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Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.

Tully DC, Ogilvie CB, Batorsky RE, Bean DJ, Power KA, Ghebremichael M, Bedard HE, Gladden AD, Seese AM, Amero MA, Lane K, McGrath G, Bazner SB, Tinsley J, Lennon NJ, Henn MR, Brumme ZL, Norris PJ, Rosenberg ES, Mayer KH, Jessen H, Kosakovsky Pond SL, Walker BD, Altfeld M, Carlson JM, Allen TM - PLoS Pathog. (2016)

Bottom Line: However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants.While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition.This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

View Article: PubMed Central - PubMed

Affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.

ABSTRACT
Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

No MeSH data available.


Related in: MedlinePlus

Mapping of signature sites on the three-dimensional structure of gp120 shows clustering around the CD4-binding site.A ribbon representation of the crystal structure from the JRFL gp120 molecule (grey) bound to CD4 molecule (green) (PDBID: 2B4C). The CD4 binding site is highlighted in transparent green while signature sites 283, 343, 362, 389, 429, 465 and 471 are all depicted as red space-filling residues.
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ppat.1005619.g006: Mapping of signature sites on the three-dimensional structure of gp120 shows clustering around the CD4-binding site.A ribbon representation of the crystal structure from the JRFL gp120 molecule (grey) bound to CD4 molecule (green) (PDBID: 2B4C). The CD4 binding site is highlighted in transparent green while signature sites 283, 343, 362, 389, 429, 465 and 471 are all depicted as red space-filling residues.

Mentions: In contrast, nearly half of the residues associated with MSM risk were located in gp120 with six residues (T283, N362, Q389, E429, T465, G471) clustered around the CD4-binding pocket with the potential to influence CD4 binding (Fig 6). In addition to residue Q389 described earlier, which is located in close proximity to the CD4-binding loop [57], position T283 has been shown to affect CD4 binding site exposure and CD4 binding of gp120s derived from brain and other tissues [60]. Similarly, presence of the N362 PNLG site in the C3 region has been shown to enhance CD4 binding to gp120 as well as cell-cell fusion [68, 98], potentially reducing CD4 dependence by stabilizing the CD4-bound confirmation of gp120 [68]. Meanwhile, at residue E429 located in the C4 domain of gp120 we observed selection for glutamine (E429Q) where prior work has identified this residue as being critically important for the binding of CD4-blocking MAbs [65] and implicated in altering resistance to the entry inhibitors BMS-806 and #155 [63], as well as enhancing HIV-1 replication in vitro [59]. Within the V5 loop, residue T465 has also been associated with a neutralization-resistant phenotype [99], while finally at residue G471 where we observed selection for an alanine (G471A) the variants G471R/E have been shown to impart resistance towards CD4 mimetic compounds [61]. Thus, many of the signature sites identified in MSM in gp120 may influence gp120-CD4 interactions for enhanced interactions with CD4.


Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.

Tully DC, Ogilvie CB, Batorsky RE, Bean DJ, Power KA, Ghebremichael M, Bedard HE, Gladden AD, Seese AM, Amero MA, Lane K, McGrath G, Bazner SB, Tinsley J, Lennon NJ, Henn MR, Brumme ZL, Norris PJ, Rosenberg ES, Mayer KH, Jessen H, Kosakovsky Pond SL, Walker BD, Altfeld M, Carlson JM, Allen TM - PLoS Pathog. (2016)

Mapping of signature sites on the three-dimensional structure of gp120 shows clustering around the CD4-binding site.A ribbon representation of the crystal structure from the JRFL gp120 molecule (grey) bound to CD4 molecule (green) (PDBID: 2B4C). The CD4 binding site is highlighted in transparent green while signature sites 283, 343, 362, 389, 429, 465 and 471 are all depicted as red space-filling residues.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862634&req=5

ppat.1005619.g006: Mapping of signature sites on the three-dimensional structure of gp120 shows clustering around the CD4-binding site.A ribbon representation of the crystal structure from the JRFL gp120 molecule (grey) bound to CD4 molecule (green) (PDBID: 2B4C). The CD4 binding site is highlighted in transparent green while signature sites 283, 343, 362, 389, 429, 465 and 471 are all depicted as red space-filling residues.
Mentions: In contrast, nearly half of the residues associated with MSM risk were located in gp120 with six residues (T283, N362, Q389, E429, T465, G471) clustered around the CD4-binding pocket with the potential to influence CD4 binding (Fig 6). In addition to residue Q389 described earlier, which is located in close proximity to the CD4-binding loop [57], position T283 has been shown to affect CD4 binding site exposure and CD4 binding of gp120s derived from brain and other tissues [60]. Similarly, presence of the N362 PNLG site in the C3 region has been shown to enhance CD4 binding to gp120 as well as cell-cell fusion [68, 98], potentially reducing CD4 dependence by stabilizing the CD4-bound confirmation of gp120 [68]. Meanwhile, at residue E429 located in the C4 domain of gp120 we observed selection for glutamine (E429Q) where prior work has identified this residue as being critically important for the binding of CD4-blocking MAbs [65] and implicated in altering resistance to the entry inhibitors BMS-806 and #155 [63], as well as enhancing HIV-1 replication in vitro [59]. Within the V5 loop, residue T465 has also been associated with a neutralization-resistant phenotype [99], while finally at residue G471 where we observed selection for an alanine (G471A) the variants G471R/E have been shown to impart resistance towards CD4 mimetic compounds [61]. Thus, many of the signature sites identified in MSM in gp120 may influence gp120-CD4 interactions for enhanced interactions with CD4.

Bottom Line: However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants.While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition.This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

View Article: PubMed Central - PubMed

Affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.

ABSTRACT
Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

No MeSH data available.


Related in: MedlinePlus