Insights to HIV-1 coreceptor usage by estimating HLA adaptation with Bayesian generalized linear mixed models.

The mechanisms triggering the human immunodeficiency virus type I (HIV-1) to switch the coreceptor usage from CCR5 to CXCR4 during the course of infection are not entirely understood. While low CD4+ T cell counts are associated with CXCR4 usage, a predominance of CXCR4 usage with still high CD4+ T cell counts remains puzzling. Here, we explore the hypothesis that viral adaptation to the human leukocyte antigen (HLA) complex, especially to the HLA class II alleles, contributes to the coreceptor switch. To this end, we sequence the viral gag and env protein with corresponding HLA class I and II alleles of a new cohort of 312 treatment-naive, subtype C, chronically-infected HIV-1 patients from South Africa. To estimate HLA adaptation, we develop a novel computational approach using Bayesian generalized linear mixed models (GLMMs). Our model allows to consider the entire HLA repertoire without restricting the model to pre-learned HLA-polymorphisms. In addition, we correct for phylogenetic relatedness of the viruses within the model itself to account for founder effects. Using our model, we observe that CXCR4-using variants are more adapted than CCR5-using variants (p-value = 1.34e-2). Additionally, adapted CCR5-using variants have a significantly lower predicted false positive rate (FPR) by the geno2pheno[coreceptor] tool compared to the non-adapted CCR5-using variants (p-value = 2.21e-2), where a low FPR is associated with CXCR4 usage. Consequently, estimating HLA adaptation can be an asset in predicting not only coreceptor usage, but also an approaching coreceptor switch in CCR5-using variants. We propose the usage of Bayesian GLMMs for modeling virus-host adaptation in general.

Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time.

Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient's viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.

Dynamics and durability of HIV-1 neutralization are determined by viral replication.

Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4+ T cell counts <200 µl-1, being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.