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High frequency of transmitted HIV-1 Gag HLA class I-driven immune escape variants but minimal immune selection over the first year of clade C infection.

Gounder K, Padayachi N, Mann JK, Radebe M, Mokgoro M, van der Stok M, Mkhize L, Mncube Z, Jaggernath M, Reddy T, Walker BD, Ndung'u T - PLoS ONE (2015)

Bottom Line: Six of 22 (27%) individuals were infected with multiple variants.These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome.These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.

View Article: PubMed Central - PubMed

Affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa.

ABSTRACT
In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.

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Multiple variant transmission and intrapatient diversity results in higher viral load set point.(A) Association of single versus multivariant transmission sequences versus viral load set point in individuals sequenced at the earliest time point (Student’s T test). (B) Significantly higher intrapatient diversity in individuals infected with multiple variants (Student’s T test). (C) Significantly higher intrapatient diversity within gag over one year of infection (Paired T test). (D) Intrapatient diversity of HIV-1 Gag at 14 days post infection correlation with viral load set point. Significant correlations of intrapatient diversity at 1 year versus viral load set point (E) and viral load at one year (F). (*) denotes statistical significant difference.
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pone.0119886.g002: Multiple variant transmission and intrapatient diversity results in higher viral load set point.(A) Association of single versus multivariant transmission sequences versus viral load set point in individuals sequenced at the earliest time point (Student’s T test). (B) Significantly higher intrapatient diversity in individuals infected with multiple variants (Student’s T test). (C) Significantly higher intrapatient diversity within gag over one year of infection (Paired T test). (D) Intrapatient diversity of HIV-1 Gag at 14 days post infection correlation with viral load set point. Significant correlations of intrapatient diversity at 1 year versus viral load set point (E) and viral load at one year (F). (*) denotes statistical significant difference.

Mentions: We next determined if infection with multiple founder viruses is predictive of disease progression, as defined by CD4 count and viral load, in the context of heterosexual transmission in men and women in an HIV-1 subtype C setting. When comparing single versus multiple variant transmissions there was a trend towards higher mean viral load set point for individuals infected with multiple variants (Mann Whitney test, p = 0.06) (Fig. 2A) but no difference in the rate of CD4 decline (Mann Whitney test, p = 0.13) over the first year of infection (data not shown).


High frequency of transmitted HIV-1 Gag HLA class I-driven immune escape variants but minimal immune selection over the first year of clade C infection.

Gounder K, Padayachi N, Mann JK, Radebe M, Mokgoro M, van der Stok M, Mkhize L, Mncube Z, Jaggernath M, Reddy T, Walker BD, Ndung'u T - PLoS ONE (2015)

Multiple variant transmission and intrapatient diversity results in higher viral load set point.(A) Association of single versus multivariant transmission sequences versus viral load set point in individuals sequenced at the earliest time point (Student’s T test). (B) Significantly higher intrapatient diversity in individuals infected with multiple variants (Student’s T test). (C) Significantly higher intrapatient diversity within gag over one year of infection (Paired T test). (D) Intrapatient diversity of HIV-1 Gag at 14 days post infection correlation with viral load set point. Significant correlations of intrapatient diversity at 1 year versus viral load set point (E) and viral load at one year (F). (*) denotes statistical significant difference.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4363590&req=5

pone.0119886.g002: Multiple variant transmission and intrapatient diversity results in higher viral load set point.(A) Association of single versus multivariant transmission sequences versus viral load set point in individuals sequenced at the earliest time point (Student’s T test). (B) Significantly higher intrapatient diversity in individuals infected with multiple variants (Student’s T test). (C) Significantly higher intrapatient diversity within gag over one year of infection (Paired T test). (D) Intrapatient diversity of HIV-1 Gag at 14 days post infection correlation with viral load set point. Significant correlations of intrapatient diversity at 1 year versus viral load set point (E) and viral load at one year (F). (*) denotes statistical significant difference.
Mentions: We next determined if infection with multiple founder viruses is predictive of disease progression, as defined by CD4 count and viral load, in the context of heterosexual transmission in men and women in an HIV-1 subtype C setting. When comparing single versus multiple variant transmissions there was a trend towards higher mean viral load set point for individuals infected with multiple variants (Mann Whitney test, p = 0.06) (Fig. 2A) but no difference in the rate of CD4 decline (Mann Whitney test, p = 0.13) over the first year of infection (data not shown).

Bottom Line: Six of 22 (27%) individuals were infected with multiple variants.These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome.These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.

View Article: PubMed Central - PubMed

Affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa.

ABSTRACT
In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.

Show MeSH
Related in: MedlinePlus