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Transmitted Escape Mutations Lead to Accelerated HIV-1 Disease Progression and Largely Define the Relative Contribution of HLA Alleles to Control
Abstract   Peer reviewed

Transmitted Escape Mutations Lead to Accelerated HIV-1 Disease Progression and Largely Define the Relative Contribution of HLA Alleles to Control

Jonathan M. Carlson, Malinda Schaefer, Chanson Brumme, Nico Pfeifer, Roger Shapiro, Thumbi Ndung'u, John Frater, Simon Mallal, Mina John, David Heckerman, …
AIDS research and human retroviruses, Vol.30(S1), pp.A40-A40
10/2014
DOI: 10.1089/aid.2014.5065a.abstract

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Abstract

Background: The extent of intra- and inter-host adaptation of HIV to HLA-mediated immune responses remains a central challenge for vaccine design, as the presence of escape mutations in circulating HIV sequences may compromise vaccine-induced immunity and reduce the protective effects of certain HLA alleles. One strategy is to vaccinate against escaped epitopes, though it is unclear whether such epitopes can elicit effective immune responses. Methods: We developed a probabilistic model of HIV sequence evolution, trained on >4,000 clade B and C sequences with matched HLA types, that yields a natural metric of the extent of HLA-specific adaptation of each sequence. HIV adaptation to HLA was strongly associated with VL and CD4 counts in cross-sectional and longitudinal early infection cohorts, validating our models and confirming the role autologous adaptation plays in disease progression. Results: Within transmission pairs, the extent to which the donors' Gag, Pol and Nef sequences were “pre-adapted” to the linked recipients' HLA alleles predicted recipient VL 24 mo post infection (Spearman r = 0.39, p = 0.0005, N = 81) and time to CD4< 250 (HR = 5.97, p = 0.03, N = 48). In cross-sectional chronic cohorts, individuals for whom the regional circulating viral sequences were well adapted had higher viral loads. Furthermore, the extent to which circulating HIV strains were adapted to individual HLA alleles predicted the VL associated with those alleles (Spearman r = 0.77, p = 0.009). Conclusions: Transmission of HIV pre-adapted to host HLA leads to accelerated disease progression and largely explains the extent to which an HLA is relatively protective or hazardous. This observation argues that the immune system is unable to mount effective responses against these adapted epitopes, even when they represent the initial challenge variant, and suggests that vaccination strategies that target such adapted epitopes must achieve a level of response that is not observed in natural infection.

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