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Low Multiplicity of HIV-1 Infection and No Vaccine Enhancement in VAX003 Injection Drug Users.

Sterrett S, Learn GH, Edlefsen PT, Haynes BF, Hahn BH, Shaw GM, Bar KJ - Open Forum Infect Dis (2014)

Bottom Line: This frequency of multiple virus transmission was greater than reported for heterosexual cohorts (19%, P = .03) but not statistically different from vaccine recipients (22.6%, P > .05), where the range was 1-3, median 1, and mean 1.3 (P > .05 for all comparisons).An atypical sieve effect was detected in Env V2 but was not associated with reduction or enhancement of virus acquisition.This finding suggests that a successful vaccine or other prevention modality generally needs to protect against only one or a few viruses regardless of risk behavior.

View Article: PubMed Central - PubMed

Affiliation: University of Alabama at Birmingham , Birmingham.

ABSTRACT

Background: We performed human immunodeficiency virus type 1 (HIV-1) transmitted/founder (T/F) virus analysis of the VAX003 vaccine efficacy trial participants to characterize the transmission bottleneck and test for vaccine-associated reduction or enhancement of infection in this injection drug user (IDU) cohort.

Methods: We performed single genome sequencing of plasma vRNA from 50 subjects sampled in early HIV infection. Sequences were analyzed phylogenetically, T/F viruses enumerated, and a sieve analysis performed.

Results: Eight of 19 (42%) placebo recipients were productively infected by more than 1 virus (range 1-5, median 1, mean 1.7). This frequency of multiple virus transmission was greater than reported for heterosexual cohorts (19%, P = .03) but not statistically different from vaccine recipients (22.6%, P > .05), where the range was 1-3, median 1, and mean 1.3 (P > .05 for all comparisons). An atypical sieve effect was detected in Env V2 but was not associated with reduction or enhancement of virus acquisition.

Conclusions: The number of T/F viruses in IDUs was surprising low, with 95% of individuals infected by only 1-3 viruses. This finding suggests that a successful vaccine or other prevention modality generally needs to protect against only one or a few viruses regardless of risk behavior. T/F analysis identified an atypical genetic sieve in the V2 region of Envelope and found no evidence for vaccine-mediated enhancement in VAX003.

No MeSH data available.


Related in: MedlinePlus

ML tree of HIV-1 gp41 env sequences from the 50 VAX003 subjects. Each subject's sequence set is shown in a different color and labeled with the subject identifier. Reference sequences are shown in gray. Forty-six subjects were infected by CRF01_AE viruses; CRF15_01B and subtype B clades are specifically indicated. Individual subject sequence sets with bootstrap values >95% are annotated with an asterisk. There are 8 individual subject sequence lineages with bootstrap values >75%: the 2 acute-to-acute transmissions (subjects 3212 and 3017 and subjects 3184 and 3090), 3 subjects with related but distinct lineages (subjects 3189, 3111 and 3112), and subject 3156. Subject 3156 (shown in mustard orange and annotated with a hashtag at the top and bottom of tree) has sequences clustering with CRF01_AE and subtype B. The single long branch in subject 3156's viral sequences at the top of the figure is a unique interlineage recombinant shown in greater detail in Supplementary material, Figure S1. Genetic distance is indicated by the scale bar. Abbreviations: HIV-1, human immunodeficiency virus type 1; ML, maximum-likelihood.
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OFU056F1: ML tree of HIV-1 gp41 env sequences from the 50 VAX003 subjects. Each subject's sequence set is shown in a different color and labeled with the subject identifier. Reference sequences are shown in gray. Forty-six subjects were infected by CRF01_AE viruses; CRF15_01B and subtype B clades are specifically indicated. Individual subject sequence sets with bootstrap values >95% are annotated with an asterisk. There are 8 individual subject sequence lineages with bootstrap values >75%: the 2 acute-to-acute transmissions (subjects 3212 and 3017 and subjects 3184 and 3090), 3 subjects with related but distinct lineages (subjects 3189, 3111 and 3112), and subject 3156. Subject 3156 (shown in mustard orange and annotated with a hashtag at the top and bottom of tree) has sequences clustering with CRF01_AE and subtype B. The single long branch in subject 3156's viral sequences at the top of the figure is a unique interlineage recombinant shown in greater detail in Supplementary material, Figure S1. Genetic distance is indicated by the scale bar. Abbreviations: HIV-1, human immunodeficiency virus type 1; ML, maximum-likelihood.

Mentions: A total of 1473 env gp160 or gp41 sequences generated by SGS were obtained with a median of 26 per subject timepoint. Gp160 sequences were generated for 42 subjects. In 8 subjects (3/19 [16%] placebo and 5/31 [19%] vaccine arm), viral loads were lower or the plasma sample was of poorer quality such that we chose to amplify gp41 to increase sequencing efficiency. The gp41 env sequences from all 50 subjects were analyzed together in a ML phylogeny along with relevant reference sequences (Fig. 1). Sequences from 43 subjects (86%) clustered unambiguously with Thai CRF01_AE reference viruses, 5 subjects clustered with Thai Subtype B viruses, 1 subject (Subject 3156) clustered with both Subtype B and CRF01_AE viruses, and 1 subject (Subject 3147) clustered with CRF15_01B viruses (Fig. 1). The use of SGS enabled detection of minority variants, including individuals infected with multiple subtypes (subject 3156; see Fig. 1 and Supplementary material, Fig. S1). In 7 subjects, there was phylogenetic evidence of epidemiologically closely related infections, including 2 likely “acute-to-acute” transmissions (subjects 3017 and 3212 and subjects 3017 and 3213; Fig. 1, Supplementary material, Figs S2 and S3).Fig. 1.


