HLA-associated polymorphisms in the HIV-2 capsid highlight key differences between HIV-1 and HIV-2 immune adaptation

Silva, Thushan I. de; Leligdowicz, Aleksandra; Carlson, Jonathan M.; Garcia-Knight, Miguel; Onyango, Clayton; Miller, Nicholas; Yindom, L M; Hué, Stéphane; Jaye, Assan; Dong, Tao; Cotten, Matthew; Rowland‐Jones, Sarah

doi:10.1097/qad.0000000000001753

Cited by 6 publications

(7 citation statements)

References 29 publications

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“…In our analysis, HIV-2 nonsynonymous evolutionary rates are an order of magnitude lower than the synonymous rates. Findings from a study of interhost evolution of HIV-2 p26 , showed little evidence of positive selection in HIV-2 p26 evolution (49). This is surprising as strong Gag-specific CTL responses are common in HIV-2 long-term non-progressors (55).…”

Section: Discussionmentioning

confidence: 99%

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Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

Boswell

Nazziwa

Kuroki

et al. 2021

Preprint

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Background: HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression. Methods: Twelve treatment-naive, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures. Results: In total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28-37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (rho = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5 alpha/p26 hexamer interface surface. Conclusions: Faster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target.

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Section: Discussionmentioning

confidence: 99%

“…We investigated whether the signature amino acid variants identified by the VESPA analysis were associated with disease progression markers in a larger, external cohort. This was done by testing the association of these p26 amino acid variants with CD4% and HIV-2 plasma viral loads in 86 HIV-2 positive participants from the Caio cohort (23,49).…”

Section: Methodsmentioning

confidence: 99%

Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

Boswell

Nazziwa

Kuroki

et al. 2021

Preprint

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“…Despite the increased sensitivity of HIV-2 capsid to TRIM5α restriction, as well as the strong cytotoxic T cell response directed towards gag, there is no evidence of positive selection pressure on gag divergence in a crosssectional analysis of viral sequences from the Caió community cohort [59]. Purifying selection pressure predominates in interhost evolution, and this reflects the constrained evolution of this gene.…”

Section: The Importance Of Gagmentioning

confidence: 93%

“…The interaction between the viral capsid, host restriction factors and the cellular immune response may be central to maintaining durable control of viral replication in HIV-2 infection. HIV-2-specific CTL may be able to control viral replication and maintain a low level of immune activation for many years, without the emergence of viral escape mutants [59]. During this process, HIV-2 capsids enriched in proline residues may favour the efficient processing of CTL epitopes that are associated with a long-lasting, protective gag-specific CTL response.…”

Section: Conclusion: Possible Causal Factors Which Promote Hiv-2 Disementioning

confidence: 99%

“…In aviraemic patients this CTL response may potentially be maintained by ongoing, low-level mucosal replication in the gut. HIV-2-specific CTL may be able to control viral replication and maintain a low level of immune activation for many years, without the emergence of viral escape mutants [59]. A caveat to the search for a functional cure is that therapies which maintain a low viral load may not always result in a reversal of immunodeficiency if immune activation remains high [106].…”

Section: Conclusion: Possible Causal Factors Which Promote Hiv-2 Disementioning

confidence: 99%

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Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

Boswell

Rowland‐Jones

2019

Clinical and Experimental Immunology

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HIV-2 is thought to have entered the human population in the 1930s through cross-species transmission of SIV from sooty mangabeys in West Africa. Unlike HIV-1, HIV-2 has not led to a global pandemic, and recent data suggest that HIV-2 prevalence is declining in some West African states where it was formerly endemic. Although many early isolates of HIV-2 were derived from patients presenting with AIDS-defining illnesses, it was noted that a much larger proportion of HIV-2-infected subjects behaved as long-term non-progressors (LTNP) than their HIV-1-infected counterparts. Many HIV-2-infected adults are asymptomatic, maintaining an undetectable viral load for over a decade. However, despite lower viral loads, HIV-2 progresses to clinical AIDS without therapeutic intervention in most patients. In addition, successful treatment with anti-retroviral therapy (ART) is more challenging than for HIV-1. HIV-2 is significantly more sensitive to restriction by host restriction factor tripartite motif TRIM5α than HIV-1, and this difference in sensitivity is linked to differences in capsid structure. In this review we discuss the determinants of HIV-2 disease progression and focus on the important interactions between TRIM5α and HIV-2 capsid in long-term viral control.

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Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

et al. 2022

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Background HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. Methods Twelve treatment-naïve, HIV-2 positive participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data were included in the analysis. CD4% change over time was analysed to stratify participants into relative faster and slower progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Results In total, 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 (IQR: 28–37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors – synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. Conclusions p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.

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HLA-associated polymorphisms in the HIV-2 capsid highlight key differences between HIV-1 and HIV-2 immune adaptation

Abstract: Supplemental Digital Content is available in the text

Cited by 6 publications

References 29 publications

Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

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