HIV-1 subtype distribution in the Gambia and the significant presence of CRF49_cpx, a novel circulating recombinant form

Silva, Thushan I. de; Turner, R. H.; Hué, Stéphane; Trikha, Roochi; Tienen, Carla van; Onyango, Clayton; Jaye, Assan; Foley, Brian; Whittle, Hilton; Rowland‐Jones, Sarah; Cotten, Matthew

doi:10.1186/1742-4690-7-82

Cited by 12 publications

(10 citation statements)

References 35 publications

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“…The V3 domain is a potentially sensitive neutralization domain that is known to be highly sensitive to conformational masking by the V1/V2 region (8,51). The sensitivities of MW965 Env and a control clade C Env, ConC Env, to neutralization by standard V3-specific antibodies were initially compared for four V3-specific MAbs (19,23,59,60), and representative neutralization curves are shown in Fig. 1A.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates

Qualls

Honnen

Prattipati

et al. 2018

J Virol

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The subtype C HIV-1 isolate MW965.26 is a highly neutralization-sensitive tier 1a primary isolate that is widely used in vaccine studies, but the basis for the sensitive neutralization phenotype of this isolate is not known. Substituting the MW965.26 V1/V2 domain into a neutralization-sensitive SF162 Env clone resulted in high resistance to standard anti-V3 monoclonal antibodies, demonstrating that this region possesses strong masking activity in a standard Env backbone and indicating that determinants elsewhere in MW965.26 Env are responsible for its unusual neutralization sensitivity. Key determinants for this phenotype were mapped by generating chimeric Envs between MW965.26 Env and a typical resistant Env clone, the consensus C (ConC) clone, and localized to two residues, Cys384 in the C3 domain and Asn502 in the C5 domain. Substituting the sensitizing mutations Y384C and K502N at these positions into several resistant primary Envs resulted in conversion to neutralization-sensitive phenotypes, demonstrating the generalizability of this effect. In contrast to the sensitizing effects of these substitutions on normally masked epitopes, these mutations reduced the sensitivity of VRC01-like epitopes overlapping the CD4-binding domain, while they had no effect on several other classes of broadly neutralizing epitopes, including members of several lineages of V2-dependent quaternary epitopes and representatives of N332 glycan-dependent epitopes (PGT121) and quaternary, cleavage-dependent epitopes centered at the gp41-gp120 interface on intact HIV-1 Env trimers (PGT151). These results identify novel substitutions in gp120 that regulate the expression of alternative conformations of Env and differentially affect the exposure of different classes of epitopes, thereby influencing the neutralization phenotype of primary HIV-1 isolates. A better understanding of the mechanisms that determine the wide range of neutralization sensitivity of circulating primary HIV-1 isolates would provide important information about the natural structural and conformational diversity of HIV-1 Env and how this affects the neutralization phenotype. A useful way of studying this is to determine the molecular basis for the unusually high neutralization sensitivities of the limited number of available tier 1a viruses. This study localized the neutralization sensitivity of MW965.26, an extremely sensitive subtype C-derived primary isolate, to two rare substitutions in the C3 and C5 domains and demonstrated that the sequences at these positions differentially affect the presentation of epitopes recognized by different classes of standard and conformation-dependent broadly neutralizing antibodies. These results provide novel insight into how these regions regulate the neutralization phenotype and provide tools for controlling the Env conformation that could have applications both for structural studies and in vaccine design.

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Section: Resultsmentioning

confidence: 99%

Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates

Qualls

Honnen

Prattipati

et al. 2018

J Virol

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“…The pervasive recombination of the HIV-1 at the early stages of the group M epidemic generated a large array of complex CRFs at the epicenter in Central Africa that usually circulates at low prevalence [5–15]. In this study, we compile a quite large number of HIV-1 pol and env sequences from four complex recombinants (CRF09_cpx, CRF11_cpx, CRF13_cpx and CRF45_cpx) displaying unique mosaic structures in pol and a common subtype A fragment in env and estimate their onset dates.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the complex CRFs (including CRF04_cpx [5], CRF06_cpx [6], CRF09_cpx [7], CRF11_cpx [8], CRF13_cpx [9], CRF18_cpx [10], CRF25_cpx [11], CRF27_cpx [12], CRF37_cpx [13], CRF45_cpx [14] and CRF49_cpx [15]) carry fragments of rare subtypes (e.g., subtypes H, J and K) and divergent unclassified (U) lineages likely derived from parental strains that may predate the current subtypes [16]. Some of these complex CRFs are widely dispersed in a given African region and reaching particularly high prevalence (40–50%) in certain countries, such as the CRF06_cpx in Burkina Faso [17] and the CRF11_cpx in the Central African Republic [18].…”