Low Multiplicity of HIV-1 Infection and No Vaccine Enhancement in VAX003 Injection Drug Users.

Sterrett S, Learn GH, Edlefsen PT, Haynes BF, Hahn BH, Shaw GM, Bar KJ - Open Forum Infect Dis (2014)

ML tree of HIV-1 gp41 env sequences from the 50 VAX003 subjects. Each subject's sequence set is shown in a different color and labeled with the subject identifier. Reference sequences are shown in gray. Forty-six subjects were infected by CRF01_AE viruses; CRF15_01B and subtype B clades are specifically indicated. Individual subject sequence sets with bootstrap values >95% are annotated with an asterisk. There are 8 individual subject sequence lineages with bootstrap values >75%: the 2 acute-to-acute transmissions (subjects 3212 and 3017 and subjects 3184 and 3090), 3 subjects with related but distinct lineages (subjects 3189, 3111 and 3112), and subject 3156. Subject 3156 (shown in mustard orange and annotated with a hashtag at the top and bottom of tree) has sequences clustering with CRF01_AE and subtype B. The single long branch in subject 3156's viral sequences at the top of the figure is a unique interlineage recombinant shown in greater detail in Supplementary material, Figure S1. Genetic distance is indicated by the scale bar. Abbreviations: HIV-1, human immunodeficiency virus type 1; ML, maximum-likelihood.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4281816&req=5

OFU056F1: ML tree of HIV-1 gp41 env sequences from the 50 VAX003 subjects. Each subject's sequence set is shown in a different color and labeled with the subject identifier. Reference sequences are shown in gray. Forty-six subjects were infected by CRF01_AE viruses; CRF15_01B and subtype B clades are specifically indicated. Individual subject sequence sets with bootstrap values >95% are annotated with an asterisk. There are 8 individual subject sequence lineages with bootstrap values >75%: the 2 acute-to-acute transmissions (subjects 3212 and 3017 and subjects 3184 and 3090), 3 subjects with related but distinct lineages (subjects 3189, 3111 and 3112), and subject 3156. Subject 3156 (shown in mustard orange and annotated with a hashtag at the top and bottom of tree) has sequences clustering with CRF01_AE and subtype B. The single long branch in subject 3156's viral sequences at the top of the figure is a unique interlineage recombinant shown in greater detail in Supplementary material, Figure S1. Genetic distance is indicated by the scale bar. Abbreviations: HIV-1, human immunodeficiency virus type 1; ML, maximum-likelihood.
Mentions: A total of 1473 env gp160 or gp41 sequences generated by SGS were obtained with a median of 26 per subject timepoint. Gp160 sequences were generated for 42 subjects. In 8 subjects (3/19 [16%] placebo and 5/31 [19%] vaccine arm), viral loads were lower or the plasma sample was of poorer quality such that we chose to amplify gp41 to increase sequencing efficiency. The gp41 env sequences from all 50 subjects were analyzed together in a ML phylogeny along with relevant reference sequences (Fig. 1). Sequences from 43 subjects (86%) clustered unambiguously with Thai CRF01_AE reference viruses, 5 subjects clustered with Thai Subtype B viruses, 1 subject (Subject 3156) clustered with both Subtype B and CRF01_AE viruses, and 1 subject (Subject 3147) clustered with CRF15_01B viruses (Fig. 1). The use of SGS enabled detection of minority variants, including individuals infected with multiple subtypes (subject 3156; see Fig. 1 and Supplementary material, Fig. S1). In 7 subjects, there was phylogenetic evidence of epidemiologically closely related infections, including 2 likely “acute-to-acute” transmissions (subjects 3017 and 3212 and subjects 3017 and 3213; Fig. 1, Supplementary material, Figs S2 and S3).Fig. 1.

Bottom Line: This frequency of multiple virus transmission was greater than reported for heterosexual cohorts (19%, P = .03) but not statistically different from vaccine recipients (22.6%, P > .05), where the range was 1-3, median 1, and mean 1.3 (P > .05 for all comparisons).An atypical sieve effect was detected in Env V2 but was not associated with reduction or enhancement of virus acquisition.This finding suggests that a successful vaccine or other prevention modality generally needs to protect against only one or a few viruses regardless of risk behavior.

View Article: PubMed Central - PubMed

Affiliation: University of Alabama at Birmingham , Birmingham.

ABSTRACT

Background: We performed human immunodeficiency virus type 1 (HIV-1) transmitted/founder (T/F) virus analysis of the VAX003 vaccine efficacy trial participants to characterize the transmission bottleneck and test for vaccine-associated reduction or enhancement of infection in this injection drug user (IDU) cohort.

Methods: We performed single genome sequencing of plasma vRNA from 50 subjects sampled in early HIV infection. Sequences were analyzed phylogenetically, T/F viruses enumerated, and a sieve analysis performed.

Results: Eight of 19 (42%) placebo recipients were productively infected by more than 1 virus (range 1-5, median 1, mean 1.7). This frequency of multiple virus transmission was greater than reported for heterosexual cohorts (19%, P = .03) but not statistically different from vaccine recipients (22.6%, P > .05), where the range was 1-3, median 1, and mean 1.3 (P > .05 for all comparisons). An atypical sieve effect was detected in Env V2 but was not associated with reduction or enhancement of virus acquisition.

Conclusions: The number of T/F viruses in IDUs was surprising low, with 95% of individuals infected by only 1-3 viruses. This finding suggests that a successful vaccine or other prevention modality generally needs to protect against only one or a few viruses regardless of risk behavior. T/F analysis identified an atypical genetic sieve in the V2 region of Envelope and found no evidence for vaccine-mediated enhancement in VAX003.

No MeSH data available.


Related in: MedlinePlus