Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence

Payne, Rebecca; Muenchhoff, Maximilian; Mann, Jaclyn K.; Roberts, Hannah; Matthews, Philippa C.; Adland, Emily; Hempenstall, Allison; Huang, Kuan-Hsiang Gary; Brockman, Mark A.; Brumme, Zabrina L.; Sinclair, Marc; Miura, Toshiyuki; Frater, John; Essex, M.; Shapiro, Roger; Walker, Bruce D.; Ndung’u, Thumbi; McLean, Angela R.; Carlson, Jonathan M.; Goulder, Philip

doi:10.1073/pnas.1413339111

Cited by 83 publications

(133 citation statements)

References 49 publications

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“…A recent study of HIV-1 Gag and Nef evolution in North America by our group also indicated that HLA-associated polymorphisms have spread in circulation over time (33). However, the extent to which this is occurring in North America appears more modest than in high-seroprevalence settings, such as Botswana and South Africa (32), or in populations with relatively limited HLA diversity, such as Japan (22,34).…”

Section: H Uman Leukocyte Antigen (Hla) Class I-restricted Cd8supporting

confidence: 52%

“…Rather, our observation that HIV-1 polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, an observation that corroborates our previous analyses of HLA-associated polymorphism spread in Gag and Nef (33), is consistent with the idea that protective alleles mount strong selection pressures on HIV-1 (8) and also select escape mutations relatively early following infection in many cases, thus possibly enhancing their probability of transmission. These findings also lend credence to the idea that population-level HIV-1 adaptation to HLA may eventually diminish or eliminate the protective capacity of certain HLA alleles over time (22); indeed, recent data suggest that this phenomenon is already discernible in Botswana, a high-seroprevalence setting with a long epidemic history, where alleles such as HLA-B*57 and B*58:01 have lost their protective status (32). In contrast, in neighboring South Africa, where the epidemic is younger, the protective effects of these alleles remain intact (32).…”

Section: Discussionmentioning

confidence: 52%

“…These findings also lend credence to the idea that population-level HIV-1 adaptation to HLA may eventually diminish or eliminate the protective capacity of certain HLA alleles over time (22); indeed, recent data suggest that this phenomenon is already discernible in Botswana, a high-seroprevalence setting with a long epidemic history, where alleles such as HLA-B*57 and B*58:01 have lost their protective status (32). In contrast, in neighboring South Africa, where the epidemic is younger, the protective effects of these alleles remain intact (32). Nevertheless, even if some polymorphisms spread in circulation and such variants are acquired at transmission, it is possible that some CTL response against the incoming virus may be preserved, especially for protective HLA alleles.…”

Section: Discussionmentioning

confidence: 52%

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Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

Kinloch

MacMillan

et al. 2016

J Virol

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HumanHIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ϳ2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era. IMPORTANCEHLA class I-restricted cytotoxic T-lymphocyte (CTL) escape mutations in HIV-1 that persist upon transmission may accumulate in circulation over time, potentially undermining host antiviral immunity to the transmitted viral strain. We studied >600 experimentally collected HIV-1 polymerase sequences linked to host HLA information dating back to 1979, along with phylogenetically reconstructed HIV-1 sequences dating back to the virus' introduction into North America. Overall, our results support the gradual spread of many-though not all-HIV-1 polymerase immune escape mutations in circulation over time. This is consistent with recent observations from other global regions, though the extent of polymorphism accumulation in North America appears to be lower than in populations with high seroprevalence, older epidemics, and/or limited HLA diversity. Importantly, the risk of acquiring an HIV-1 polymerase sequence at transmission that is substantially preadapted to one's HLA profile remains relatively low in North America, even in the present era.

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Section: H Uman Leukocyte Antigen (Hla) Class I-restricted Cd8supporting

confidence: 52%

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 52%

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Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

Kinloch

MacMillan

et al. 2016

J Virol

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“…Taking into account that the 20 Gag CD8+ T-cell escape mutants are only those that represent the strongest HLA footprints on the virus, and therefore meet the statistical criteria (usually q<0.05 or q<0.2) [11,15,45] to be included, the likelihood is that the selection of Gag escape mutants by CD8+ T-cell responses has a substantially greater impact on VRC even than these data would indicate. Furthermore, the correlations between VRC and number of Gag escape mutants would diminish and ultimately disappear if in the majority of cases compensatory mutants were successfully selected by the virus to nullify any adverse impact on VRC.…”

Section: Discussionmentioning

confidence: 99%

Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

et al. 2015

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HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

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“…However, the latter might also be influenced by demographic differences between the two cohorts. Although certain Gag polymorphisms are known to carry substantial fitness costs, the effect of the transmitted Gag on disease progression ultimately depends on the degree of preadaptation to the recipient's HLA molecules (44)(45)(46). Hence, factors such as the cohort's HLA profile and the age of the epidemic can influence this correlation.…”

Section: Figmentioning

confidence: 99%

Replication Capacity of Viruses from Acute Infection Drives HIV-1 Disease Progression

Selhorst

Combrinck

Ndabambi

et al. 2017

J Virol

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The viral genotype has been shown to play an important role in HIV pathogenesis following transmission. However, the viral phenotypic properties that contribute to disease progression remain unclear. Most studies have been limited to the evaluation of Gag function in the context of a recombinant virus backbone. Using this approach, important biological information may be lost, making the evaluation of viruses obtained during acute infection, representing the transmitted virus, a more biologically relevant model. Here, we evaluate the roles of viral infectivity and the replication capacity of viruses from acute infection in disease progression in women who seroconverted in the CAPRISA 004 tenofovir microbicide trial. We show that viral replication capacity, but not viral infectivity, correlates with the set point viral load (Spearman r ϭ 0.346; P ϭ 0.045) and that replication capacity (hazard ratio [HR] ϭ 4.52; P ϭ 0.01) can predict CD4 decline independently of the viral load (HR ϭ 2.9; P ϭ 0.004) or protective HLA alleles (HR ϭ 0.61; P ϭ 0.36). We further demonstrate that Gag-Pro is not the main driver of this association, suggesting that additional properties of the transmitted virus play a role in disease progression. Finally, we find that although viruses from the tenofovir arm were 2-fold less infectious, they replicated at rates similar to those of viruses from the placebo arm. This indicates that the use of tenofovir gel did not select for viral variants with higher replication capacity. Overall, this study supports a strong influence of the replication capacity in acute infection on disease progression, potentially driven by interaction of multiple genes rather than a dominant role of the major structural gene gag.IMPORTANCE HIV disease progression is known to differ between individuals, and defining which fraction of this variation can be attributed to the virus is important both clinically and epidemiologically. In this study, we show that the replication capacity of viruses isolated during acute infection predicts subsequent disease progression and drives CD4 decline independently of the viral load. This provides further support for the hypothesis that the replication capacity of the transmitted virus determines the initial damage to the immune system, setting the pace for later disease progression. However, we did not find evidence that the major structural gene gag drives this correlation, highlighting the importance of other genes in determining disease progression.

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Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence

Cited by 83 publications

References 49 publications

Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

Replication Capacity of Viruses from Acute Infection Drives HIV-1 Disease Progression

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