HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression

Ng, Oon Tek; Laeyendecker, Oliver; Redd, Andrew D.; Munshaw, Supriya; Grabowski, M Kate; Paquet, Agnès; Evans, Mark C.; Haddad, Mojgan; Huang, Wei; Robb, Merlin L.; Reynolds, Steven J.; Gray, Ronald H.; Wawer, Maria J.; Serwadda, David; Eshleman, Susan H.; Quinn, Thomas C.

doi:10.1093/infdis/jit425

Cited by 18 publications

(24 citation statements)

References 22 publications

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“…However, there are conflicting reports of the disease progression rate of subtype C relative to that of subtypes A and D (12,(15)(16)(17)59). Nevertheless, overall, our data suggest that the lower Gag-protease-driven replication capacity of subtypes A and C (in addition to the lower Pol-driven replication capacity for subtype A [35]) may contribute to slower disease progression in individuals infected with these subtypes. The associated increased longevity is expected to result in greater opportunity for transmission (17) and hence in an increased prevalence of these subtypes.…”

Section: Discussionmentioning

confidence: 73%

“…Furthermore, biological differences between subtype C and subtype B and/or other subtypes in the Env (29), reverse transcriptase (30), protease (31), Vif (32), and long terminal repeat (LTR) regions (33,34) have been reported; however, the implications of these factors for disease progression and epidemic spread remain unclear. More recently, a study of Ͼ100 clinical isolates showed that subtype D had higher Pol-driven replication capacity than subtype A and directly linked these differences to faster disease progression in the former than in the latter subtype (35). Furthermore, we recently demonstrated subtype-specific differ-ences in Nef function (36) and showed that Nef functional differences in acute infection correlate with markers of disease progression (37).…”

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confidence: 95%

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Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

Kiguoya

Mann

Chopera

et al. 2017

J Virol

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There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates (r ϭ 0.51; P ϭ 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-proteasedriven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases (P Ͻ 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C Ͻ D Ͻ intersubtype recombinants (P Ͻ 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gagprotease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes.IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with Citation Kiguoya MW, Mann JK, Chopera D, Gounder K, Lee GQ, Hunt PW, Martin JN, Ball TB, Kimani J, Brumme ZL, Brockman MA, Ndung'u T. 2017. Subtype-specific differences in Gagprotease-driven replication capacity are consistent with intersubtype differences in HIV-1 disease progression. J Virol 91:e00253-17.

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Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 95%

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

Kiguoya

Mann

Chopera

et al. 2017

J Virol

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“…While our study focusses on the subtype based differences in the Env glycoprotein, the role of other viral proteins like Pol and Gag in this phenomenon cannot be overlooked. Ng et al described that polymorphisms in the pol gene were responsible for differences in replication capacity and disease progression in subtype A and D HIV infected individuals in Uganda (Ng et al, 2014). Similarly, Clairborne et al attributed the early T-cell activation and immune dysfunction in HIV infected Zambians to the replicative fitness of the transmitted virus with the gag gene contributing significantly to the phenomenon (Claiborne et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites

et al. 2017

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HIV subtypes not only predominate in different geographical regions but also differ in key phenotypic characteristics. To determine if genotypic and/or phenotypic differences in the Envelope (Env) glycoprotein can explain subtype related differences, we cloned 37 full length Envs from Subtype B and AE HIV infected individuals from Singapore. Our data demonstrates that CRF01_AE Envs have lower Potential N Glycosylation Sites and higher risk of X4 development. Phenotypically, CRF01_AE were less infectious than subtype B Envs in cells expressing low levels of CCR5. Moreover, the Maraviroc IC50 was higher for subtype B Envs and correlated with infectivity in low CCR5 expressing cells as well as PNGS. Specifically, the glycosylation site N301 in the V3 loop was seen less frequently in AE subtype and CXCR4 topic viruses. CRF01_AE differs from B subtype in terms of CCR5 usage and Maraviroc susceptibility which may have implications for HIV pathogenesis and virus evolution.

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“…Previous studies identified a valine instead of an isoleucine at position 62 and 64 in the protease (I62V and I64V), and a proline instead of an alanine at position 272 in the reverse transcriptase as amino acid substitutions that could be associated with perparasite pathogenicity (Ng et al, 2014) (see the Result section for more details). To test for associations of per-parasite pathogenicity with the substitutions I62V, I64V, and A272P, we regressed per-parasite pathogenicty, but also the other two traits, set-point viral load and CD4+ T cells decline, against categorical variables indicating the presence of the mutated amino acid at the respective position.…”

Section: Testing For Genetic Associations With Per-parasite Pathogenimentioning

confidence: 99%

“…These intersubtype difference in disease progression have been mapped to the pol gene and were associated with replicative capacity (Ng et al, 2014). In particular, a valine instead of an isoleucine at position 62 and 64 in the protease (I62V and I64V), and a proline instead of an alanine at position 272 in the reverse transcriptase were found to be associated with high replicative capacity (Ng et al, 2014) We tested if these amino acid polymorphisms are associated with set-point viral load, CD4+ T cell decline, and per-parasite pathogenicity within HIV-1 subtype B. Indeed isoleucine and valine at positions 62 and 64 of the protease, and alanine and proline at position 272 in the reverse transcriptase were the most prevalent amino acids in our study population.…”

Section: Testing For Genetic Associations With Per-parasite Pathogenimentioning

confidence: 99%

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T Cell Decline and Per-Parasite Pathogenicity

Bertels

Marzel

Leventhal

et al. 2017

Preprint

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Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as "per-parasite pathogenicity". Using viral load and CD4þ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence-measured as the rate of decline of CD4þ T cells-and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4þ T-cell declines and perparasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4þ T-cell decline is 17% (5-30%), and that of the per-parasite pathogenicity is 17% (4-29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12-46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4þ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

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HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression

Abstract: HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms.

Cited by 18 publications

References 22 publications

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T Cell Decline and Per-Parasite Pathogenicity

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