Section: Introductionmentioning

confidence: 99%

“…Some of these complex CRFs are widely dispersed in a given African region and reaching particularly high prevalence (40–50%) in certain countries, such as the CRF06_cpx in Burkina Faso [17] and the CRF11_cpx in the Central African Republic [18]. Others complex CRFs circulate at a very low prevalence (<5%) throughout several countries from West (CRF09_cpx and CRF49_cpx) [15, 17, 19–21] and Central (CRF13_cpx, CRF45_cpx) [22–25] Africa. The remaining of those complex CRFs were sporadically detected in Africa, but have successfully disseminated to other locations, as the CRF04_cpx in Greece and Cyprus [26, 27] and the CRF18_cpx in Cuba [10].…”

Section: Introductionmentioning

confidence: 99%

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Time-scale of minor HIV-1 complex circulating recombinant forms from Central and West Africa

Delatorre

Bello

2016

BMC Evol Biol

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BackgroundSeveral HIV-1 circulating recombinant forms with a complex mosaic structure (CRFs_cpx) circulate in central and western African regions. Here we reconstruct the evolutionary history of some of these complex CRFs (09_cpx, 11_cpx, 13_cpx and 45_cpx) and further investigate the dissemination dynamic of the CRF11_cpx clade by using a Bayesian coalescent-based method.ResultsThe analysis of two HIV-1 datasets comprising 181 pol (36 CRF09_cpx, 116 CRF11_cpx, 20 CRF13_cpx and 9 CRF45_cpx) and 125 env (12 CRF09_cpx, 67 CRF11_cpx, 17 CRF13_cpx and 29 CRF45_cpx) sequences pointed to quite consistent onset dates for CRF09_cpx (~1966: 1958–1979), CRF11_cpx (~1957: 1950–1966) and CRF13_cpx (~1965: 1958–1973) clades; while some divergence was found for the estimated date of origin of CRF45_cpx clade [pol = 1970 (1964–1976); env = 1960 (1952–1969)]. Phylogeographic reconstructions indicate that the HIV-1 CRF11_cpx clade most probably emerged in Cameroon and from there it was first disseminated to the Central Africa Republic and Chad in the early 1970s and to other central and western African countries from the early 1980s onwards. Demographic reconstructions suggest that the CRF11_cpx epidemic grew between 1960 and 1990 with a median exponential growth rate of 0.27 year−1, and stabilized after.ConclusionsThese results reveal that HIV-1 CRFs_cpx clades have been circulating in Central Africa for a period comparable to other much more prevalent HIV-1 group M lineages. Cameroon was probably the epicenter of dissemination of the CRF11_cpx clade that seems to have experienced a long epidemic growth phase before stabilization. The epidemic growth of the CRF11_cpx clade was roughly comparable to other HIV-1 group M lineages circulating in Central Africa.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0824-8) contains supplementary material, which is available to authorized users.

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“…Three new V3 mAbs isolated in the Robinson laboratory, 5.8C, 1.4E and 7.1C, were included in this study. 5.8C was derived from an HIV-1 infected patient from Malawi, where the dominant serotype is subtype C. 1.4E was derived from Gambia patient N036703, where several CRF strains along with subtype C and A are common (de Silva et al, 2010). 7.1C was obtained from a subject in South Africa, where subtype C is dominant.…”

Section: Methodsmentioning

confidence: 99%

Specific sequences commonly found in the V3 domain of HIV-1 subtype C isolates affect the overall conformation of native Env and induce a neutralization-resistant phenotype independent of V1/V2 masking

et al. 2014

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Primary HIV-1 isolates are relatively resistant to neutralization by antibodies commonly induced after infection or vaccination. This is generally attributed to masking of sensitive epitopes by the V1/V2 domain and/or glycans situated at various positions in Env. Here we identified a novel masking effect mediated by subtype C-specific V3 sequences that contributes to the V1/V2-independent and glycan-independent neutralization resistance of chimeric and primary Envs to antibodies directed against multiple neutralization domains. Positions at several conserved charged and hydrophobic sites in the V3 crown and stem were also shown to affect neutralization phenotype. These results indicated that substitutions typically present in subtype C and related V3 sequences influence the overall conformation of native Env in a way that occludes multiple neutralization targets located both within and outside of the V3 domain, and may reflect an alternative mechanism for neutralization resistance that is particularly active in subtype C and related isolates.

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HIV-1 subtype distribution in the Gambia and the significant presence of CRF49_cpx, a novel circulating recombinant form

Cited by 12 publications

References 35 publications

Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates

Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates

Time-scale of minor HIV-1 complex circulating recombinant forms from Central and West Africa

Specific sequences commonly found in the V3 domain of HIV-1 subtype C isolates affect the overall conformation of native Env and induce a neutralization-resistant phenotype independent of V1/V2 masking

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