuka, Noah; Gray, Ronald H.; Serwadda, David; Sewankambo, Nelson; Quinn, Thomas C.; Michael, Nelson L.; Wâbwire-Mângen, Fred; Sandberg, Johan K.; Robb, Merlin L.

doi:10.1093/infdis/jiu646

Cited by 18 publications

(17 citation statements)

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“…Second, it suggests that HIV subtype studies on disease progression and clinical impacts could be biased depending on the genomic region used for subtyping. For instance, numerous studies reported that subtype D infections (by pol ) as being more aggressive with a faster disease progression [20–22]. However, in our current report, multiple patients had subtype D in pol , but A1 in GP41.…”

Section: Discussioncontrasting

confidence: 70%

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches

Lee¹,

Bangsberg²,

et al. 2017

Aids

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Objectives To estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with HIV-1 intersubtype recombination under a full-genome sequencing context in a rural community in Mbarara, Uganda, where HIV-1 subtypes A1 and D co-circulate. Methods Near-full-genome HIV-1 Sanger sequence data was collected from plasma samples of 504 treatment-naïve individuals, who then received PI or NNRTI-containing regimens and were monitored for up to 7.5 years. Subtypes were inferred by Los Alamos RIP 3.0 and compared with Sanger/REGA and MiSeq/RIP. “Non-recombinants” and “recombinants” infections were compared in terms of pre-therapy viral load, CD4 count, post-therapy time to virologic suppression, virologic rebound, first CD4 rise above baseline and sustained CD4 recovery. Results Prevalence of intersubtype recombinants varied depending on the genomic region examined: gag (15%), prrt (11%), int (8%), vif (10%), vpr (2%), vpu (9%), GP120 (8%), GP41 (18%), and nef (4%). Of the 200 patients with near-full-genome data, prevalence of intersubtype recombination was 46%; the most frequently observed recombinant was A1-D (25%). Sanger/REGA and MiSeq/RIP yielded generally consistent results. Phylogenetic tree revealed most recombinants did not share common ancestors. No temporal trend was observed (all p>0.1). Subsequent subtype switches were detected in 27 of 143 (19%) subjects with follow-up sequences. Non-recombinant versus recombinants infections were not significantly different in any pre- nor post-therapy clinical correlates examined (all p>0.2). Conclusion Intersubtype recombination was highly prevalent (46%) in Uganda if the entire HIV genome was considered, but was not associated with clinical correlates nor therapy outcomes.

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Section: Discussioncontrasting

confidence: 70%

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches

Lee¹,

Bangsberg²,

et al. 2017

Aids

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“…HIV-1 subtype A1 was predominant in the study children—representing 62.5% and 76.2% of all isolates as determined by the nef and gag sequences, respectively—followed by subtypes D and C. Some samples showed discordant subtypes between the nef and gag sequences, suggesting that the children were infected with recombinant viruses. A study in Uganda described a correlation between HIV-1 subtype D infection and rapid disease progression in adults, although HIV-1 load appeared to be the primary determinant [ 37 ]. However, our present findings indicated that subtype distribution did not significantly differ between the rapid and slow progressors.…”

Section: Discussionmentioning

confidence: 99%

Comparison of HIV-1 nef and gag Variations and Host HLA Characteristics as Determinants of Disease Progression among HIV-1 Vertically Infected Kenyan Children

Saina

Lihana

et al. 2015

PLoS ONE

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ObjectivesDisease progression varies among HIV-1-infected individuals. The present study aimed to explore possible viral and host factors affecting disease progression in HIV-1-infected children.MethodsSince 2000, 102 HIV-1 vertically-infected children have been followed-up in Kenya. Here we studied 29 children (15 male/14 female) who started antiretroviral treatment at <5 years of age (rapid progressors; RP), and 32 (17 male/15 female) who started at >10 years of age (slow progressors; SP). Sequence variations in the HIV-1 gag and nef genes and the HLA class I-related epitopes were compared between the two groups.ResultsBased on nef sequences, HIV-1 subtypes A1/D were detected in 62.5%/12.5% of RP and 66.7%/20% of SP, with no significant difference in subtype distribution between groups (p = 0.8). In the ten Nef functional domains, only the PxxP3 region showed significantly greater variation in RP (33.3%) than SP (7.7%, p = 0.048). Gag sequences did not significantly differ between groups. The reportedly protective HLA-A alleles, A*74:01, A*32:01 and A*26, were more commonly observed in SP (50.0%) than RP (11.1%, p = 0.010), whereas the reportedly disease-susceptible HLA-B*45:01 was more common in RP (33.3%) than SP (7.4%, p = 0.045). Compared to RP, SP showed a significantly higher median number of predicted HLA-B-related 12-mer epitopes in Nef (3 vs. 2, p = 0.037), HLA-B-related 11-mer epitopes in Gag (2 vs. 1, p = 0.029), and HLA-A-related 9-mer epitopes in Gag (4 vs. 1, p = 0.051). SP also had fewer HLA-C-related epitopes in Nef (median 4 vs. 5, p = 0.046) and HLA-C-related 11-mer epitopes in Gag (median 1 vs. 1.5, p = 0.044) than RP.ConclusionsCompared to rapid progressors, slow progressors had more protective HLA-A alleles and more HLA-B-related epitopes in both the Nef and Gag proteins. These results suggest that the host factor HLA plays a stronger role in disease progression than the Nef and Gag sequence variations in HIV-1-infected Kenyan children.

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“…However, to the best of our knowledge, the predictive value of CA RNA for the response to ART has not yet been reported. Likewise, CD4 + count and plasma VL are firmly established as independent predictors of disease progression in the absence of treatment (7)(8)(9), and studies have reported an independent predictive value of total HIV-1 DNA for disease progression (10)(11)(12)(13). However, no study has directly compared plasma VL and CA HIV-1 RNA for the prediction of the rate of CD4 + T cell decline in the setting of untreated HIV-1 infection.…”

Section: Introductionmentioning

confidence: 99%

Cell-associated HIV-1 RNA predicts viral rebound and disease progression after discontinuation of temporary early ART

Pasternak¹,

Grijsen²,

Wit³

et al. 2020

JCI Insight

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HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels

Cited by 18 publications

References 50 publications

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches

Comparison of HIV-1 nef and gag Variations and Host HLA Characteristics as Determinants of Disease Progression among HIV-1 Vertically Infected Kenyan Children

Cell-associated HIV-1 RNA predicts viral rebound and disease progression after discontinuation of temporary early ART

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